Prostate cancer

Page editor		Section editor
	Laura S. Graham, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, WA LauraGrahamMD		Ali Raza Khaki, MD University of Washington Seattle, WA arkhaki

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80 regimens on this page 111 variants on this page

Guidelines

ASCO

• 2018: Morris et al. Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline
• 2017: Virgo et al. Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion PubMed
• 2016: Active Surveillance for the Management of Localized Prostate Cancer Endorsement
• 2015: Prostate Cancer Survivorship Care Guideline Endorsement

Older

• 2014: Adjuvant and Salvage Radiotherapy After Prostatectomy Endorsement
• 2012: Screening for Prostate Cancer with Prostate-Specific Antigen (PSA) Testing PCO
• 2009: Use of 5-alpha Reductase Inhibitors for Prostate Cancer Chemoprevention
• 2007: Non-Hormonal Therapy for Men With Metastatic Hormone-Refractory (castration-resistant) Prostate Cancer Endorsement

ASCO & CCO

• 2014: Basch et al. Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline

AUA

• Castration-Resistant Prostate Cancer: AUA Guideline @ AUAnet
  • PDF (2015) @ AUAnet
• Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2015 PubMed

EAU/ESTRO/SIOG

• 2017: EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer PubMed

ESMO

• 2015: Parker et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2013: Horwich et al. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
• 2012: Horwich et al. ESMO Consensus Conference Guidelines PubMed

NCCN

• NCCN Guidelines - Prostate Cancer

St Gallen

• 2015: Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC)

Induction ADT

ADT

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ADT: Androgen Deprivation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Roach et al. 2003 (RTOG 94-13)	1995-1999	Phase III (E-switch-ic)	ADT; adjuvant	Did not meet primary endpoint of PFS
Pisansky et al. 2014 (RTOG 9910)	2000-2004	Phase III (C)	ADT x 28 weeks	Did not meet primary endpoint of disease-specific mortality

Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.

Hormonotherapy

• LHRH agonist
• Bicalutamide (Casodex) or Flutamide (Eulexin)

8-week course

Subsequent treatment

• ADT & RT

References

1. RTOG 94-13: Roach M 3rd, DeSilvio M, Lawton C, Uhl V, Machtay M, Seider MJ, Rotman M, Jones C, Asbell SO, Valicenti RK, Han S, Thomas CR Jr, Shipley WS; Radiation Therapy Oncology Group. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003 May 15;21(10):1904-11. link to original article PubMed
   1. Update: Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch R, Seider M, Rotman M, Jones C, Asbell S, Valicenti R, Hahn S, Thomas CR Jr. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55. Epub 2007 May 24. link to original article link to PMC article PubMed
2. RTOG 9910: Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. link to original article link to PMC article PubMed NCT00005044

Flutamide & Goserelin

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Crook et al. 2004	1995-2001	Phase III (C)	Flutamide & Goserelin x 8 mo	Did not meet primary endpoint of PSA-PFS

Hormonotherapy

• Flutamide (Eulexin)
• Goserelin (Zoladex)

3-month course

Subsequent treatment

• RT

References

1. Crook J, Ludgate C, Malone S, Lim J, Perry G, Eapen L, Bowen J, Robertson S, Lockwood G. Report of a multicenter Canadian phase III randomized trial of 3 months vs 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):15-23. link to original article PubMed

Leuprolide monotherapy

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Regimen

Study	Evidence
Denham et al. 2014 (RADAR)	Non-randomized portion of RCT (*)

Note: this trial had 4 arms including a randomization to zoledronic acid; see paper for details.

Hormonotherapy

• Leuprolide (Lupron) 3-month depot 22.5 mg IM once on day 1

3-month cycle for 2 cycles

Subsequent treatment

• RT, then Leuprolide x 12 mo versus Observation

References

1. RADAR: Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial. Lancet Oncol. 2014 Sep;15(10):1076-89. Epub 2014 Aug 14. link to original article PubMed
   1. Update: Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019 Feb;20(2):267-281. Epub 2018 Dec 19. link to original article PubMed

Definitive therapy, including active surveillance

Active surveillance

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Holmberg et al. 2002 (SPCG-4)	1989-1999	Phase III (C)	Radical prostatectomy	Inferior OS (*)
Wilt et al. 2012 (PIVOT)	1994-2002	Phase III (C)	Radical prostatectomy	Did not meet primary endpoint of OS
Fleshner et al. 2012 (REDEEM)	2006-2007	Phase III (C)	Dutasteride	Inferior TTP
Azzouzi et al. 2016 (CLIN1001 PCM301)	2011-2013	Phase III (C)	Padeliporfin	Inferior TTP

No antineoplastic therapy; consists of various strategies of close monitoring and re-biopsy. Efficacy for SPCG-4 is based on the 2014 update.

References

1. SPCG-4: Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Häggman M, Andersson SO, Spångberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlén BJ; Scandinavian Prostatic Cancer Group. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002 Sep 12;347(11):781-9. link to original article PubMed
   1. Update: Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005 May 12;352(19):1977-84. link to original article PubMed
   2. Update: Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst. 2008 Aug 20;100(16):1144-54. Epub 2008 Aug 11. link to original article link to PMC article PubMed
   3. Update: Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Steineck G, Adami HO, Johansson JE; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011 May 5;364(18):1708-17. link to original article PubMed
   4. Update: Bill-Axelson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Spångberg A, Andrén O, Palmgren J, Steineck G, Adami HO, Johansson JE. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014 Mar 6;370(10):932-42. link to original article link to PMC article PubMed
   5. Update: Bill-Axelson A, Holmberg L, Garmo H, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Andrén O, Steineck G, Adami HO, Johansson JE. Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up. N Engl J Med. 2018 Dec 13;379(24):2319-2329. link to original article PubMed
2. REDEEM: Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, Black L, Rittmaster RS. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet. 2012 Mar 24;379(9821):1103-11. Epub 2012 Jan 24. link to original article PubMed NCT00363311
3. PIVOT: Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, Gingrich JR, Wei JT, Gilhooly P, Grob BM, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Sharifi R, Blank W, Pandya P, Andriole GL, Culkin D, Wheeler T; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012 Jul 19;367(3):203-13. Erratum in: N Engl J Med. 2012 Aug 9;367(6):582. link to original article link to PMC article PubMed NCT00007644
   1. Update: Wilt TJ, Jones KM, Barry MJ, Andriole GL, Culkin D, Wheeler T, Aronson WJ, Brawer MK. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med. 2017 Jul 13;377(2):132-142. link to original article PubMed
4. CLIN1001 PCM301: Azzouzi AR, Vincendeau S, Barret E, Cicco A, Kleinclauss F, van der Poel HG, Stief CG, Rassweiler J, Salomon G, Solsona E, Alcaraz A, Tammela TT, Rosario DJ, Gomez-Veiga F, Ahlgren G, Benzaghou F, Gaillac B, Amzal B, Debruyne FM, Fromont G, Gratzke C, Emberton M; PCM301 Study Group. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017 Feb;18(2):181-191. Epub 2016 Dec 20. link to original article PubMed NCT01310894

ADT

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ADT: Androgen Deprivation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Warde et al. 2011 (NCIC CTG PR.3/UK MRC PR07)	1995-2005	Phase III (C)	ADT & RT	Seems to have inferior OS

Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.

Hormonotherapy

• ADT with ONE of the following:
  • LHRH agonist/analogue
  • LHRH antagonist
  • Bilateral orchiectomy

References

1. NCIC CTG PR.3/UK MRC PR07: Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC CTG; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. link to original article link to PMC article PubMed NCT00002633

ADT & RT

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ADT & RT: Androgen Deprivation Therapy & Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
d'Amico et al. 2004	1995-2001	Phase III (E-esc)	RT	Seems to have superior OS
Warde et al. 2011 (NCIC CTG PR.3/UK MRC PR07)	1995-2005	Phase III (E-esc)	ADT	Seems to have superior OS
Bolla et al. 2009 (EORTC 22961)	1997-2001	Non-randomized portion of RCT
Mottet et al. 2012	2000-2003	Phase III (E-esc)	ADT	Superior PFS
Rosenthal et al. 2008 (RTOG 9902)	2000-2004	Non-randomized portion of RCT
Pisansky et al. 2014 (RTOG 9910)	2000-2004	Non-randomized portion of RCT
Nabid et al. 2018 (PCS IV)	2000-2008	Non-randomized portion of RCT
Bolla et al. 2016 (EORTC 22991)	2001-2008	Phase III (E-esc)	RT	Superior PFS
Zapatero et al. 2015 (DART01/05 GICOR)	2005-2010	Non-randomized portion of RCT

Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.

Preceding treatment

• RTOG 9902 & DART01/05 GICOR: ADT x 8 weeks
• RTOG 9910: ADT x 8 weeks versus ADT x 28 weeks

Hormonotherapy

• ADT with ONE of the following:
  • LHRH agonist
  • Some protocols: Bilateral orchiectomy
  • Some protocols: Bicalutamide (Casodex) or Flutamide (Eulexin)

Radiotherapy

• External beam radiotherapy

8-week course

Subsequent treatment

• RTOG 9902: ADT x 2 y versus TEE x 4, then ADT x 2 y
• EORTC 22961: ADT for 6 months versus ADT for 36 months
• DART01/05 GICOR: ADT for 24 months versus no further treatment
• PCS IV: ADT for 18 months versus ADT for 36 months

References

1. D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004 Aug 18;292(7):821-7. link to original article PubMed
2. RTOG 9902: Rosenthal SA, Bae K, Pienta KJ, Sobczak ML, Asbell SO, Rajan R, Kerlin KJ, Michalski JM, Sandler HM; Radiation Therapy Oncology Group. Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):672-8. Epub 2008 Nov 5. link to original article PubMed
   1. Update: Rosenthal SA, Hunt D, Sartor AO, Pienta KJ, Gomella L, Grignon D, Rajan R, Kerlin KJ, Jones CU, Dobelbower M, Shipley WU, Zeitzer K, Hamstra DA, Donavanik V, Rotman M, Hartford AC, Michalski J, Seider M, Kim H, Kuban DA, Moughan J, Sandler H. A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: final results of radiation therapy oncology group phase 3 randomized trial NRG Oncology RTOG 9902. Int J Radiat Oncol Biol Phys. 2015 Oct 1;93(2):294-302. Epub 2015 Jul 21. link to original article link to PMC article PubMed
3. EORTC 22961: Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, Poortmans PM, Gez E, Kil P, Akdas A, Soete G, Kariakine O, van der Steen-Banasik EM, Musat E, Piérart M, Mauer ME, Collette L; EORTC Radiation Oncology Group; EORTC Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009 Jun 11;360(24):2516-27. link to original article PubMed NCT00003026
4. NCIC CTG PR.3/UK MRC PR07: Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. link to original article link to PMC article PubMed NCT00002633
5. Mottet N, Peneau M, Mazeron JJ, Molinie V, Richaud P. Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial. Eur Urol. 2012 Aug;62(2):213-9. Epub 2012 Apr 3. link to original article PubMed
6. RTOG 9910: Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. link to original article link to PMC article PubMed NCT00005044
7. DART01/05 GICOR: Zapatero A, Guerrero A, Maldonado X, Alvarez A, Gonzalez San Segundo C, Cabeza Rodríguez MA, Macias V, Pedro Olive A, Casas F, Boladeras A, de Vidales CM, Vazquez de la Torre ML, Villà S, Perez de la Haza A, Calvo FA. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Mar;16(3):320-7. Epub 2015 Feb 19. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article PubMed NCT02175212
8. EORTC 22991: Bolla M, Maingon P, Carrie C, Villa S, Kitsios P, Poortmans PM, Sundar S, van der Steen-Banasik EM, Armstrong J, Bosset JF, Herrera FG, Pieters B, Slot A, Bahl A, Ben-Yosef R, Boehmer D, Scrase C, Renard L, Shash E, Coens C, van den Bergh AC, Collette L. Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: results of EORTC trial 22991. J Clin Oncol. 2016 May 20;34(15):1748-56. Epub 2016 Mar 14. link to original article PubMed NCT00021450
9. PCS IV: Nabid A, Carrier N, Martin AG, Bahary JP, Lemaire C, Vass S, Bahoric B, Archambault R, Vincent F, Bettahar R, Duclos M, Garant MP, Souhami L. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol. 2018 Oct;74(4):432-441. Epub 2018 Jul 3. link to original article PubMed NCT00223171

Flutamide, Goserelin, RT

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Flutamide, Goserelin, RT: Flutamide, Goserelin, Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pilepich et al. 1995	1987-1991	Phase III (E-RT-esc)	RT	Superior DFS
Pilepich et al. 2001 (RTOG 86-10)	1987-1991	Phase III (E-esc)	RT	Seems to have superior cause-specific mortality
Hanks et al. 2003 (RTOG 92-02)	1992-1995	Non-randomized portion of RCT
Jones et al. 2011 (RTOG 94-08)	1994-2001	Phase III (E-esc)	RT	Seems to have superior OS
D'Amico et al. 2008 (DFCI 95-096)	1995-2001	Phase III (E-esc)	RT	Superior OS
Denham et al. 2005 (TTROG 96.01)	1996-2000	Phase III (E-esc)	1. Flutamide & Goserelin x 6 mo, RT	Not reported
			2. RT	Superior EFS

