Prostate cancer

Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer.

Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.

80 regimens on this page 112 variants on this page

Guidelines

ASCO & CCO

• Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline - Journal of Clinical Oncology (JCO) PubMed

ESMO

• Prostate cancer: ESMO Consensus Conference Guidelines 2012 PubMed
• Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2015) PubMed

NCCN

• NCCN Guidelines - Prostate Cancer

Androgen deprivation therapy (ADT) & radiation therapy

Goserelin & RT

back to top

RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Pilepich et al. 2005 (RTOG 85-31)	Phase III	RT	Superior DFS
Bolla et al. 1997	Phase III	RT	Superior OS

Endocrine & Radiotherapy

• Goserelin (Zoladex) 3.6 mg SC once every 4 weeks, to start during the last week of radiation therapy and to continue indefinitely or until progression
• Radiation therapy, 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

References

1. 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. 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

Goserelin, Flutamide, RT

back to top

RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Pilepich et al. 2001 (RTOG 86-10)	Phase III	RT	Seems to have superior cause-specific mortality
Hanks et al. 2003 (RTOG 92-02)	Non-randomized
Denham et al. 2005 (TTROG 96.01)	Phase III	Goserelin & Flutatmide x 6m, RT	Not reported
		RT	Superior DFS
D'Amico et al. 2008	Phase III	RT	Superior OS
Jones et al. 2011	Phase III	RT	Seems to have superior OS

Endocrine & Radiotherapy

• Goserelin (Zoladex) 3.6 mg SC once every 4 weeks, to start 2 months prior to radiation therapy and to continue at least through the end of radiation therapy
• Flutamide (Eulexin) 250 mg PO three times per day, to start 2 months prior to radiation therapy and to continue at least through the end of radiation therapy
• Radiation therapy 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

Patients in RTOG 92-02 were subsequently randomized to adjuvant goserelin x 2 years versus no further treatment.

References

1. 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
2. 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
3. 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
4. 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
5. 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

Leuprolide, Flutamide, RT

back to top

RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Jones et al. 2011	Phase III	RT	Seems to have superior OS

Endocrine & Radiotherapy

• Leuprolide (Lupron) 7.5 mg SC once every 4 weeks x 4 months, to start 2 months prior to radiation therapy
• Flutamide (Eulexin) 250 mg PO three times per day x 4 months, to start 2 months prior to radiation therapy
• Radiation therapy 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

References

1. 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

RT

back to top

RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Pilepich et al. 1997 (RTOG 85-31)	Phase III	Goserelin & RT	Inferior DFS
Bolla et al. 1997	Phase III	Goserelin & RT	Inferior OS
Pilepich et al. 2001 (RTOG 86-10)	Phase III	Goserelin, Flutatmide, RT	Seems to have inferior cause-specific mortality
Denham et al. 2005 (TTROG 96.01)	Phase III	Goserelin & Flutatmide x 3m, RT	Inferior DFS
		Goserelin & Flutatmide x 6m, RT	Seems to have inferior prostate cancer-specific survival
D'Amico et al. 2008	Phase III	Goserelin, Flutatmide, RT	Inferior OS
Jones et al. 2011	Phase III	Goserelin, Flutatmide, RT Leuprolide, Flutamide, RT	Seems to have inferior OS

Demonstrated to be inferior; here for reference purposes only.

References

1. 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. 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
3. 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
4. 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
5. 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
6. 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

Hormonal therapy, adjuvant

Goserelin (Zoladex)

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Hanks et al. 2003 (RTOG 92-02)	Phase III	No further treatment	Superior DFS

Treatment preceded by goserelin, flutamide, RT.

Endocrine therapy

• Goserelin (Zoladex) 3.6 mg SC once per month

2-year course

References

1. 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

Observation

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Hanks et al. 2003 (RTOG 92-02)	Phase III	Goserelin	Inferior DFS

Preceded by goserelin, flutamide, RT. No further treatment.