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day
• Goserelin (Zoladex) 3.6 mg SC once on day 1

28-day cycles, starting 2 months prior to radiation therapy and continuing at least through the end of radiation therapy

Radiotherapy

• External beam radiotherapy is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy

7-week course

Subsequent treatment

• RTOG 92-02: adjuvant goserelin x 2 y versus no further treatment

References

1. Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause WT, Lawton CA, Abrams RA, Rotman M, Rubin P, Soloway MS; Radiation Therapy Oncology Group. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology. 1995 Apr;45(4):616-23. link to original article PubMed
2. RTOG 86-10: Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52. link to original article contains verified protocol PubMed
   1. Update: Roach M 3rd, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R, Grignon D, Pilepich MV. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol. 2008 Feb 1;26(4):585-91. Epub 2008 Jan 2. link to original article contains verified protocol PubMed
3. RTOG 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. link to original article contains protocol PubMed
   1. Update: Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. link to original article contains verified protocol PubMed
   2. Update: Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. PubMed
4. TTROG 96.01: Denham JW, Steigler A, Lamb DS, Joseph D, Mameghan H, Turner S, Matthews J, Franklin I, Atkinson C, North J, Poulsen M, Christie D, Spry NA, Tai KH, Wynne C, Duchesne G, Kovacev O, D'Este C; Trans-Tasman Radiation Oncology Group. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol. 2005 Nov;6(11):841-50. link to original article contains protocol PubMed
   1. Update: Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, Matthews J, Atkinson C, North J, Christie D, Spry NA, Tai KH, Wynne C, D'Este C. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol. 2011 May;12(5):451-9. link to original article PubMed
5. DFCI 95-096: D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008 Jan 23;299(3):289-95. link to original article PubMed content property of HemOnc.org
   1. Update: D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA. 2015 Sep 22-29;314(12):1291-3. link to original article PubMed
6. RTOG 94-08: Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. link to original article contains verified protocol PubMed

Flutamide, Leuprolide, RT

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Flutamide, Leuprolide, RT: Flutamide, Leuprolide, Radiation Therapy

Regimen variant #1, 4 months of ADT

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jones et al. 2011 (RTOG 94-08)	1994-2001	Phase III (E-esc)	RT	Seems to have superior OS

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day, to start 2 months prior to radiation therapy
• Leuprolide (Lupron) 7.5 mg SC once on day 1, to start 2 months prior to radiation therapy

28-day cycle for 4 cycles

Radiotherapy

• External beam radiotherapy is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy

Regimen variant #2, indefinite ADT

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Widmark et al. 2008 (SPCG-7/SFUO-3)	1996-2002	Phase III (C)	Flutamide & Leuprolide	Superior OS

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day, to start 3 months prior to radiation therapy
• Leuprolide (Lupron) by one of the following, to start 3 months prior to radiation therapy:
  • 3.75 mg SC once per month for 3 months
  • 11.25 mg SC once

Radiotherapy

• External beam radiotherapy 50 Gy + 20 Gy boost (total dose minimum of 70 Gy)

References

1. RTOG 94-08: Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. link to original article contains verified protocol PubMed
2. SPCG-7/SFUO-3: Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fosså SD; Scandinavian Prostate Cancer Group; Swedish Association for Urological Oncology. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009 Jan 24;373(9660):301-8. Epub 2008 Dec 16. Erratum in: Lancet. 2009 Apr 4;373(9670):1174. link to original article contains verified protocol PubMed ISRCTN01534787

Goserelin & RT

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Goserelin & RT: Goserelin & Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pilepich et al. 2005 (RTOG 85-31)	1987-1992	Phase III (E-esc)	RT	Superior DFS
Bolla et al. 1997 (EORTC 22863)	1987-1995	Phase III (E-esc)	RT	Superior OS

Hormonotherapy

• Goserelin (Zoladex) 3.6 mg SC once on day 1, started during the last week of radiation therapy

28-day cycles

Radiotherapy

• External beam radiotherapy, 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional boost to the prostate that resulted in a total dose of 65 to 70 Gy in definitive radiation patients; 60 to 65 Gy total dose for post-prostatectomy patients

One course

References

1. RTOG 85-31: Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, Hanks GE, Coughlin CT, Porter A, Shipley WU, Grignon D. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol. 1997 Mar;15(3):1013-21. link to original article contains protocol PubMed
   1. Update: Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):937-46. link to original article contains protocol PubMed
   2. Update: Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, Hug EB, Asbell SO, Grignon D. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90. link to original article contains verified protocol PubMed
2. EORTC 22863: Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997 Jul 31;337(5):295-300. link to original article PubMed
   1. Update: Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6. link to original article PubMed
   2. Update: Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Billiet I, Torecilla JL, Pfeffer R, Cutajar CL, Van der Kwast T, Collette L. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010 Nov;11(11):1066-73. Epub 2010 Oct 7. link to original article PubMed

Adjuvant therapy

Bicalutamide & Goserelin

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dorff et al. 2011 (SWOG S9921)	2000-2007	Phase III (C)	ADT & Mitoxantrone	Not reported

Dosing details are not available in the manuscript; this is the common dosing used.

Preceding treatment

• Radical prostatectomy

Hormonotherapy

• Bicalutamide (Casodex) 50 mg PO once per day
• Goserelin (Zoladex) 10.8 mg SC once on day 1

12-week cycle for 9 cycles (2 years)

References

1. SWOG S9921: Dorff TB, Flaig TW, Tangen CM, Hussain MH, Swanson GP, Wood DP Jr, Sakr WA, Dawson NA, Haas NB, Crawford ED, Vogelzang NJ, Thompson IM, Glode LM. Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol. 2011 May 20;29(15):2040-5. Epub 2011 Apr 18. link to original article does not contain protocol link to PMC article PubMed NCT00004124

Goserelin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Messing et al. 1999 (ECOG E3886)	1988-1993	Phase III (E-esc)	No further treatment	Seems to have superior OS
Hanks et al. 2003 (RTOG 92-02)	1992-1995	Phase III (E-esc)	No further treatment	Seems to have superior OS (*)

Efficacy of RTOG 92-02 based on the 2017 update.

Preceding treatment

• ECOG E3886: Radical prostatectomy
• RTOG 92-02: Flutamide, Goserelin, RT

Hormonotherapy

• Goserelin (Zoladex) 3.6 mg SC once per month

2-year course (RTOG 92-02) or until rising PSA detected (ECOG E3886)

References

1. ECOG E3886: Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D; ECOG. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999 Dec 9;341(24):1781-8. link to original article contains verified protocol PubMed
   1. Update: Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; ECOG. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006 Jun;7(6):472-9. link to original article PubMed
2. RTOG 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. link to original article contains protocol PubMed
   1. Update: Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. link to original article contains verified protocol PubMed
   2. Update: Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. PubMed

Triptorelin & RT

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sargos et al. 2020 (GETUG-AFU 17)	2008-20016	Phase III (E-esc)	Salvage Triptorelin & RT	Did not meet primary endpoint of EFS

Statistical power was compromised due to unexpectedly low event rate. GETUG-AFU 17 was published concurrently along with two other Phase III trials looking at timing of radiotherapy following radical prostatectomy: RADICALS-RT and ANZUP RAVES. All three trials were also analyzed as part of a pre-planned meta-analysis ARTISTIC which failed to show an EFS benefit with adjuvant radiotherapy vs. salvage radiotherapy.

Preceding treatment

• Radical prostatectomy

Hormonotherapy

• Triptorelin 11.25 mg IM every 12 weeks

12-week cycle for 2 cycles (6 months)

References

1. GETUG-AFU 17: Sargos P, Chabaud S, Latorzeff I, Magne N, Benyoucef A, Supiot S, Pasquier D, Abdiche MS, Gilliot O, Graff-Cailleaud P, Silva M, Bergerot P, Baumann P, Belkacemi Y, Azria D, Brihoum M, Soulie M, Richaud P. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol. 2020 Oct; 21(10):1341-1352.

link to original article does not contain protocol PubMed NCT00667069

Salvage ADT & radiotherapy

Bicalutamide & RT

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Bicalutamide & RT: Bicalutamide & Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shipley et al. 2017 (RTOG 9601)	1998-2003	Phase III (E-esc)	RT	Seems to have superior OS

Preceding treatment

• Prostatectomy with lymphadenectomy, with a postoperative detectable PSA level of 0.2 to 4.0 ng/mL

Hormonotherapy

• Bicalutamide (Casodex) 150 mg PO once per day

2-year course

Radiotherapy

• External beam radiotherapy, 64.8 Gy in 36 daily fractions of 1.80 Gy

7-week course

References

1. RTOG 9601: Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CA, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017 Feb 2;376(5):417-428. link to original article contains verified protocol link to PMC article PubMed NCT00002874

Goserelin & RT

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Goserelin & RT: Goserelin & Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Carrie et al. 2016 (GETUG-AFU 16)	2006-2010	Phase III (E-esc)	Salvage RT	Superior PFS

Preceding treatment

• Prostatectomy, with rising PSA

Hormonotherapy

• Goserelin (Zoladex) 0.8 mg SC once on day 1

3-month cycle for 2 cycles

Radiotherapy

• External beam radiotherapy, 66 Gy in 33 daily fractions of 2 Gy

7-week course

References

1. GETUG-AFU 16: Carrie C, Hasbini A, de Laroche G, Richaud P, Guerif S, Latorzeff I, Supiot S, Bosset M, Lagrange JL, Beckendorf V, Lesaunier F, Dubray B, Wagner JP, N'Guyen TD, Suchaud JP, Créhange G, Barbier N, Habibian M, Ferlay C, Fourneret P, Ruffion A, Dussart S. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016 Jun;17(6):747-756. Epub 2016 May 6. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. link to original article contains protocol PubMed NCT00423475
   1. Update: Carrie C, Magné N, Burban-Provost P, Sargos P, Latorzeff I, Lagrange JL, Supiot S, Belkacemi Y, Peiffert D, Allouache N, Dubray BM, Servagi-Vernat S, Suchaud JP, Crehange G, Guerif S, Brihoum M, Barbier N, Graff-Cailleaud P, Ruffion A, Dussart S, Ferlay C, Chabaud S. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol. 2019 Dec;20(12):1740-1749. Epub 2019 Oct 16. link to original article PubMed

Hormonal therapy for non-metastatic castrate sensitive disease

ADT

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ADT: Androgen Deprivation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Oudard et al. 2019 (RisingPSA)	2003-2007	Phase III (C)	ADT & Docetaxel	Did not meet primary endpoint of PSA-PFS
Duchesne et al. 2016 (TOAD)	2004-2012	Phase III (E-switch-ic)	Delayed ADT	Seems to have superior OS
Schulman et al. 2015 (ICELAND)	2006-NR	Phase III (C)	Intermittent ADT	Did not meet primary endpoint of TTP

Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.

Hormonotherapy

• LHRH agonist
• Bicalutamide (Casodex) or Flutamide (Eulexin)

12-month course (RisingPSA) or continued indefinitely

References

1. ICELAND: Schulman C, Cornel E, Matveev V, Tammela TL, Schraml J, Bensadoun H, Warnack W, Persad R, Salagierski M, Gómez Veiga F, Baskin-Bey E, López B, Tombal B. Intermittent versus continuous androgen deprivation therapy in patients with relapsing or locally advanced prostate cancer: a phase 3b randomised study (ICELAND). Eur Urol. 2016 Apr;69(4):720-727. Epub 2015 Oct 29. link to original article PubMed NCT00378690
2. TOAD: Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D'Este C, Frydenberg M, King M, Ledwich L, Loblaw A, Malone S, Millar J, Milne R, Smith RG, Spry N, Stockler M, Syme RA, Tai KH, Turner S. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016 Jun;17(6):727-737. Epub 2016 May 4. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. Lancet Oncol. 2017 Sep;18(9):e510. link to original article PubMed NCT00110162
3. RisingPSA: Oudard S, Latorzeff I, Caty A, Miglianico L, Sevin E, Hardy-Bessard AC, Delva R, Rolland F, Mouret L, Priou F, Beuzeboc P, Gravis G, Linassier C, Gomez P, Voog E, Muracciole X, Abraham C, Banu E, Ferrero JM, Ravaud A, Krakowski I, Lagrange JL, Deplanque G, Zylberait D, Bozec L, Houede N, Culine S, Elaidi R. Effect of adding docetaxel to androgen-deprivation therapy in patients with high-risk prostate cancer with rising prostate-specific antigen levels after primary local therapy: a randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):623-632. Epub 2019 Jan 31. link to original article link to PMC article PubMed NCT00764166

Hormonal therapy for non-metastatic castrate resistant disease

ADT

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ADT: Androgen Deprivation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Smith et al. 2017 (SPARTAN)	2013-2016	Phase III (C)	ADT & Apalutamide	Seems to have inferior OS (*)
Hussain et al. 2018 (PROSPER)	2013-2017	Phase III (C)	ADT & Enzalutamide	Inferior MFS
Fizazi et al. 2019 (ARAMIS)	2014-2018	Phase III (C)	ADT & Darolutamide	Inferior OS (*)

Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details. Reported efficacy for SPARTAN is based on the 2019 update. Reported efficacy for ARAMIS is based on the 2020 update.

Hormonotherapy

• GnRH agonist or GnRH antagonist or a history of bilateral orchiectomy

Continued indefinitely

References

1. SPARTAN: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. link to original article link to supplementary appendix contains verified protocol PubMed NCT01946204
   1. Update: Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. link to original article link to PMC article PubMed
2. PROSPER: Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. link to original article contains protocol PubMed
3. ARAMIS: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. link to original article PubMed NCT02200614
   1. Update: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. link to original article PubMed

ADT & Apalutamide

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ADT & Apalutamide: Androgen Deprivation Therapy & Apalutamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Smith et al. 2017 (SPARTAN)	2013-2016	Phase III (E-RT-esc)	ADT	Seems to have superior OS (*)

Metastasis-free survival	Comparator metastasis-free survival	Pt Population
40.5 months	16.2 months	Castrate-resistant, non-metastatic, PSA doubling time <10 months

Note: reported efficacy is based on the 2019 update.

Hormonotherapy

• Apalutamide (Erleada) 240 mg PO once per day
• Patients should concurrently be receiving GnRH analog or have had bilateral orchiectomy

Continued indefinitely

References

1. SPARTAN: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. link to original article link to supplementary appendix contains verified protocol PubMed NCT01946204
   1. Update: Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. link to original article link to PMC article PubMed

ADT & Darolutamide

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fizazi et al. 2019 (ARAMIS)	2014-2018	Phase III (E-RT-esc)	ADT	Superior OS (*)

Note: reported efficacy is based on the 2020 update.

Hormonotherapy

• GnRH agonist or GnRH antagonist
• Darolutamide (Nubeqa) 600 mg PO twice per day

Continued indefinitely

References

1. ARAMIS: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. link to original article PubMed NCT02200614
   1. Update: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. link to original article PubMed

ADT & Enzalutamide

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ADT & Enzalutamide: Androgen Deprivation Therapy & Enzalutamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hussain et al. 2018 (PROSPER)	2013-2017	Phase III (E-RT-esc)	ADT	Superior MFS

Patients had castrate-resistant, non-metastatic, prostate cancer with PSA doubling time less than 10 months.

Hormonotherapy

• Enzalutamide (Xtandi) 160 mg PO once per day
• Patients should concurrently be receiving GnRH agonist or GnRH antagonist or have had bilateral orchiectomy

Continued indefinitely

References

1. PROSPER: Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. link to original article contains protocol PubMed

Hormonal therapy for metastatic or locally advanced disease

ADT

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ADT: Androgen Deprivation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schröder et al. 2004 (EORTC 30846)	1986-1998	Phase III (C)	Delayed ADT	Did not meet primary endpoint of OS
Fizazi et al. 2015 (GETUG 12)	2002-2006	Phase III (C)	ADT, Docetaxel, Estramustine	Seems to have inferior RFS
Gravis et al. 2013 (GETUG-AFU 15)	2004-2008	Phase III (C)	ADT & Docetaxel	Did not meet primary endpoint of OS
James et al. 2012 (STAMPEDE)	2005-2011	Phase III (C)	ADT & Celecoxib	Did not meet intermediate primary endpoint of FFS
James et al. 2015 (STAMPEDE)	2005-2011	Phase III (C)	ADT & Docetaxel	Inferior OS
James et al. 2017 (STAMPEDE)	2005-2011	Phase III (C)	ADT & Abiraterone	Inferior OS
Sweeney et al. 2015 (CHAARTED)	2006-2012	Phase III (C)	ADT & Docetaxel	Inferior OS (*)
Kamba et al. 2016 (ZAPCA)	2008-2010	Phase III (C)	ADT & Zoledronic acid	Might have inferior TTTF
Fizazi et al. 2017 (LATITUDE)	2013-2014	Phase III (C)	ADT & Abiraterone	Inferior OS

Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples. In the 2018 update of CHAARTED, only patients with high-volume disease had inferior survival in the control arm.

Hormonotherapy

• ADT with ONE of the following:
  • LHRH agonist/analogue
  • LHRH antagonist
  • Bilateral orchiectomy

Continued indefinitely

References

1. EORTC 30846: Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, Debois M, Collette L; European Organisation for the Research and Treatment of Cancer Genito-urinary Group. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol. 2004 Sep;172(3):923-7. link to original article PubMed
2. STAMPEDE: James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, Dwyer J, Jovic G, Ritchie AW, Russell JM, Sanders K, Thalmann GN, Bertelli G, Birtle AJ, O'Sullivan JM, Protheroe A, Sheehan D, Srihari N, Parmar MK; STAMPEDE Investigators. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 2012 May;13(5):549-58. Epub 2012 Mar 26. Erratum in: Lancet Oncol. 2013 Jan;14(1):e5. link to original article link to PMC article PubMed NCT00268476
3. GETUG-AFU 15: Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. link to original article PubMed NCT00104715
   1. Update: Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. link to original article PubMed
4. GETUG 12: Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. link to original article PubMed NCT00055731
5. CHAARTED: Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. link to original article contains verified protocol Pubmed NCT00309985
   1. Update: Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. link to original article link to PMC article PubMed
   2. QoL analysis: Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. link to original article link to PMC article PubMed
6. STAMPEDE: James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. link to original article link to PMC article contains verified protocol PubMed NCT00268476
   1. Update: Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. link to original article link to PMC article PubMed
7. ZAPCA: Kamba T, Kamoto T, Maruo S, Kikuchi T, Shimizu Y, Namiki S, Fujimoto K, Kawanishi H, Sato F, Narita S, Satoh T, Saito H, Sugimoto M, Teishima J, Masumori N, Egawa S, Sakai H, Okada Y, Terachi T, Ogawa O; ZAPCA Study Group. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial. Int J Clin Oncol. 2017 Feb;22(1):166-173. Epub 2016 Sep 10. link to original article PubMed NCT00685646
8. STAMPEDE: James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. link to original article link to PMC article supplementary protocol contains verified protocol in supplement PubMed NCT00268476
9. LATITUDE: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. link to original article supplementary protocol contains verified protocol in supplement PubMed
   1. HRQoL analysis: Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. link to original article PubMed
   2. Update: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. link to original article PubMed

ADT & Abiraterone

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ADT & Abiraterone: Androgen Deprivation Therapy & Abiraterone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
James et al. 2017 (STAMPEDE)	2005-2011	Phase III (E-esc)	ADT	Superior OS
Fizazi et al. 2017 (LATITUDE)	2013-2014	Phase III (E-RT-esc)	ADT	Superior OS

Note: while LATITUDE allowed for a dose increase in prednisone, the FDA recommended dose is 5 mg PO once per day.

Hormonotherapy

• Abiraterone (Zytiga) 1000 mg PO once per day
• ADT with ONE of the following:
  • LHRH agonist/analogue
  • STAMPEDE only: LHRH antagonist
  • Bilateral orchiectomy

Supportive medications

• Prevention of mineralocorticoid excess with ONE of the following:
  • STAMPEDE except Switzerland: Prednisolone (Millipred) 5 mg PO once per day
  • LATITUDE and STAMPEDE in Switzerland: Prednisone (Sterapred) 5 mg PO once per day
    • LATITUDE: "dose increase of up to 10 mg/day is permitted to manage refractory mineralocorticoid related toxicities"

Continued indefinitely unless radiotherapy planned, in which case continued for up to 2 years

References

1. STAMPEDE: James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. link to original article link to PMC article supplementary protocol contains verified protocol in supplement PubMed NCT00268476
2. LATITUDE: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. link to original article supplementary protocol contains verified protocol in supplement PubMed
   1. HRQoL analysis: Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. link to original article PubMed
   2. Update: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. link to original article PubMed

ADT & Apalutamide

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ADT & Apalutamide: Androgen Deprivation Therapy & Apalutamide

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chi et al. 2019 (TITANprostate)	2015-2017	Phase III (E-RT-esc)	ADT	Superior OS

Note: there are several other trials in other cancer subtypes named TITAN.

Hormonotherapy

• Apalutamide (Erleada) 240 mg PO once per day
• LHRH agonist/analogue

Continued indefinitely

References

1. TITAN: Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. Epub 2019 May 31. link to original article contains protocol PubMed

ADT & Docetaxel

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ADT & Docetaxel: Androgen Deprivation Therapy & Docetaxel

Regimen variant #1, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
James et al. 2015 (STAMPEDE)	2005-2011	Phase III (E-esc)	ADT	Superior OS
Sweeney et al. 2015 (CHAARTED)	2006-2012	Phase III (E-esc)	ADT	Superior OS (*)

Patients already on androgen deprivation therapy were eligible to participate in CHAARTED if there was no evidence of disease progression and if they had started ADT no more than 120 days before randomization. In the 2018 update of CHAARTED, only patients with high-volume disease had superior survival in the experimental arm.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• ADT with ONE of the following:
  • LHRH agonist/analogue
  • LHRH antagonist
  • Bilateral orchiectomy
  • Intermittent hormonal therapy was not allowed. Antiandrogens e.g. bicalutamide were allowed at the start of therapy "at the discretion of the investigator."

Supportive medications

• Dexamethasone (Decadron) 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before Docetaxel (Taxotere)
• Daily prednisone was not required
• At least calcium 500 mg and vitamin D 400 IU PO once per day

21-day cycle for up to 6 cycles

Regimen variant #2, 9 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gravis et al. 2013 (GETUG-AFU 15)	2004-2008	Phase III (E-esc)	ADT	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• ADT with one of the following:
  • LHRH agonist/analogue with or without nonsteroidal androgen receptor inhibitors
  • Bilateral orchiectomy with or without nonsteroidal androgen receptor inhibitors

21-day cycle for up to 9 cycles

References

1. GETUG-AFU 15: Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. link to original article PubMed NCT00104715
   1. Update: Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. link to original article PubMed
2. CHAARTED: Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. link to original article contains verified protocol Pubmed NCT00309985
   1. Update: Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. link to original article link to PMC article PubMed
   2. QoL analysis: Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. link to original article link to PMC article PubMed
3. STAMPEDE: James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. link to original article link to PMC article contains verified protocol PubMed NCT00268476
   1. Update: Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. link to original article link to PMC article PubMed

ADT, Docetaxel, Estramustine

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ADT, Docetaxel, Estramustine: Androgen Deprivation Therapy, Docetaxel, Estramustine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fizazi et al. 2015 (GETUG 12)	2002-2006	Phase III (E-esc)	ADT	Seems to have superior RFS

Chemotherapy

• Docetaxel (Taxotere)
• Estramustine (Emcyt)

Hormonotherapy

• ADT with one of the following:
  • LHRH agonist/analogue with or without nonsteroidal androgen receptor inhibitors
  • Bilateral orchiectomy with or without nonsteroidal androgen receptor inhibitors

References

1. GETUG 12: Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. link to original article PubMed NCT00055731

ADT & Enzalutamide

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ADT & Enzalutamide: Androgen Deprivation Therapy & Enzalutamide

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Davis et al. 2019 (ENZAMET)	2014-2017	Phase III (E-switch-ic)	1. ADT & Bicalutamide 2. ADT & Flutamide 3. ADT & Niluatmide	Superior OS
Armstrong et al. 2019 (ARCHES)	2016-2018	Phase III (E-RT-esc)	ADT	Superior rPFS

Hormonotherapy

• Enzalutamide (Xtandi) 160 mg PO once per day
• ADT with one of the following:
  • LHRH agonist/analogue
  • Bilateral orchiectomy

Continued indefinitely

References

1. ENZAMET: Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. link to original article contains protocol PubMed NCT02446405
2. ARCHES: Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. Epub 2019 Jul 22. link to original article contains protocol PubMed

Bicalutamide monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tyrrell et al. 1998	NR in abstract	Phase III (E-switch-ic)	Castration	Did not meet primary endpoints of PFS/OS (*)
Iversen et al. 2002 (SPCG-6)	1995-1998	Phase III (E-esc)	Placebo	Superior OS (*)

Not approved for monotherapy in the United States. See combination regimens with goserelin & leuprolide. Reported efficacy for Tyrrell et al. 1998 is based on the 2000 update. Reported efficacy for SPCG-6 is based on the 2006 update and is only for the locally advanced subgroup.