References

1. 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

Hormonal therapy, metastatic or locally advanced disease

Androgen Deprivation Therapy (ADT) & Docetaxel

Regimen

Study	Evidence	Comparator	Efficacy
Sweeney et al. 2015 (ECOG E3805)	Phase III	Leuprolide	Superior OS

Patients already on androgen deprivation therapy were eligible to participate in ECOG E3805 if there was no evidence of disease progression and if they had started ADT no more than 120 days before randomization.

Chemohormonal therapy

• Docetaxel (Taxotere) 75 mg/m² IV over 1 hour once on day 1
• ADT - LHRH agonist or antagonist or surgical castration. 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 by mouth 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 per day

21-day cycle for up to 6 cycles

References

1. 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

Bicalutamide (Casodex)

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Tyrrell et al. 1998	Phase III	Castration	Not reported

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

Endocrine therapy

• Bicalutamide (Casodex) 150 mg PO once per day

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. 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

Bicalutamide & Goserelin

back to top

Regimen #1

Study	Evidence	Comparator	Efficacy
Akaza et al. 2004	Phase III	Leuprolide	Seems to have superior TTP

Endocrine therapy

• Bicalutamide (Casodex) 80 mg PO once per day
• Goserelin (Zoladex) 3.6 mg SC once every 4 weeks

Regimen #2

Study	Evidence	Comparator	Efficacy
Schellhammer et al. 1995 (CASODEX Combination Study Group)	Phase III	Bicalutamide & Leuprolide	Not reported
		Flutamide & Goserelin Flutamide & Leuprolide	Superior TTTF

Endocrine therapy

• Bicalutamide (Casodex) 50 mg PO once per day
• Goserelin (Zoladex) 3.6 mg SC once every 4 weeks

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. A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol 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

Bicalutamide & Leuprolide

back to top

Regimen #1

Study	Evidence	Comparator	Efficacy
Akaza et al. 2004	Phase III	Leuprolide	Seems to have superior TTP

Endocrine therapy

• Bicalutamide (Casodex) 80 mg PO once per day
• Leuprolide (Lupron) 1-month depot 3.75 mg SC once every 4 weeks

Regimen #2

Study	Evidence	Comparator	Efficacy
Schellhammer et al. 1995 (CASODEX Combination Study Group)	Phase III	Bicalutamide & Goserelin	Not reported
		Flutamide & Goserelin Flutamide & Leuprolide	Superior TTTF

Endocrine therapy

• Bicalutamide (Casodex) 50 mg PO once per day
• Leuprolide (Lupron) 1-month depot 7.5 mg IM once every 4 weeks

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. A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol 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

Castration

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Soloway et al. 1991 (Zoladex Prostate Study Group)	Phase III	Goserelin	Seems not superior
Kaisary et al. 1991	Phase III	Goserelin	Seems not superior
Janknegt et al. 1993 (International Anandron Study Group)	Phase III	Nilutamide & Orchiectomy	Inferior PFS
Denis et al. 1993 (EORTC 30853)	Phase III	Flutamide & Goserelin	Seems to have inferior OS
Boccon-Gibod et al. 1997	Phase III	Flutamide	Seems not superior
Tyrrell et al. 1998	Phase III	Bicalutamide	Not reported

Not widely used as monotherapy in the United States; included for reference purposes only.

References

1. Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA Jr, Scott M, Kennealey G, Gau TC. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Zoladex Prostate Study Group. Urology. 1991 Jan;37(1):46-51. PubMed
   1. Update: Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, Caplan RJ, Kennealey GT. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. 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. PubMed
3. Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, Da Silva FC, Chisholm G, Crawford ED, Debruyne FM et al. 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; discussion 83. PubMed
   1. Update: Janknegt RA. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Anandron International Study Group. Cancer. 1993 Dec 15;72(12 Suppl):3874-7. PubMed
   2. Update: Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group. 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
4. Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. Urology. 1993 Aug;42(2):119-29; discussion 129-30. contains protocol PubMed
   1. Update: Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Eur Urol. 1998;33(2):144-51. PubMed
5. 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; discussion 395-6. contains protocol PubMed
6. 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. 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

Degarelix (Firmagon)

Example orders

• Example orders for Degarelix (Firmagon) in prostate cancer

back to top

Regimen #1, 240/80

Study	Evidence	Comparator	Efficacy
Klotz et al. 2008 (CS21)	Phase III	Degarelix 240/160	Non-inferior testosterone suppression
		Leuprolide	Non-inferior testosterone suppression

This is the recommended dose in package insert.