Hormonotherapy

• Bicalutamide (Casodex) 150 mg PO once per day

Continued indefinitely

References

1. Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, Chamberlain M, Webster A, Blackledge G. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol. 1998;33(5):447-56. link to original article contains protocol PubMed
   1. Update: Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol. 2000 Nov;164(5):1579-82. link to original article contains verified protocol PubMed
2. SPCG-6: Iversen P, Tammela TL, Vaage S, Lukkarinen O, Lodding P, Bull-Njaa T, Viitanen J, Hoisaeter P, Lundmo P, Rasmussen F, Johansson JE, Persson BE, Carroll K; Scandinavian Prostatic Cancer Group. A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer: first report from the Scandinavian Prostatic Cancer Group Study No 6. Eur Urol. 2002 Sep;42(3):204-11. link to original article PubMed
   1. Update: Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol. 2004 Nov;172(5 Pt 1):1871-6. link to original article PubMed
   2. Update: Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J; Scandinavian Prostate Cancer Group. Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years. Scand J Urol Nephrol. 2006;40(6):441-52. link to original article PubMed

Bicalutamide & Goserelin

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Regimen variant #1, 50/3.6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schellhammer et al. 1995	1992-1993	Phase III (E-RT-switch-ic)	1. Bicalutamide & Leuprolide	Not reported
			2. Flutamide & Goserelin 3. Flutamide & Leuprolide	Equivalent TTP (*)

Note: reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Hormonotherapy

• Bicalutamide (Casodex) 50 mg PO once per day
• Goserelin (Zoladex) 3.6 mg SC once on day 1

28-day cycles

Regimen variant #2, 80/3.6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Akaza et al. 2004	2000-2001	Phase III (E-esc)	1. Goserelin 2. Leuprolide	Seems to have superior OS (*)

Note: reported efficacy is based on the 2009 update.

Hormonotherapy

• Bicalutamide (Casodex) 80 mg PO once per day
• Goserelin (Zoladex) 3.6 mg SC once on day 1

28-day cycles

References

1. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. link to original article PubMed
   1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol PubMed
   2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol PubMed
   3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
2. Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. link to original article contains verified protocol PubMed
   1. Update: Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. link to original article PubMed

Bicalutamide & Leuprolide

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Regimen variant #1, 50/7.5

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schellhammer et al. 1995	1992-1993	Phase III (E-RT-switch-ic)	1. Bicalutamide & Goserelin	Not reported
			2. Flutamide & Goserelin 3. Flutamide & Leuprolide	Equivalent TTP (*)
Trachtenberg et al. 2002	NR	Phase III (C)	Abarelix	Inferior primary endpoint

Note: Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Hormonotherapy

• Bicalutamide (Casodex) 50 mg PO once per day
• Leuprolide (Lupron) 1-month depot 7.5 mg IM once on day 1

28-day cycles

Regimen variant #2, 80/3.75

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Akaza et al. 2004	2000-2001	Phase III (E-esc)	1. Goserelin 2. Leuprolide	Seems to have superior OS (*)

Note: reported efficacy is based on the 2009 update.

Hormonotherapy

• Bicalutamide (Casodex) 80 mg PO once per day
• Leuprolide (Lupron) 1-month depot 3.75 mg SC once on day 1

28-day cycles

References

1. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. link to original article PubMed
   1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol PubMed
   2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol PubMed
   3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
2. Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, Fotheringham N, Campion M, Garnick MB; Abarelix Study Group. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol. 2002 Apr;167(4):1670-4. link to original article contains protocol PubMed
3. Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. link to original article contains verified protocol PubMed
   1. Update: Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. link to original article PubMed

Degarelix monotherapy

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Example orders

• Example orders for Degarelix (Firmagon) in prostate cancer

Regimen variant #1, 240/80

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Klotz et al. 2008 (CS21)	2006-2007	Phase III (E-RT-switch-ic)	1. Degarelix; 240/160	Non-inferior testosterone suppression
			2. Leuprolide	Non-inferior testosterone suppression

Hormonotherapy

• Degarelix (Firmagon) as follows:
  • Cycle 1: 240 mg SC once on day 1
  • Cycle 2 onwards: 80 mg SC once on day 1

28-day cycles

Regimen variant #2, 240/160

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Klotz et al. 2008 (CS21)	2006-2007	Phase III (E-RT-switch-ic)	1. Degarelix; 240/80	Non-inferior testosterone suppression
			2. Leuprolide	Non-inferior testosterone suppression

Hormonotherapy

• Degarelix (Firmagon) as follows:
  • Cycle 1: 240 mg SC once on day 1
  • Cycle 2 onwards: 160 mg SC once on day 1

28-day cycles

Regimen variant #3, 240/480

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ozono et al. 2018 (3550-CL-0010)	2013-NR	Phase III (E-switch-ic)	Goserelin	Non-inferior testosterone suppression

Hormonotherapy

• Degarelix (Firmagon) as follows:
  • Cycle 1: 240 mg SC once on day 1
  • Cycle 2 onwards: 480 mg SC once on day 1

28-day cycle for 1 cycle, then 12-week cycles

References

1. CS21: Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. link to original article contains verified protocol PubMed
   1. Update: Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. link to original article contains verified protocol PubMed
2. 3550-CL-0010: Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. link to original article link to PMC article PubMed NCT01964170

Flutamide monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Boccon-Gibod et al. 1997	1989-1991	Phase III (E-switch-ic)	Bilateral orchiectomy	Did not meet primary endpoint of PFS
Fosså et al. 2001 (EORTC 30903)	1992-1998	Phase III (E-switch-ic)	Prednisone	Did not meet primary endpoints of TTP/OS

Not approved for monotherapy in the United States. See combination regimens with Goserelin & Leuprolide.

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day

Continued indefinitely

References

1. Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P, Hubert J, Soret JY, Mangin P, Mallo C, Fraysse CE. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol. 1997;32(4):391-5. link to original article contains protocol PubMed
2. EORTC 30903: Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. link to original article contains protocol PubMed

Flutamide & Goserelin

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Denis et al. 1993 (EORTC 30853)	1986-1988	Phase III (E-switch-ic)	Bilateral orchiectomy	Seems to have superior OS
Schellhammer et al. 1995	1992-1993	Phase III (C)	1. Bicalutamide & Goserelin 2. Bicalutamide & Leuprolide	Equivalent TTP (*)
			3. Flutamide & Leuprolide	Not reported
Hussain et al. 2013 (SWOG-9346)	1995-2008	Phase III (C)	Intermittent ADT	Inconclusive whether non-inferior OS

Note: Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day
• Goserelin (Zoladex) 3.6 mg SC once on day 1

28-day cycles

References

1. EORTC 30853: Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M; EORTC GU Group. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology. 1993 Aug;42(2):119-29. link to original article contains protocol PubMed
   1. Update: Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R; EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. Eur Urol. 1998;33(2):144-51. PubMed
2. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. link to original article PubMed
   1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol PubMed
   2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol PubMed
   3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
3. SWOG-9346: Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. link to original article link to PMC article supplementary protocol contains verified protocol in supplementary protocol PubMed NCT00002651

Flutamide & Leuprolide

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Regimen variant #1, daily Lupron

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Crawford et al. 1989 (SWOG-8494)	1985-1986	Phase III (E-RT-esc)	Leuprolide	Seems to have superior OS

Note: this is likely of historic importance only, given the formulation of leuoprolide.

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day
• Leuprolide (Lupron) 1 mg SC once per day

Continued indefinitely

Regimen variant #2, 1-month depot Lupron

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schellhammer et al. 1995	1992-1993	Phase III (C)	1. Bicalutamide & Goserelin 2. Bicalutamide & Leuprolide	Equivalent TTP (*)
			3. Flutamide & Goserelin	Not reported
Hussain et al. 2013 (SWOG-9346)	1995-2008	Phase III (C)	Intermittent ADT	Inconclusive whether non-inferior OS

Note: Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Hormonotherapy

• Flutamide (Eulexin) 250 mg PO three times per day
• Leuprolide (Lupron) 1-month depot 7.5 mg IM once on day 1

28-day cycles

References

1. SWOG-8494: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. link to original article contains verified protocol PubMed
2. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. Urology. 1995 May;45(5):745-52. link to original article PubMed
   1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol PubMed
   2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol PubMed
   3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
3. SWOG-9346: Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. link to original article link to PMC article supplementary protocol contains verified protocol in supplementary protocol PubMed NCT00002651

Goserelin monotherapy

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Example orders

• Example orders for Goserelin (Zoladex) in prostate cancer

Regimen variant #1, 28-day cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Soloway et al. 1991	NR	Phase III (E-switch-ic)	Bilateral orchiectomy	Did not meet efficacy endpoints
Kaisary et al. 1991	1983-1986	Phase III (E-switch-ic)	Bilateral orchiectomy	Did not meet efficacy endpoints
Waymont et al. 1992	1985-1987	Phase III (E-switch-ic)	DES	Seems to have superior time to first response
Tyrrell et al. 1991 (IPCSG)	1986-1987	Phase III (C)	Flutamide & Goserelin	Did not meet efficacy endpoints
Boccardo et al. 1993 (PONCAP)	1987-1990	Phase III (C)	Flutamide & Goserelin	Might have inferior PFS50%

Hormonotherapy

• Goserelin (Zoladex) 3.6 mg SC once on day 1

28-day cycles

Regimen variant #2, 12-week cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ozono et al. 2018 (3550-CL-0010)	2015-NR	Phase III (C)	Degarelix	Non-inferior testosterone suppression

Hormonotherapy

• Goserelin (Zoladex) as follows:
  • Cycle 1: 3.6 mg SC once on day 1
  • Cycle 2 onwards: 10.8 mg SC once on day 1

28-day cycle for 1 cycle, then 12-week cycles

References

1. Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA Jr, Scott M, Kennealey G, Gau TC; Zoladex Prostate Study Group. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Urology. 1991 Jan;37(1):46-51. link to original article PubMed
   1. Update: Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, Caplan RJ, Kennealey GT; Zoladex Prostate Study Group. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Urology. 1995 Aug;46(2):220-6. link to original article contains verified protocol PubMed
2. Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol. 1991 May;67(5):502-8. link to original article PubMed
3. IPCSG: Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, Holdaway IM, Haefliger JM, Jordaan JP; International Prostate Cancer Study Group. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol. 1991 Nov;146(5):1321-6. link to original article PubMed
4. Waymont B, Lynch TH, Dunn JA, Emtage LA, Arkell DG, Wallace DM, Blackledge GR. Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol. 1992 Jun;69(6):614-20. link to original article PubMed
5. PONCAP: Boccardo F, Pace M, Rubagotti A, Guarneri D, Decensi A, Oneto F, Martorana G, Giuliani L, Selvaggi F, Battaglia M, Delli Ponti U, Petracco S, Cortellini P, Ziveri M, Ferraris V, Bruttini GP, Epis R, Comeri G, Gallo G; Italian Prostatic Cancer Project (PONCAP) Study Group. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. Eur J Cancer. 1993;29A(8):1088-93. link to original article PubMed
6. 3550-CL-0010: Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. link to original article link to PMC article PubMed NCT01964170

Histrelin monotherapy

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Regimen

Study	Years of enrollment	Evidence
Schlegel 2006	NR	Non-randomized (RT)

Hormonotherapy

• Histrelin (Vantas)

References

1. Schlegel PN; Histrelin Study Group. Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancer. J Urol. 2006 Apr;175(4):1353-8. link to original article PubMed

Intermittent ADT

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IHT: Intermittent Hormone Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Calais da Silva et al. 2009 (SEUG 9401)	NR	Phase III (E-de-esc)	Continuous ADT	Did not meet primary endpoint of TTP
Hussain et al. 2013 (SWOG-9346)	1995-2008	Phase III (E-de-esc)	Continuous ADT	Inconclusive whether non-inferior OS
Crook et al. 2012 (NCIC CTG PR.7)	1999-2005	Phase III (E-de-esc)	Continuous ADT	Non-inferior OS
Calais da Silva et al. 2013 (SEUG 9901)	2000-2007	Phase III (E-de-esc)	Continuous ADT	Non-inferior OS

See papers for details about treatment holidays.

Hormonotherapy

• LHRH agonist
• Nonsteroidal antiandrogen for at least 4 weeks

8-month cycles

References

1. SEUG 9401: Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, Kirkali Z, Calais da Silva FM, Robertson C. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009 Jun;55(6):1269-77. Epub 2009 Feb 21. link to original article PubMed
2. NCIC CTG PR.7: Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012 Sep 6;367(10):895-903. Erratum in: N Engl J Med. 2012 Dec 6;367(23):2262. link to original article link to PMC article PubMed NCT00003653
3. SWOG-9346: Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. link to original article link to PMC article supplementary protocol contains verified protocol in supplementary protocol PubMed NCT00002651
4. SEUG 9901: Calais da Silva F, Calais da Silva FM, Gonçalves F, Santos A, Kliment J, Whelan P, Oliver T, Antoniou N, Pastidis S, Marques Queimadelos A, Robertson C. Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group. Eur Urol. 2014 Aug;66(2):232-9. Epub 2013 Apr 4. link to original article PubMed

Leuprolide monotherapy

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Example orders

• Example orders for Leuprolide (Lupron) in prostate cancer

Regimen variant #1, daily

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Garnick et al. 1984	1981-NR	Phase III (E-switch-ic)	DES	Did not meet efficacy endpoints	Less toxic
Crawford et al. 1989 (SWOG-8494)	1985-1986	Phase III (C)	Flutamide & Leuprolide	Seems to have inferior OS

Note: this is of historic importance only, given the wide availability of depot formulations of leuoprolide.