Endocrine therapy

• Degarelix (Firmagon) 240 mg (given as 2 x 120 mg injections) SC once, then 80 mg SC once every 28 days

Regimen #2, 240/160

Study	Evidence	Comparator	Efficacy
Klotz et al. 2008 (CS21)	Phase III	Degarelix 240/80	Non-inferior testosterone suppression
		Leuprolide	Non-inferior testosterone suppression

Endocrine therapy

• Degarelix (Firmagon) 240 mg (given as 2 x 120 mg injections) SC once, then 160 mg SC once every 28 days

References

1. 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

Flutamide (Eulexin)

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Boccon-Gibod et al. 1997	Phase III	Orchiectomy	Seems not superior

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

Endocrine therapy

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

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; discussion 395-6. contains protocol PubMed

Flutamide & Goserelin

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Denis et al. 1993 (EORTC 30853)	Phase III	Bilateral orchiectomy	Seems to have superior OS
Schellhammer et al. 1995 (CASODEX Combination Study Group)	Phase III	Bicalutamide & Goserelin Bicalutamide & Leuprolide	Inferior TTTF
		Flutamide & Leuprolide	Not reported

Endocrine therapy

• Flutamide (Eulexin) 250 mg PO three times per day
• Goserelin (Zoladex) 3.6 mg SC once every 4 weeks

References

1. Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. Urology. 1993 Aug;42(2):119-29; discussion 129-30. contains protocol PubMed
   1. Update: Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. 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. 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. A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol PubMed

Flutamide & Leuprolide

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Schellhammer et al. 1995 (CASODEX Combination Study Group)	Phase III	Bicalutamide & Goserelin Bicalutamide & Leuprolide	Inferior TTTF
		Flutamide & Goserelin	Not reported

Endocrine therapy

• Flutamide (Eulexin) 250 mg PO three times per day
• Leuprolide (Lupron) 1-month depot 7.5 mg IM once every 4 weeks

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. A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group. Eur Urol. 1996;29 Suppl 2:105-9. contains protocol PubMed

Goserelin (Zoladex)

Example orders

• Example orders for Goserelin (Zoladex) in prostate cancer

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Soloway et al. 1991 (Zoladex Prostate Study Group)	Phase III	Bilateral orchiectomy	Seems not superior
Kaisary et al. 1991	Phase III	Bilateral orchiectomy	Seems not superior

Endocrine therapy

• Goserelin (Zoladex) 3.6 mg SC once every 4 weeks

References

1. Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA Jr, Scott M, Kennealey G, Gau TC. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Zoladex Prostate Study Group. Urology. 1991 Jan;37(1):46-51. PubMed
   1. Update: Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, Caplan RJ, Kennealey GT. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. 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. PubMed

Leuprolide (Lupron)

Example orders

• Example orders for Leuprolide (Lupron) in prostate cancer

back to top

Regimen #1, 1-month depot, 3.75 mg

Study	Evidence	Comparator	Efficacy
Akaza et al. 2004	Phase III	Bicalutamide & Goserelin Bicalutamide & Leuprolide	Seems to have inferior TTP

Endocrine therapy

• Leuprolide (Lupron) 1-month depot 3.75 mg SC once every 4 weeks

Regimen #2, 1-month depot, 7.5 mg

Study	Evidence	Comparator	Efficacy
Klotz et al. 2008 (CS21)	Phase III	Degarelix 240/80	Non-inferior testosterone suppression
		Degarelix 240/160	Non-inferior testosterone suppression

Endocrine therapy

• Leuprolide (Lupron) 1-month depot 7.5 mg IM once every 4 weeks

Regimen #3, 3-month depot

Study	Evidence
Sharifi et al. 1996	Phase II

Endocrine therapy

• Leuprolide (Lupron) 3-month depot 22.5 mg IM once every 12 weeks

Regimen #4, 4-month depot

Study	Evidence
Sharifi et al. 1998	Phase II

Endocrine therapy

• Leuprolide (Lupron) 4-month depot 30 mg IM once every 16 weeks

Other

• One of the following:
  • Leuprolide (Lupron) 6-month depot 45 mg IM once every 24 weeks
  • Leuprolide (Lupron) 4-month depot 30 mg IM once every 16 weeks
  • Leuprolide (Lupron) 3-month depot 22.5 mg IM once every 12 weeks
  • Leuprolide (Lupron) 1-month depot 7.5 mg IM once every 4 weeks

Supportive medications

• (varies depending on reference):
• Bicalutamide (Casodex) 50 mg PO once per day for protection from testosterone flare

References

1. 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
2. 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
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
4. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin M, Vogelzang NJ, Wade JL 3rd, Bennett CL, Scher HI; American Society of Clinical Oncology. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007 Apr 20;25(12):1596-605. Epub 2007 Apr 2. link to original article PubMed
5. 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
6. 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

Nilutamide & Orchiectomy

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Janknegt et al. 1993 (International Anandron Study Group)	Phase III	Orchiectomy	Superior PFS

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

Endocrine therapy

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

References

1. Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, Da Silva FC, Chisholm G, Crawford ED, Debruyne FM et al. 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; discussion 83. PubMed
   1. Update: Janknegt RA. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Anandron International Study Group. Cancer. 1993 Dec 15;72(12 Suppl):3874-7. PubMed
   2. Update: Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group. 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
2. Nilutamide (Nilandron) package insert

Second-line hormonal therapy

Abiraterone & Prednisone

back to top

Regimen

Study	Evidence	ORR, PSA RR	Comparator	Comparator ORR, PSA RR	Efficacy	Pt Population
de Bono et al. 2011 (COU-AA-301)	Phase III	14% (95% CI n/a), 29%	Prednisone	3% (95% CI n/a), 6%	Superior OS	Chemo-exposed
Ryan et al. 2013 (COU-AA-302)	Phase III	36% (95% CI n/a), 62%	Prednisone	16% (95% CI n/a), 24%	Seems to have superior OS	Chemo-naive

Endocrine therapy

• Abiraterone (Zytiga) 1000 mg PO once per day, 1 hour before or 2 hours after meals
• Prednisone (Sterapred) 5 mg PO BID

References

1. 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 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. 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 PubMed

Antiandrogen withdrawal

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Small et al. 2004 (CALGB 9583)	Phase III	Ketoconazole & Hydrocortisone	Inferior PSA response

Refers to cessation of antiandrogen therapy.

References

1. 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

Bicalutamide (Casodex)

back to top

Regimen

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

Patients continued ADT while on study; details not provided.

Endocrine therapy

• Bicalutamide (Casodex) 50 mg PO once per day

Continued until progression

References

1. 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

Enzalutamide (Xtandi)

back to top

Regimen

Study	Evidence	ORR, PSA RR	Comparator	Comparator ORR, PSA RR	Efficacy	Pt Population
Scher et al. 2012 (AFFIRM)	Phase III	29% (95% CI n/a), 54%	Placebo	4% (95% CI n/a), 2%	Superior OS	Chemo-exposed (docetaxel)
Beer et al. 2014 (PREVAIL)	Phase III	59% (95% CI n/a), 78%	Placebo	5% (95% CI n/a), 3%	Superior OS	Chemo and abiraterone naive
Penson et al. 2016 (STRIVE)	Randomized Phase II	60% (95% CI n/a), 81%	Bicalutamide	14% (95% CI n/a), 31%	Superior PFS	Chemo and bicalutamide naive

Patients in STRIVE continued ADT while on study; details not provided.