Hormonotherapy

• Leuprolide (Lupron) 1 mg SC once per day

Continued indefinitely

Regimen variant #2, 1-month depot, 3.75 mg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Akaza et al. 2004	2000-2001	Phase III (C)	1. Bicalutamide & Goserelin 2. Bicalutamide & Leuprolide	Seems to have inferior OS (*)

Note: efficacy is based on the 2009 update.

Hormonotherapy

• Leuprolide (Lupron) 1-month depot 3.75 mg SC once on day 1

28-day cycles

Regimen variant #3, 1-month depot, 7.5 mg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sharifi & Soloway 1990	1986-NR	Non-randomized (RT)
Klotz et al. 2008 (CS21)	2006-2007	Phase III (C)	1. Degarelix 240/80	Non-inferior testosterone suppression
			2. Degarelix 240/160	Non-inferior testosterone suppression

Hormonotherapy

• Leuprolide (Lupron) 1-month depot 7.5 mg IM once on day 1

28-day cycles

Regimen variant #4, 3-month depot

Study	Years of enrollment	Evidence
Sharifi et al. 1996	NR	Phase II (RT)

Hormonotherapy

• Leuprolide (Lupron) 3-month depot 22.5 mg IM once on day 1

84-day cycles

Regimen variant #5, 4-month depot

Study	Years of enrollment	Evidence
Sharifi et al. 1998	NR	Phase II (RT)

Hormonotherapy

• Leuprolide (Lupron) 4-month depot 30 mg IM once on day 1

16-week cycles

Regimen variant #6, 6-month depot

Study	Years of enrollment	Evidence
Spitz et al. 2011 (L-PC07-169)	2008-2009	Non-randomized (RT)

Hormonotherapy

• Leuprolide (Lupron) 6-month depot 45 mg IM once on day 1

26-week cycles

References

1. Garnick MB, Glode LM; Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med. 1984 Nov 15;311(20):1281-6. link to original article contains protocol PubMed
2. SWOG-8494: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. link to original article contains verified protocol PubMed
3. Sharifi R, Soloway M; Leuprolide Study Group. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol. 1990 Jan;143(1):68-71. link to original article PubMed
4. Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD Jr, Hudson PB, Stein B. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther. 1996 Jul-Aug;18(4):647-57. link to original article contains verified protocol PubMed
5. Sharifi R, Knoll LD, Smith J, Kramolowsky E. Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. Urology. 1998 Feb;51(2):271-6. link to original article PubMed
6. Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. link to original article contains verified protocol PubMed
   1. Update: Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. link to original article PubMed
7. CS21: Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. link to original article contains verified protocol PubMed
   1. Update: Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. link to original article contains verified protocol PubMed
8. L-PC07-169: Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K. Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2012 Mar;15(1):93-9. Epub 2011 Oct 25. link to original article link to PMC article PubMed

Nilutamide & Orchiectomy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Janknegt et al. 1993 (International Anandron Study)	1986-NR	Phase III (E-RT-esc)	Bilateral orchiectomy	Superior PFS

Nilutamide to start the day of, or day after surgical castration/orchiectomy.

Hormonotherapy

• Nilutamide (Nilandron) 300 mg PO once per day x 1 month, then 150 mg PO once per day
• Bilateral orchiectomy

Continued indefinitely

References

1. International Anandron Study: Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, Da Silva FC, Chisholm G, Crawford ED, Debruyne FM, Dijkman GD, Frick J, Goedhals J, Knönagel H, Venner PM. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol. 1993 Jan;149(1):77-82. link to original article PubMed
   1. Update: Janknegt RA; Anandron International Study Group. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Cancer. 1993 Dec 15;72(12 Suppl):3874-7. PubMed
   2. Update: Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM; International Anandron Study Group. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997 Jul;158(1):160-3. PubMed
   3. Update: de Reijke T, Derobert E; Anandron /Nilutamide Study Group. Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: a final update. Eur Urol. 2002 Aug;42(2):139-46. link to original article contains verified protocol PubMed

Triptorelin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Heyns et al. 2003	NR	Phase III (E-RT-switch-ic)	Leuprolide	Seems to have superior 9-month OS (*)

Note: survival was a secondary endpoint.

Hormonotherapy

• Triptorelin (Trelstar LA) 3.75 mg IM once on day 1

28-day cycle for 9 cycles

References

1. Heyns CF, Simonin MP, Grosgurin P, Schall R, Porchet HC; South African Triptorelin Study Group. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003 Aug;92(3):226-31. link to original article contains verified protocol PubMed

Metastatic disease, second-line hormonal therapy

Abiraterone monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR, PSA RR	Comparator ORR, PSA RR	Pt Population
de Bono et al. 2011 (COU-AA-301)	2008-2009	Phase III (E-RT-esc)	Prednisone	Superior OS	14% (95% CI n/a), 29%	3% (95% CI n/a), 6%	Chemo-exposed
Ryan et al. 2013 (COU-AA-302)	2009-2010	Phase III (E-RT-esc)	Prednisone	Seems to have superior OS	36% (95% CI n/a), 62%	16% (95% CI n/a), 24%	Chemo-naive
Ye et al. 2017 (ABI-PRO-3002)	2012-2013	Phase III (E-esc)	Prednisone	Superior TTPP			Chemo-naive
Attard et al. 2018 (PLATO)	2013-NR	Phase III (C)	Abiraterone, Enzalutamide, Prednisone	Did not meet primary endpoint of PFS			Chemo-naive
Smith et al. 2019 (ERA 223)	2014-2016	Phase III (C)	Abiraterone, Radium-223, Prednisone	Did not meet primary endpoint of symptomatic skeletal EFS			Chemo-naive

Preceding treatment

• PLATO: Enzalutamide, with rising PSA

Hormonotherapy

• Abiraterone (Zytiga) 1000 mg PO once per day, 1 hour before or 2 hours after meals

Supportive medications

• Prednisone (Sterapred) 5 mg PO twice per day

Continued indefinitely

References

1. COU-AA-301: de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. link to original article contains verified protocol PubMed
   2. Update: Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. link to original article contains verified protocol PubMed
2. COU-AA-302: Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. link to original article PubMed
3. ABI-PRO-3002: Ye D, Huang Y, Zhou F, Xie K, Matveev V, Li C, Alexeev B, Tian Y, Qiu M, Li H, Zhou T, De Porre P, Yu M, Naini V, Liang H, Wu Z, Sun Y. A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol. 2017 Apr;4(2):75-85. Epub 2017 Jan 23. link to original article link to PMC article contains verified protocol PubMed NCT01591122
4. PLATO: Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. link to original article contains verified protocol PubMed NCT01995513
5. ERA 223: Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nolè F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):408-419. Epub 2019 Feb 6. link to original article contains protocol PubMed NCT02043678
6. PROfound: de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. link to original article contains verified protocol link to supplementary appendix PubMed NCT02987543

Antiandrogen withdrawal

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Small et al. 2004 (CALGB 9583)	NR	Phase III (C)	Ketoconazole & Hydrocortisone	Inferior PSA response

Refers to cessation of antiandrogen therapy.

References

1. CALGB 9583: Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. link to original article contains verified protocol PubMed

Apalutamide monotherapy

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Regimen

Study	Evidence
Rathkopf et al. 2017 (ARN-509-001)	Non-randomized

Hormonotherapy

• Apalutamide (Erleada) 240 mg PO once per day

Continued indefinitely

References

1. ARN-509-001: Rathkopf DE, Antonarakis ES, Shore ND, Tutrone RF, Alumkal JJ, Ryan CJ, Saleh M, Hauke RJ, Bandekar R, Maneval EC, de Boer CJ, Yu MK, Scher HI. Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res. 2017 Jul 15;23(14):3544-3551. Epub 2017 Feb 17. link to original article link to PMC article PubMed

Bicalutamide monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR, PSA RR	Comparator ORR, PSA RR	Pt Population
Penson et al. 2016 (STRIVE)	2012-2014	Randomized Phase II (C)	Enzalutamide	Inferior PFS	pts w/ measurable disease: 14% (95% CI n/a), 31% (95% CI n/a)	pts w/ measurable disease: 60% (95% CI n/a), 81% (95% CI n/a)	Chemo-naive, abi and keto-naive

Patients continued ADT while on study; details not provided.

Hormonotherapy

• Bicalutamide (Casodex) 50 mg PO once per day

Continued indefinitely

References

1. STRIVE: Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. link to original article contains protocol PubMed NCT01664923

Enzalutamide monotherapy

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Regimen variant #1, 160 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Efficacy, PSA RR	Comparator ORR, PSA RR	Pt Population
Scher et al. 2012 (AFFIRM)	2009-2010	Phase III (E-RT-esc)	Placebo	Superior OS	29% (95% CI n/a), 54%	4% (95% CI n/a), 2%	Chemo-exposed (docetaxel)
Beer et al. 2014 (PREVAIL)	2010-2012	Phase III (E-RT-esc)	Placebo	Superior OS	59% (95% CI n/a), 78%	5% (95% CI n/a), 3%	Chemo and abiraterone naive
Shore et al. 2016 (TERRAIN)	2011-2013	Randomized Phase II (E-RT-switch-ic)	Bicalutamide	Superior PFS
Penson et al. 2016 (STRIVE)	2012-2014	Randomized Phase II (E-switch-ic)	Bicalutamide	Superior PFS	60% (95% CI n/a), 81%	14% (95% CI n/a), 31%	Chemo and bicalutamide naive
Attard et al. 2018 (PLATO)	2013-NR	Non-randomized portion of RCT					Chemo-naive

Patients in STRIVE & PLATO continued ADT while on study or had a history of bilateral orchiectomy; details not provided.

Hormonotherapy

• Enzalutamide (Xtandi) 160 mg PO once per day

Continued indefinitely

Subsequent treatment

• PLATO, with rising PSA: Abiraterone versus Abiraterone & Enzalutamide

Regimen variant #2, 240 mg/day

Study	Evidence
Scher et al. 2010 (S-3100-1-01)	Phase I/II

Note: this is the reported MTD from the phase I portion of the trial; however, it is NOT the dose used in subsequent phase III studies.

Hormonotherapy

• Enzalutamide (Xtandi) 240 mg PO once per day

Continued indefinitely

References

1. S-3100-1-01: Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL; Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010 Apr 24;375(9724):1437-46. Epub 2010 Apr 14. link to original article link to PMC article contains protocol PubMed
2. AFFIRM: Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97. Epub 2012 Aug 15. link to original article contains verified protocol PubMed
3. PREVAIL: Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. Epub 2014 Jun 1. link to original article link to PMC article PubMed
   1. Update: Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, Iversen P, Evans CP, Kim CS, Kimura G, Miller K, Saad F, Bjartell AS, Borre M, Mulders P, Tammela TL, Parli T, Sari S, van Os S, Theeuwes A, Tombal B. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: Extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017 Feb;71(2):151-154. Epub 2016 Jul 28. link to original article link to PMC article PubMed
   2. HRQoL analysis: Devlin N, Herdman M, Pavesi M, Phung D, Naidoo S, Beer TM, Tombal B, Loriot Y, Ivanescu C, Parli T, Balk M, Holmstrom S. Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. Health Qual Life Outcomes. 2017 Jun 23;15(1):130. link to original article link to PMC article PubMed
4. TERRAIN: Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-163. Epub 2016 Jan 14. link to original article PubMed
5. STRIVE: Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. link to original article contains protocol PubMed NCT01664923
6. PLATO: Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. link to original article contains verified protocol PubMed NCT01995513
7. PROfound: de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. link to original article contains verified protocol link to supplementary appendix PubMed NCT02987543

Hydrocortisone monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantoff et al. 1999 (CALGB 9182)	1992-1995	Phase III (C)	Mitoxantrone & Hydrocortisone	Did not meet primary endpoint of OS
Small et al. 2000	1994-1996	Phase III (C)	Suramin & Hydrocortisone	Inferior TTP
Abratt et al. 2004	1997-2001	Phase III (C)	Vinorelbine & Hydrocortisone	Might have inferior PFS

Hormonotherapy

• Hydrocortisone (Cortef) 40 mg/day PO

Continued indefinitely

References

1. CALGB 9182: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. link to original article PubMed
2. Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, Lenehan PF, Chen L, Slichenmyer WJ, Eisenberger M. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol. 2000 Apr;18(7):1440-50. link to original article PubMed
3. Abratt RP, Brune D, Dimopoulos MA, Kliment J, Breza J, Selvaggi FP, Beuzeboc P, Demkow T, Oudard S. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol. 2004 Nov;15(11):1613-21. link to original article PubMed