Endocrine therapy

• Enzalutamide (Xtandi) 160 mg PO once per day

Continued until progression

References

1. 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
2. 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 PubMed
3. 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

Ketoconazole & Hydrocortisone

back to top

Regimen

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

Endocrine therapy

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

References

1. 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

back to top

Regimen

Study	Evidence
Taplin et al. 2009	Phase II

Endocrine therapy

• 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

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 PubMed

Placebo

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Scher et al. 2012 (AFFIRM)	Phase III	Enzalutamide	Inferior OS
Beer et al. 2014 (PREVAIL)	Phase III	Enzalutamide	Inferior OS

No active antineoplastic treatment; this was the comparator arm in at least one randomized trial and is included for reference purposes, only.

References

1. 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
2. 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 PubMed

Prednisone

back to top

Regimen

Study	Evidence	Comparator	Efficacy
de Bono et al. 2011 (COU-AA-301)	Phase III	Abiraterone & Prednisone	Inferior OS
Ryan et al. 2013 (COU-AA-302)	Phase III	Abiraterone & Prednisone	Seems to have inferior OS

Not used as monotherapy in routine practice; this was the comparator arm in at least one randomized trial and is included for reference purposes, only.

References

1. 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 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. 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 PubMed

Chemotherapy for metastatic castrate-resistant disease

Cabazitaxel & Prednisone

Example orders

• Example orders for Cabazitaxel (Jevtana) in prostate cancer

back to top

Regimen

Study	Evidence	ORR, PSA RR	Comparator	Comparator ORR, PSA RR	Efficacy	Pt Population
de Bono et al. 2010 (TROPIC)	Phase III	pts w/ measurable disease: 14.4% (95% CI 9.6 - 19.3), 39.2% (95% CI 33.9 - 44.5)	Mitoxantrone & Prednisone	pts w/ measurable disease: 4.4% (95% CI 1.6 - 7.2), 17.8% (95% CI 13.7 - 22.0)	Superior OS	Progressed on docetaxel

Chemotherapy

• Cabazitaxel (Jevtana) 25 mg/m² IV over 1 hour once on day 1
• Prednisone (Sterapred) 10 mg PO once per day on days 1 to 21

Supportive medications

• Antihistamine given at least 30 minutes before Cabazitaxel (Jevtana)
• Corticosteroid (dexamethasone 8 mg or equivalent) given at least 30 minutes before Cabazitaxel (Jevtana)
• Histamine H2-antagonist (except cimetidine) given at least 30 minutes before Cabazitaxel (Jevtana)

21-day cycle for up to 10 cycles

References

1. 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

Cabozantinib (Cometriq)

back to top

Regimen

Study	Evidence
Smith et al. 2012	Phase II

Chemotherapy

• Cabozantinib (Cometriq) 100 mg PO once per day

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 PubMed

Carboplatin & Docetaxel

back to top

Example orders

• Example orders for Docetaxel & Carboplatin in prostate cancer

Regimen #1

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 1 hour once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 1 hour once on day 1, given first

Supportive medications

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

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2, weekly docetaxel

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 1 hour 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.
• Prednisone (Sterapred) 5 mg PO BID on days 1 to 28

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, given until progression of disease or unacceptable toxicity

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. 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
3. 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

back to top

Regimen #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 1 hour 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 "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 "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, given until progression of disease or unacceptable toxicity

Regimen #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, given until progression of disease or unacceptable toxicity

References

1. 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. 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

CMF

CMF: Cyclophosphamide, Methotrexate, Five-FU

back to top

Regimen

Study	Evidence
Wozniak et al. 1993	Phase II

This regimen is "minimally active in hormone-refractory metastatic prostate cancer" per Wozniak et al. 1993 and is included for historical reference only.