Ketoconazole & Hydrocortisone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR, PSA RR	Comparator ORR, PSA RR	Pt Population
Trachtenberg & Pont 1984	NR	Pilot
Small et al. 2004 (CALGB 9583)	NR	Phase III (E-esc)	Antiandrogen withdrawal	Superior PSA response	pts w/ measurable disease: 20% (95% CI 11 - 32), 27% (95% CI 20 - 35)	pts w/ measurable disease: 2% (95% CI 0 - 11), 11% (95% CI 7 - 17)	Progression at ADT, i.e. CRPC

Hormonotherapy

• Ketoconazole (Nizoral) 400 mg PO three times per day
• Hydrocortisone (Cortef) 30 mg PO QAM and 10 mg PO QPM

Continued indefinitely

References

1. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet. 1984 Aug 25;2(8400):433-5. link to original article PubMed
2. CALGB 9583: Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. link to original article contains verified protocol PubMed

Ketoconazole, Hydrocortisone, Dutasteride

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Regimen

Study	Evidence
Taplin et al. 2009	Phase II

Hormonotherapy

• Ketoconazole (Nizoral) 400 mg PO three times per day
• Hydrocortisone (Cortef) 30 mg PO QAM and 10 mg PO QPM
• Dutasteride (Avodart) 0.5 mg PO once per day

Continued indefinitely

References

1. Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L, Beer TM, Ryan CW, Mathew P, Tu SM, Denmeade SR, Oh WK, Sartor O, Mantzoros CS, Rittmaster R, Kantoff PW, Balk SP. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res. 2009 Nov 15;15(22):7099-105. Epub 2009 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Prednisone monotherapy

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Regimen variant #1, 5 mg twice per day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tannock et al. 1989	1976-1980	Retrospective
Tannock et al. 1996 (CCI-NOV22)	1990-1994	Phase III (C)	Mitoxantrone & Prednisone	Inferior palliation
Berry et al. 2002	1997-1999	Phase III (C)	Mitoxantrone & Prednisone	Seems to have inferior TTTF
Sternberg et al. 2009 (SPARC)	2003-2006	Phase III (C)	Satraplatin & Prednisone	Inferior PFS
de Bono et al. 2011 (COU-AA-301)	2008-2009	Phase III (C)	Abiraterone	Inferior OS
Michaelson et al. 2013 (SUN 1120)	2008-2010	Phase III (C)	Sunitinib & Prednisone	Did not meet primary endpoint of OS
Ryan et al. 2013 (COU-AA-302)	2009-2010	Phase III (C)	Abiraterone	Seems to have inferior OS
Saad et al. 2015 (ELM-PC 4)	2010-2012	Phase III (C)	Orteronel & Prednisone	Inferior PFS
Fizazi et al. 2015 (ELM-PC 5)	2010-NR	Phase III (C)	Orteronel & Prednisone	Did not meet primary endpoint of OS
Smith et al. 2016 (COMET-1)	2012-2014	Phase III (C)	Cabozantinib	Did not meet primary endpoint of OS

Hormonotherapy

• Prednisone (Sterapred) 5 mg PO twice per day

Continued indefinitely

Regimen variant #2, 5 mg QID

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fosså et al. 2001 (EORTC 30903)	1992-1998	Phase III (C)	Flutamide	Did not meet primary endpoints of TTP/OS

Hormonotherapy

• Prednisone (Sterapred) 5 mg PO four times per day

Continued indefinitely

References

1. Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol. 1989 May;7(5):590-7. link to original article PubMed
2. CCI-NOV22: Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. link to original article contains verified protocol PubMed
   1. HRQoL analysis: Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. link to original article PubMed
3. EORTC 30903: Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. link to original article contains protocol PubMed
4. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. link to original article contains protocol PubMed
5. SPARC: Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabrò F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009 Nov 10;27(32):5431-8. Epub 2009 Oct 5. link to original article contains protocol PubMed NCT00069745
6. COU-AA-301: de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. link to original article contains verified protocol PubMed
   2. Update: Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. link to original article contains verified protocol PubMed
7. COU-AA-302: Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. link to original article PubMed
8. SUN 1120: Michaelson MD, Oudard S, Ou YC, Sengeløv L, Saad F, Houede N, Ostler P, Stenzl A, Daugaard G, Jones R, Laestadius F, Ullèn A, Bahl A, Castellano D, Gschwend J, Maurina T, Chow Maneval E, Wang SL, Lechuga MJ, Paolini J, Chen I. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol. 2014 Jan 10;32(2):76-82. Epub 2013 Dec 9. link to original article contains protocol PubMed NCT00676650
9. ELM-PC 5: Fizazi K, Jones R, Oudard S, Efstathiou E, Saad F, de Wit R, De Bono J, Cruz FM, Fountzilas G, Ulys A, Carcano F, Agarwal N, Agus D, Bellmunt J, Petrylak DP, Lee SY, Webb IJ, Tejura B, Borgstein N, Dreicer R. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. 2015 Mar 1;33(7):723-31. Epub 2015 Jan 26. link to original article link to PMC article contains protocol PubMed NCT01193257
10. ELM-PC 4: Saad F, Fizazi K, Jinga V, Efstathiou E, Fong PC, Hart LL, Jones R, McDermott R, Wirth M, Suzuki K, MacLean DB, Wang L, Akaza H, Nelson J, Scher HI, Dreicer R, Webb IJ, de Wit R; ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 2015 Mar;16(3):338-48. Epub 2015 Feb 18. link to original article contains protocol PubMed NCT01193244
11. COMET-1: Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. link to original article contains verified protocol PubMed NCT01605227

Chemotherapy for metastatic castrate-sensitive disease

Cabazitaxel & Prednisone

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Example orders

• Example orders for Cabazitaxel (Jevtana) in prostate cancer

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
de Wit et al. 2019 (CARD)	2015-2018	Phase III (E-switch-ooc)	1. Abiraterone 2. Enzalutamide	Superior OS

Note: patients in CARD had already received and progressed on the alternate androgen signaling targeted inhibitor.

Chemotherapy

• Cabazitaxel (Jevtana) 25 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• Prednisone (Sterapred) 10 mg PO once per day

Supportive medications

• Antihistamine once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)
• Corticosteroid (dexamethasone 8 mg or equivalent) once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)
• Histamine H2-antagonist (except cimetidine) once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)

21-day cycles

References

1. CARD: de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. Epub 2019 Sep 30. link to original article contains verified protocol PubMed

Chemotherapy for metastatic castrate-resistant disease

Cabazitaxel & Prednisone

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Example orders

• Example orders for Cabazitaxel (Jevtana) in prostate cancer

Regimen variant #1, 20/10, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Oudard et al. 2017 (FIRSTANA)	2011-2013	Phase III (E-switch-ic)	Cabazitaxel & Prednisone; 25/10	Did not meet primary endpoint of OS
			Docetaxel & Prednisone	Did not meet primary endpoint of OS
Eisenberger et al. 2017 (PROSELICA)	2011-2013	Phase III (E-RT-de-esc)	Cabazitaxel & Prednisone; 25/10	Non-inferior OS

Chemotherapy

• Cabazitaxel (Jevtana) 20 mg/m² IV once on day 1

Hormonotherapy

• Prednisone (Sterapred) 10 mg PO once per day

21-day cycles

Regimen variant #2, 25/10 x 10

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR, PSA RR	Comparator ORR, PSA RR	Pt Population
de Bono et al. 2010 (TROPIC)	2007-2008	Phase III (E-RT-switch-ic)	Mitoxantrone & Prednisone	Superior OS	14% (95% CI 10-19) 39% (95% CI 34-44) (*)	4% (95% CI 2-7) 18% (95% CI 14-22) (*)	Progressed on docetaxel
Beer et al. 2017 (AFFINITY)	2012-2014	Phase III (C)	Cabazitaxel, Prednisone, Custirsen	Did not meet primary endpoint of OS			Progressed on docetaxel

Note: ORRs in TROPIC were only reported for patients with measurable disease.

Chemotherapy

• Cabazitaxel (Jevtana) 25 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• Prednisone (Sterapred) 10 mg PO once per day

Supportive medications

• Antihistamine once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)
• Corticosteroid (dexamethasone 8 mg or equivalent) once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)
• Histamine H2-antagonist (except cimetidine) once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)

21-day cycle for up to 10 cycles

Regimen variant #3, 25/10, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Oudard et al. 2017 (FIRSTANA)	2011-2013	Phase III (E-switch-ic)	Cabazitaxel & Prednisone; 20/10	Did not meet primary endpoint of OS
			Docetaxel & Prednisone	Did not meet primary endpoint of OS
Eisenberger et al. 2017 (PROSELICA)	2011-2013	Phase III (C)	Cabazitaxel & Prednisone; 20/10	Non-inferior OS

Chemotherapy

• Cabazitaxel (Jevtana) 25 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• Prednisone (Sterapred) 10 mg PO once per day

Supportive medications

• Antihistamine once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)
• Corticosteroid (dexamethasone 8 mg or equivalent) once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)
• Histamine H2-antagonist (except cimetidine) once on day 1, at least 30 minutes prior to Cabazitaxel (Jevtana)

21-day cycles

References

1. TROPIC: de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. link to original article contains verified protocol PubMed NCT00417079
2. FIRSTANA: Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. link to original article contains verified protocol PubMed NCT01308567
3. PROSELICA: Eisenberger M, Hardy-Bessard AC, Kim CS, Géczi L, Ford D, Mourey L, Carles J, Parente P, Font A, Kacso G, Chadjaa M, Zhang W, Bernard J, de Bono J. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m(2)) and the currently approved dose (25 mg/m(2)) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol. 2017 Oct 1;35(28):3198-3206. Epub 2017 Aug 15 link to original article contains verified protocol in supplement PubMed
4. AFFINITY: Beer TM, Hotte SJ, Saad F, Alekseev B, Matveev V, Fléchon A, Gravis G, Joly F, Chi KN, Malik Z, Blumenstein B, Stewart PS, Jacobs CA, Fizazi K. Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1532-1542. Epub 2017 Oct 9. link to original article PubMed NCT01578655

Cabozantinib monotherapy

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Regimen variant #1, 60 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Smith et al. 2016 (COMET-1)	2012-2014	Phase III (E-switch-ooc)	Prednisone	Did not meet primary endpoint of OS

Targeted therapy

• Cabozantinib (Cometriq) 60 mg PO once per day

Regimen variant #2, 100 mg/day

Study	Evidence
Smith et al. 2012	Phase II

Targeted therapy

• Cabozantinib (Cometriq) 100 mg PO once per day

Continued indefinitely

References

1. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schöffski P, Scheffold C, Weitzman AL, Hussain M. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013 Feb 1;31(4):412-9. Epub 2012 Nov 19. link to original article contains verified protocol link to PMC article PubMed
2. COMET-1: Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. link to original article contains verified protocol PubMed NCT01605227

Carboplatin & Docetaxel

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Example orders

• Example orders for Docetaxel & Carboplatin in prostate cancer

Regimen

Study	Evidence
Ross et al. 2008	Phase II

Patients enrolled in the trial had hormone-refractory prostate cancer and progression of disease during docetaxel treatment or within 45 days of stopping docetaxel treatment.

Chemotherapy

• Carboplatin (Paraplatin) AUC 4 (Calvert formula) IV over 60 minutes once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1, given first

Supportive medications

• "Standard dexamethasone premedication was used"
• Patients continued to receive androgen deprivation therapy

21-day cycles

References

1. Ross RW, Beer TM, Jacobus S, Bubley GJ, Taplin ME, Ryan CW, Huang J, Oh WK; Prostate Cancer Clinical Trials Consortium. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel. Cancer. 2008 Feb 1;112(3):521-6. link to original article contains verified protocol PubMed
2. Retrospective: Nakabayashi M, Sartor O, Jacobus S, Regan MM, McKearn D, Ross RW, Kantoff PW, Taplin ME, Oh WK. Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int. 2008 Feb;101(3):308-12. link to original article PubMed

Carboplatin, Docetaxel, Prednisone

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Regimen

Study	Evidence
Reuter et al. 2010	Phase II

Patients enrolled in the trial had progression of disease on docetaxel chemotherapy and castration-resistant disease.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1
• Docetaxel (Taxotere) 35 mg/m² IV over 60 minutes once per day on days 1, 8, 15
  • Note: In contrast to its abstract, Reuter et al. 2010 sometimes used "days 1, 8, (15)" to describe when docetaxel was given. The paper did not specifically say what "(15)" meant, such as whether this meant that the day 15 dose was optional.