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 7
• Methotrexate (MTX) 15 mg/m² IV once on day 1
• Fluorouracil (5-FU) 300 mg/m² IV once on day 1

7-day cycles, given until progression of disease or unacceptable toxicity

References

1. Wozniak AJ, Blumenstein BA, Crawford ED, Boileau M, Rivkin SE, Fletcher WS. Cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of metastatic prostate cancer. A Southwest Oncology Group study. Cancer. 1993 Jun 15;71(12):3975-8. link to original article contains verified protocol PubMed

CPD

CPD: Cyclophosphamide, Prednisone, Diethylstilbestrol

back to top

Regimen

Study	Evidence
Hellerstedt et al. 2003	Phase II

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg PO once per day on days 1 to 20
• Prednisone (Sterapred) 10 mg PO once per day on days 1 to 30
• Diethylstilbestrol (DES) 1 mg PO once per day on days 1 to 30

Supportive medications

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

30-day cycles, given until progression of disease or unacceptable toxicity

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 & Prednisone

back to top

Example orders

• Example orders for Docetaxel (Taxotere) in prostate cancer

Regimen #1, every 3-weeks schedule, limited duration

Study	Evidence	ORR, PSA RR	Comparator	Comparator ORR, PSA RR	Efficacy	Pt Population
Tannock et al. 2004 (TAX 327)	Phase III	pts w/ measurable disease:12% (95% CI 7-19), 45% (95% CI 40-51)	Weekly Docetaxel & Prednisone	pts w/ measurable disease:8% (95% CI 4-14), 48% (95% CI 42-54)	Not reported	Chemo-naive
			Mitoxantrone & Prednisone	pts w/ measurable disease:7% (95% CI 3-12), 32% (95% CI 26-37)	Superior OS	Chemo-naive

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 1 hour once on day 1
• Prednisone (Sterapred) 5 mg PO BID on days 1 to 21

Supportive medications

• Dexamethasone (Decadron) 8 mg (route not specified) 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 #2, every 3-weeks schedule, indefinite

Study	Evidence	Comparator	Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY)	Phase III	Every 2-weeks Docetaxel & Prednisone	Seems to have inferior TTTF

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1
• Prednisolone (Millipred) 10 mg PO once per day on days 1 to 21

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, given until progression of disease or unacceptable toxicity

Regimen #3, weekly schedule

Study	Evidence	Comparator	Efficacy
Tannock et al. 2004 (TAX 327)	Phase III	Every 3-week Docetaxel & Prednisone	Not reported
		Mitoxantrone & Prednisone	Seems not superior

Chemotherapy

• Docetaxel (Taxotere) 30 mg/m² IV over 30 minutes once per day on days 1, 8, 15, 22, 29
• Prednisone (Sterapred) 5 mg PO BID on days 1 to 42

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 #4

Study	Evidence	Comparator	Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY	Phase III	Every 3-weeks Docetaxel & Prednisone	Seems to have superior TTTF

Chemotherapy

• Docetaxel (Taxotere) 50 mg/m² IV over 60 minutes once per day on days 1 & 15
• Prednisolone (Millipred) 10 mg PO once per day on days 1 to 28

Supportive medications

• Dexamethasone (Decadron) 7.5 to 8 mg 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); 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"

28-day cycles, given until progression of disease or unacceptable toxicity

References

1. 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. 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; for the 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

Mitoxantrone & Prednisone

back to top

Example orders

• Example orders for Mitoxantrone (Novantrone) in prostate cancer

Regimen

Study	Evidence	ORR, PSA RR	Comparator	Comparator ORR, PSA RR	Efficacy	Pt Population
Tannock et al. 2004 (TAX 327)	Phase III	pts w/ measurable disease: 7% (95% CI 3-12), 32% (95% CI 26-37)	Weekly Docetaxel & Prednisone	pts w/ measurable disease: 8% (95% CI 4-14), 48% (95% CI 42-54)	Seems not superior	Chemo naive
			Every 3-week Docetaxel & Prednisone	pts w/ measurable disease: 12% (95% CI 7-19), 45% (95% CI 40-51)	Inferior OS	Chemo naive
Petrylak et al. 2004 (SWOG 99-16)	Phase III		Docetaxel & Estramustine		Seems to have inferior OS
de Bono et al. 2010 (TROPIC)	Phase III	pts w/ measurable disease: 4.4% (95% CI 1.6 - 7.2), 17.8% (95% CI 13.7 - 22.0)	Cabazitaxel & Prednisone	pts w/ measurable disease: 14.4% (95% CI 9.6 - 19.3), 39.2% (95% CI 33.9 - 44.5)	Inferior OS	Progressed on docetaxel