Hormonotherapy

• Prednisone (Sterapred) 5 mg PO twice per day

Supportive medications

• "Standard dexamethasone premedication was used"
• Patients continued to receive LHRH (luteinizing hormone releasing hormone) agonists
• No routine use of granulocyte colony-stimulating factor (G-CSF)

28-day cycles

References

1. Reuter CW, Morgan MA, Ivanyi P, Fenner M, Ganser A, Grünwald V. Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. World J Urol. 2010 Jun;28(3):391-8. Epub 2010 Mar 14. link to original article contains verified protocol PubMed

Carboplatin & Paclitaxel

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Regimen variant #1

Study	Evidence
Kentepozidis et al. 2012	Phase II

Chemotherapy

• Carboplatin (Paraplatin) AUC 3 (Calvert formula) IV once per day on days 1 & 15, given second
• Paclitaxel (Taxol) 135 mg/m² IV over 60 minutes once per day on days 1 & 15, given first

Supportive medications

• "All patients received a concomitant anti-emetic prophylaxis"
• Dexamethasone (Decadron) 20 mg PO given twice, 12 and 6 hours prior to Paclitaxel (Taxol)
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of Paclitaxel (Taxol))
• Cimetidine (Tagamet) 300 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of Paclitaxel (Taxol))
• No prophylactic G-CSF

28-day cycles

Regimen variant #2

Study	Evidence
Jeske et al. 2010	Retrospective

Chemotherapy

• Carboplatin (Paraplatin) AUC 4 to 6 IV once on day 1
• Paclitaxel (Taxol) 60 to 80 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. Retrospective: Jeske S, Tagawa ST, Olowokure O, Selzer J, Giannakakou P, Nanus DM. Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer. Urol Oncol. 2011 Nov-Dec;29(6):676-81. Epub 2010 May 7. link to original article contains verified protocol PubMed
2. Kentepozidis N, Soultati A, Giassas S, Vardakis N, Kalykaki A, Kotsakis A, Papadimitraki E, Pantazopoulos N, Bozionellou V, Georgoulias V; Hellenic Oncology Research Group. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic Oncology Research Group multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jul;70(1):161-8. Epub 2012 Jun 3. link to original article contains verified protocol PubMed

Cyclophosphamide, Prednisone, Diethylstilbestrol

CPD: Cyclophosphamide, Prednisone, Diethylstilbestrol

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Regimen

Study	Evidence	Efficacy
Hellerstedt et al. 2003	Phase II	50% or greater decline in PSA: 42%

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg PO once per day on days 1 to 20

Hormonotherapy

• Prednisone (Sterapred) 10 mg PO once per day
• Diethylstilbestrol (DES) 1 mg PO once per day

Supportive medications

• Warfarin (Coumadin) 1 mg PO once per day to decrease risk of DVT

30-day cycles

References

1. Hellerstedt B, Pienta KJ, Redman BG, Esper P, Dunn R, Fardig J, Olson K, Smith DC. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer. 2003 Oct 15;98(8):1603-10. link to original article contains verified protocol PubMed

Docetaxel & Estramustine

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Petrylak et al. 2004 (SWOG S9916)	1999-2003	Phase III (E-switch-ic)	Mitoxantrone & Prednisone	Seems to have superior OS

Chemotherapy

• Docetaxel (Taxotere)

Hormonotherapy

• Estramustine (Emcyt)

References

1. SWOG S9916: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. link to original article PubMed

Docetaxel & Prednisone

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Example orders

• Example orders for Docetaxel (Taxotere) in prostate cancer

Regimen variant #1, 30 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tannock et al. 2004 (TAX 327)	2000-2002	Phase III (E-RT-switch-ic)	1. Docetaxel & Prednisone; q3wk	Not reported
			2. Mitoxantrone & Prednisone	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 30 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29

Hormonotherapy

• Prednisone (Sterapred) 5 mg PO twice per day

Supportive medications

• Dexamethasone (Decadron) 8 mg (route not specified) once 1 hour before Docetaxel (Taxotere)
• Antiemetics "according to local practice"

42-day cycle for up to 5 cycles

Regimen variant #2, 75 mg/m² q3wk x 10

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR, PSA RR	Comparator ORR, PSA RR	Pt Population
Tannock et al. 2004 (TAX 327)	2000-2002	Phase III (E-RT-switch-ic)	1. Docetaxel & Prednisone; weekly	Not reported	pts w/ measurable disease:12% (95% CI, 7-19), 45% (95% CI, 40-51)	pts w/ measurable disease:8% (95% CI, 4-14), 48% (95% CI, 42-54)	Chemo-naive
			2. Mitoxantrone & Prednisone	Superior OS		pts w/ measurable disease:7% (95% CI, 3-12), 32% (95% CI, 26-37)	Chemo-naive
Beer et al. 2011 (ASCENT)	2002-2004	Phase III (C)	Calcitriol, Docetaxel, Prednisone	Superior OS (*)
Meulenbeld et al. 2012 (NePro)	2004-2010	Phase II/III (C)	Docetaxel, Prednisone, Risedronate	Did not meet primary endpoint of TTP

Note: reported efficacy for ASCENT is based on the 2011 update.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• Prednisone (Sterapred) 5 mg PO twice per day

Supportive medications

• Dexamethasone (Decadron) 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before Docetaxel (Taxotere)
• Antiemetics "according to local practice"

21-day cycle for up to 10 cycles

Regimen variant #3, 75 mg/m² q3wk x 12

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Quinn et al. 2013 (SWOG S0421)	2006-2010	Phase III (C)	Atrasentan, Docetaxel, Prednisone	Did not meet primary endpoints of PFS/OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• Prednisone (Sterapred) 5 mg PO twice per day

Supportive medications

• Dexamethasone (Decadron) 8 mg PO given three times; 12 hours, 3 hours, and 1 hour before Docetaxel (Taxotere)
• Antiemetics "according to local practice"

21-day cycle for up to 12 cycles

Regimen variant #4, 75 mg/m² q3wk, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kelly et al. 2012 (CALGB 90401)	2005-2007	Phase III (C)	Docetaxel, Prednisone, Bevacizumab	Did not meet primary endpoint of OS
Tannock et al. 2013 (VENICE)	2007-2010	Phase III (C)	Aflibercept, Docetaxel, Prednisone	Did not meet primary endpoint of OS
Araujo et al. 2013 (READY)	2008-2011	Phase III (C)	Dasatinib, Docetaxel, Prednisone	Did not meet primary endpoint of OS
Fizazi et al. 2013 (ENTHUSE)	2008-NR	Phase III (C)	Docetaxel, Prednisone, Zibotentan	Did not meet primary endpoint of OS
Petrylak et al. 2015 (MAINSAIL)	2009-2011	Phase III (C)	Docetaxel, Lenalidomide, Prednisone	Superior OS
Chi et al. 2017 (SYNERGY)	2010-2012	Phase III (C)	Custirsen, Docetaxel, Prednisone	Did not meet primary endpoint of OS
Oudard et al. 2017 (FIRSTANA)	2011-2013	Phase III (C)	Cabazitaxel 20 mg/m2 & Prednisone	Did not meet primary endpoint of OS
			Cabazitaxel 25 mg/m2 & Prednisone	Did not meet primary endpoint of OS

Note: patients in CALGB 90401 discontinued treatment after a maximum of 2 years.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Hormonotherapy

• Prednisone (Sterapred) as follows:
  • CALGB 90401: 5 mg PO once per day
  • Others: 10 mg/day; some regimens give as 5 mg PO twice per day, some as 10 mg PO once per day

21-day cycles

References

1. TAX 327: Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. link to original article contains verified protocol PubMed
   1. Update: Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. link to original article contains verified protocol PubMed
2. ASCENT: Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM, Carducci MA, Vicario D, Dreicer R, Higano CS, Ahmann FR, Chi KN, Henner WD, Arroyo A, Clow FW; ASCENT Investigators. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007 Feb 20;25(6):669-74. link to original article PubMed
   1. Update: Scher HI, Jia X, Chi K, de Wit R, Berry WR, Albers P, Henick B, Waterhouse D, Ruether DJ, Rosen PJ, Meluch AA, Nordquist LT, Venner PM, Heidenreich A, Chu L, Heller G. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011 Jun 1;29(16):2191-8. Epub 2011 Apr 11. link to original article PubMed
3. CALGB 90401: Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012 May 1;30(13):1534-40. Epub 2012 Mar 26. link to original article contains verified protocol link to PMC article PubMed NCT00110214
4. NePro: Meulenbeld HJ, van Werkhoven ED, Coenen JL, Creemers GJ, Loosveld OJ, de Jong PC, Ten Tije AJ, Fosså SD, Polee M, Gerritsen W, Dalesio O, de Wit R. Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). Eur J Cancer. 2012 Nov;48(16):2993-3000. Epub 2012 Jun 6. link to original article contains verified protocol PubMed
5. VENICE: Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Arén O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013 Jul;14(8):760-8. Epub 2013 Jun 4.link to original article contains protocol PubMed NCT00519285
6. SWOG S0421: Quinn DI, Tangen CM, Hussain M, Lara PN Jr, Goldkorn A, Moinpour CM, Garzotto MG, Mack PC, Carducci MA, Monk JP, Twardowski PW, Van Veldhuizen PJ, Agarwal N, Higano CS, Vogelzang NJ, Thompson IM Jr. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013 Aug;14(9):893-900. Epub 2013 Jul 17. link to original article link to PMC article contains verified protocol PubMed
7. READY: Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, Efstathiou E, Oudard S, Morris MJ, Sizer B, Goebell PJ, Heidenreich A, de Bono JS, Begbie S, Hong JH, Richardet E, Gallardo E, Paliwal P, Durham S, Cheng S, Logothetis CJ. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1307-16. Epub 2013 Nov 8. link to original article contains protocol link to PMC article PubMed NCT00744497
8. MAINSAIL: Petrylak DP, Vogelzang NJ, Budnik N, Wiechno PJ, Sternberg CN, Doner K, Bellmunt J, Burke JM, de Olza MO, Choudhury A, Gschwend JE, Kopyltsov E, Flechon A, Van As N, Houede N, Barton D, Fandi A, Jungnelius U, Li S, de Wit R, Fizazi K. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2015 Apr;16(4):417-25. Epub 2015 Mar 3.link to original article contains protocol PubMed NCT00988208
9. SYNERGY: Chi KN, Higano CS, Blumenstein B, Ferrero JM, Reeves J, Feyerabend S, Gravis G, Merseburger AS, Stenzl A, Bergman AM, Mukherjee SD, Zalewski P, Saad F, Jacobs C, Gleave M, de Bono JS. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2017 Apr;18(4):473-485. Epub 2017 Mar 8. link to original article contains protocol PubMed NCT01188187
10. FIRSTANA: Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. link to original article contains verified protocol PubMed NCT01308567

Docetaxel & Prednisolone

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Example orders

• Example orders for Docetaxel (Taxotere) in prostate cancer

Regimen variant #1, 50 mg/m² bi-weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY)	2004-2009	Phase III (E-switch-ic)	Docetaxel & Prednisolone; q3wk	Seems to have superior TTTF

Chemotherapy

• Docetaxel (Taxotere) 50 mg/m² IV over 60 minutes once per day on days 1 & 15

Hormonotherapy

• Prednisolone (Millipred) 10 mg PO once per day

Supportive medications

• Dexamethasone (Decadron) 7.5 to 8 mg (route not specified) once per day, started 1 day before Docetaxel (Taxotere) and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3)
• G-CSF not recommended unless patients developed febrile neutropenia or severe infection
• "Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"

28-day cycles

Regimen variant #2, 75 mg/m² q3wk, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY)	2004-2009	Phase III (C)	Docetaxel & Prednisolone; q2wk	Seems to have inferior TTTF
Fizazi et al. 2013 (ENTHUSE)	2008-NR	Phase III (C)	Docetaxel, Zibotentan, Prednisolone	Did not meet primary endpoint of OS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Hormonotherapy

• Prednisolone (Millipred) 10 mg PO once per day
  • Fizazi et al. 2013: Given as 5 mg PO twice per day

Supportive medications

• Dexamethasone (Decadron) 7.5 to 8 mg daily, started 1 day before Docetaxel (Taxotere) and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3); reference did not specify route of administration
• G-CSF not recommended unless patients developed febrile neutropenia or severe infection
• "Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"

21-day cycles

References

1. PROSTY: Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, McDermott R, Hervonen P, Ginman C, Luukkaa M, Nyandoto P, Hemminki A, Nilsson S, McCaffrey J, Asola R, Turpeenniemi-Hujanen T, Laestadius F, Tasmuth T, Sandberg K, Keane M, Lehtinen I, Luukkaala T, Joensuu H; PROSTY study group. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):117-24. Epub 2013 Jan 4. link to original article contains verified protocol PubMed NCT00255606
2. ENTHUSE: Fizazi K, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, Nathan FE, McIntosh S, Pemberton K, Moul JW. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013 May 10;31(14):1740-7. Epub 2013 Apr 8. Erratum in: J Clin Oncol. 2014 Oct 20;32(30):3461. Fizazi, Karim S [Corrected to Fizazi, Karim]. link to original article contains verified protocol PubMed NCT00617669

Mitoxantrone & Hydrocortisone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantoff et al. 1999 (CALGB 9182)	1992-1995	Phase III (E-RT-esc)	Hydrocortisone	Did not meet primary endpoint of OS

Chemotherapy

• Mitoxantrone (Novantrone)

Hormonotherapy

• Hydrocortisone (Cortef)

References

1. CALGB 9182: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. link to original article PubMed

Mitoxantrone & Prednisone

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Example orders

• Example orders for Mitoxantrone (Novantrone) in prostate cancer

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR, PSA RR	Comparator ORR, PSA RR	Pt Population
Moore et al. 1994	NR	Phase II (RT)
Tannock et al. 1996 (CCI-NOV22)	1990-1994	Phase III (E-RT-esc)	Prednisone	Superior palliation
Berry et al. 2002	1997-1999	Phase III (E-esc)	Prednisone	Seems to have superior TTTF
Petrylak et al. 2004 (SWOG S9916)	1999-2003	Phase III (C)	Docetaxel & Estramustine	Seems to have inferior OS
Tannock et al. 2004 (TAX 327)	2000-2002	Phase III (C)	1. Weekly Docetaxel & Prednisone	Did not meet primary endpoint of OS	pts w/ measurable disease: 7% (95% CI 3-12), 32% (95% CI 26-37)	pts w/ measurable disease: 8% (95% CI 4-14), 48% (95% CI 42-54)	Chemo naive
			2. Every 3-week Docetaxel & Prednisone	Inferior OS		pts w/ measurable disease: 12% (95% CI 7-19), 45% (95% CI 40-51)	Chemo naive
de Bono et al. 2010 (TROPIC)	2007-2008	Phase III (C)	Cabazitaxel & Prednisone	Inferior OS	pts w/ measurable disease: 4.4% (95% CI 1.6 - 7.2), 17.8% (95% CI 13.7 - 22.0)	pts w/ measurable disease: 14.4% (95% CI 9.6 - 19.3), 39.2% (95% CI 33.9 - 44.5)	Progressed on docetaxel

Chemotherapy

• Mitoxantrone (Novantrone) 12 mg/m² IV over 15 to 30 minutes once on day 1

Hormonotherapy

• Prednisone (Sterapred) 10 mg PO once per day on days 1 to 21
  • Some protocols give 5 mg PO twice per day

21-day cycle for up to 10 cycles

References

1. Moore MJ, Osoba D, Murphy K, Tannock IF, Armitage A, Findlay B, Coppin C, Neville A, Venner P, Wilson J. Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol. 1994 Apr;12(4):689-94. link to original article PubMed
2. CCI-NOV22: Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. link to original article PubMed
   1. HRQoL analysis: Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. link to original article PubMed
3. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. link to original article contains protocol PubMed
4. TAX 327: Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. link to original article contains verified protocol PubMed
   1. Update: Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. link to original article contains verified protocol PubMed
5. SWOG S9916: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. link to original article PubMed
6. TROPIC: de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. link to original article contains verified protocol PubMed NCT00417079

Olaparib monotherapy

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Regimen Variant #1, 300 mg BID

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Efficacy, PFS	Comparator ORR, PFS	Pt Population
de Bono et al. 2020 (PROfound)	2017-2018	Phase III (E-RT-ooc)	1. Abiraterone 2. Enzalutamide	Superior PFS	7.4 months (95% CI 0.25 to 0.47, p<0.001)	3.6 months	Progressed on abiraterone or enzalutamide, at least one alteration in BRCA1, BRCA2, or ATM

Biomarker eligibility criteria

• Cohort A: 1+ alterations in BRCA1, BRCA2, or ATM
• Cohort B: 1+ alterations in BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L

Targeted therapy

• Olaparib (Lynparza) 300 mg PO twice per day

Continued indefinitely

Regimen Variant #2, 400 mg BID

Study	Evidence
Kaufman et al. 2014 (Study 42)	Phase II, <20 pts in subgroup
Mateo et al. 2015 (TOPARP-A)	Phase II

• Patients in Study 42 had germline BRCA1/2 mutations and had progression on hormonal and one systemic therapy.
• Patients in Mateo et al. 2015 (TOPARP-A) who were found to have homozygous deletions, deleterious mutations, or both in DNA-repair genes were much more likely to respond to olaparib.

Targeted therapy

• Olaparib (Lynparza) 400 mg PO twice per day

Continued indefinitely

References

1. Study 42: Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. link to original article contains verified protocol PubMed
2. TOPARP-A: Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. link to original article contains verified protocol link to PMC article PubMed
3. PROfound: de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. Epub 2020 Apr 28. link to original article contains verified protocol link to supplementary appendix PubMed NCT02987543

Immunotherapy for metastatic castrate-resistant disease

Ipilimumab & RT

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Ipilimumab & RT: Ipilimumab & Radiation Therapy

Regimen

Study	Evidence	Efficacy	Patient population
Slovin et al. 2013	Phase I/II	ORR: 4% (95% CI n/a), PSA RR: 16%;	Most had ADT, some had docetaxel use. 10 mg/kg cohort reported here.

Immunotherapy

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1
  • Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study

Radiotherapy

• Radiation therapy given focally at a single dose of 8 Gy per target bone lesion for up to three bone lesions per patient, given 24 to 48 h before the first ipilimumab dose

21-day cycle for 4 cycles

References

1. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB, Beer TM. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013 Jul;24(7):1813-21. link to original article contains verified protocol link to PMC article PubMed NCT00323882

Sipuleucel-T monotherapy

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Example orders

• Example orders for Sipuleucel-T (Provenge) in prostate cancer

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Small et al. 2006 (D9901)	2000-2001	Phase III (E-RT-esc)	Placebo	Might have superior TTP
Higano et al. 2009 (D9902A)	2000-2003	Phase III (E-esc)	Placebo	Might have superior TTP
Kantoff et al. 2010 (IMPACTprostate)	2003-2007	Phase III (E-RT-esc)	Placebo	Seems to have superior OS

Note: Higano et al. 2009 was a pooled update but also the first publication to describe results of D9902A. IMPACT should not be confused with the studies of the same name in breast cancer and colorectal cancer.

Immunotherapy

• Sipuleucel-T (Provenge): leukapheresis followed 3 days later with at least 50 million autologous CD54+ cells activated with PAP-GM-CSF, to be done on weeks 0, 2, and 4

Supportive medications

• Acetaminophen (Tylenol) PO once per week on weeks 0, 2, 4; 30 minutes prior to Sipuleucel-T (Provenge)
• Antihistamine PO once per week on weeks 0, 2, 4; 30 minutes prior to Sipuleucel-T (Provenge)

One course

References

1. D9901: Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 Jul 1;24(19):3089-94. link to original article PubMed
   1. Pooled Update: Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. link to original article PubMed
2. D9902A: Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. link to original article PubMed
3. IMPACT: Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. link to original article contains verified protocol PubMed
4. Safety analysis: Hall SJ, Klotz L, Pantuck AJ, George DJ, Whitmore JB, Frohlich MW, Sims RB. Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol. 2011 Sep;186(3):877-81. Epub 2011 Jul 23. link to original article contains verified protocol PubMed

Radioactive agents for bony metastatic disease

Radium-223 monotherapy

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Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Parker et al. 2013 (ALSYMPCA)	2008-2011	Phase III (E-RT-esc)	Placebo	Superior OS	Superior EQ-5D score

Radiotherapy

• Radium-223 (Xofigo) 50 kBq/kg IV once on day 1

28-day cycle for 6 cycles

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nilsson et al. 2007	2004-2005	Randomized Phase II (E-esc)	Placebo	Might have superior OS

Patients in the study had "bone pain needing EBRT" (external beam radiation therapy). Treatment with radium 223 began within 7 days after EBRT.

Radiotherapy

• Radium-223 (Xofigo) 50 kBq/kg IV once on day 1

28-day cycle for 4 cycles

References

1. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007 Jul;8(7):587-94. link to original article contains verified protocol PubMed
   1. Update: Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O'Bryan-Tear CG, Thuresson M, Bolstad B, Bruland ØS. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013 Mar;11(1):20-6. Epub 2012 Sep 26. link to original article contains verified protocol PubMed
2. ALSYMPCA: Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. link to original article contains verified protocol PubMed
   1. Subgroup analysis: Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. Epub 2014 May 13. link to original article PubMed
   2. Subgroup analysis: Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. Epub 2014 Oct 17. link to original article PubMed
   3. HRQoL analysis: Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O'Sullivan JM, Reuning-Scherer J, Shan M, Zhan L, Parker C. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016 May;27(5):868-74. Epub 2016 Feb 23. link to original article link to PMC article PubMed

Samarium-153 monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Resche et al. 1997	NR	Phase III (E-esc)	Samarium-153; 0.5 mCi/kg	Seems to have superior pain control at week 4
Sartor et al. 2004	NR	Phase III (E-esc)	Samarium-152 (non-radioactive)	Seems to have superior pain control at week 4

Radiotherapy

• Samarium-153 (Quadramet) 1 mCi/kg IV over 1 minute once on day 1

Supportive medications

• 1000 mL of fluid IV or PO given twice, 4 hours before and 6 hours after treatment

1 dose

References

1. Resche I, Chatal JF, Pecking A, Ell P, Duchesne G, Rubens R, Fogelman I, Houston S, Fauser A, Fischer M, Wilkins D. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997 Sep;33(10):1583-91. link to original article contains verified protocol PubMed
2. Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, Coleman RE, Kotler JA, Freeman LM, Olivier P; Quadramet 424Sm10/11 Study Group. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004 May;63(5):940-5. link to original article contains verified protocol PubMed

Measuring disease progression

• Criteria used for disease progression in prostate cancer clinical trials, Prostate Cancer Clinical Trials Working Group 2 (PCWG2):
  • Castrate level of serum testosterone is less than 50 ng/dL (less than 1.7 nmol/L)
    • However, there is controversy/disagreement in other references about whether a lower level should be used, such as less than 20 ng/dL (0.7 nmol/L)
  • PSA rise
    • Starting PSA of at least 2.0 ng/mL
    • Rising PSA values which are measured at least 1-week apart
    • Pretherapy PSA doubling times (PSA-DT) can be estimated if there are at least 3 PSA values measured at least 4 weeks apart
  • Bony metastases
    • At least 2 new lesions indicates progressive disease
    • It is recommended to assess ambiguous results with other imaging modalities such as CT or MRI
  • Measurable lesions (RECIST) - this is a lower priority criteria by the PCWG2 because fewer patients have measurable lesions as compared to, for example, bony metastases
    • Baseline imaging involves chest imaging with x-ray or CT, CT or MRI of the abdomen/pelvis, and radionuclide bone scan
    • It is recommended that local disease is assessed by endorectal MRI or prostatic ultrasound
    • Neurologic symptoms should be assessed with MRI of the spine and base of the skull
    • Positron emission tomography (PET) is not recommended and is considered investigational
    • Measurable lesions should be followed with RECIST criteria
    • "Up to 10 visceral and nodal lesions in total should be recorded (with a maximum of five in any one organ)"
    • It is suggested that a lymph node must be at least 2 cm in maximal dimension on spiral CT to count as a target lesion.

Statistics

• Four-Year Actuarial Progression-Free Probability (PFP) After Salvage Radiotherapy based on Gleason score, PSA, positive margins, etc. (flowchart is in Figure 2)
• SEER Stat Fact Sheets: Prostate Cancer
• CDC Prostate Cancer Statistics
• Cancer.Net Prostate Cancer Statistics

Links

• Decipher, GenomeDx's genomic prognostic prostate cancer assay
  • "the Decipher Test uses the expression of these biomarkers to calculate the probability of clinical metastasis within 5 years of radical prostatectomy surgery, and within 3 years of successive PSA rise (biochemical recurrence)."
• MSKCC prostate cancer nomograms
• MSKCC PSA doubling time calculator
• MSKCC Prostate volume calculator
• Oncotype DX Prostate Genomic Health's Genomic Prostate Score (GPS) & prognostic prostate cancer assay
• Partin tables to predict pathologic stage based on clinical TNM stage, PSA, and Gleason score
• PCA3 RNA urine test
  • PCA3.org
• Prolaris, Myriad's biomarker prognostic prostate cancer assay
• Roswell Park's Calculator for Estimating Overall Life Expectancy and Lifetime Risk for Prostate Cancer Death in Newly Diagnosed Men Managed without Definitive Local Therapy
• UCSF-CAPRA score

Quality of life assessment tools

• EPIC-CP: Expanded Prostate Cancer Index Composite for Clinical Practice (twice per dayMC)
• AUA Symptom Score (OR) (local backup); AUA Symptom Score (UCF) (local backup). Also known as International Prostate Symptom Score (I-PSS/IPSS) or AUASS