Chemotherapy

• Mitoxantrone (Novantrone) 12 mg/m² IV over 15 to 30 minutes once on day 1
• Prednisone (Sterapred) 10 mg PO once per day (or 5 mg PO BID) on days 1 to 21

21-day cycle for up to 10 cycles

References

1. 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. 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
3. 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

Olaparib (Lynparza)

back to top

Regimen

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

• Patients in Kaufman et al. 2014 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.

Chemotherapy

• Olaparib (Lynparza) 400 mg PO BID

Given until progression of disease or unacceptable toxicity

References

1. 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. 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 PubMed

Immunotherapy for metastatic castrate-resistant disease

Ipilimumab & RT

back to top

RT: Radiation Therapy

Regimen

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

Immunoradiotherapy

• 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
• Concurrent radiotherapy given focally at a single dose of 8 Gy per target bone lesion for up to three bone lesions per patient at 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 PubMed

Placebo

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Kantoff et al. 2010 (IMPACT)	Phase III	Sipuleucel-T	Seems to have inferior OS

No active antineoplastic treatment; this was the comparator arm in at least one randomized trial and is included for reference purposes, only.

References

1. 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

Sipuleucel-T (Provenge)

Example orders

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

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Kantoff et al. 2010 (IMPACT)	Phase III	Placebo	Seems to have superior OS

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 30 minutes before each dose
• Antihistamine PO once 30 minutes before each dose

References

1. 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
2. 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
3. Sipuleucel-T (Provenge) package insert

Radioactive agents for bony metastases

Placebo

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Nilsson et al. 2007	Randomized Phase II	Radium-223	Might have inferior OS
Parker et al. 2013 (ALSYMPCA)	Phase III	Radium-223	Inferior OS

No active antineoplastic treatment; this was the comparator arm in at least one randomized trial and is included for reference purposes, only.

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. 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: Prof Peter Hoskin MD, Prof Oliver Sartor MD, Prof Joe M O'Sullivan MD, Dag Clement Johannessen MD, Svein I Helle MD, John Logue FRCR, David Bottomley FRCR, Prof Sten Nilsson MD, Prof Nicholas J Vogelzang MD, Fang Fang PhD, Mona Wahba MD, Anne-Kirsti Aksnes PhD, Christopher Parker MD. 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. The Lancet Oncology, Volume 15, Issue 12, Pages 1397 - 1406, November 2014. link to original article

Radium-223 (Xofigo)

back to top

Regimen #1

Study	Evidence	Comparator	Efficacy
Parker et al. 2013 (ALSYMPCA)	Phase III	Placebo	Superior OS

Radiotherapy

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

28-day cycle for 6 cycles

Regimen #2

Study	Evidence	Comparator	Efficacy
Nilsson et al. 2007	Randomized Phase II	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. 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: Prof Peter Hoskin MD, Prof Oliver Sartor MD, Prof Joe M O'Sullivan MD, Dag Clement Johannessen MD, Svein I Helle MD, John Logue FRCR, David Bottomley FRCR, Prof Sten Nilsson MD, Prof Nicholas J Vogelzang MD, Fang Fang PhD, Mona Wahba MD, Anne-Kirsti Aksnes PhD, Christopher Parker MD. 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. The Lancet Oncology, Volume 15, Issue 12, Pages 1397 - 1406, November 2014. link to original article

Samarium-153 (Quadramet)

back to top

Regimen

Study	Evidence	Comparator	Efficacy
Resche et al. 1997	Phase III	Samarium-153 0.5 mCi/kg	Seems to have superior pain control at week 4
Sartor et al. 2004 (Quadramet 424Sm10/11 Study Group)	Phase III	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 PO/IV 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 <50 ng/dL (<1.7 nmol/L)
    • However, there is controversy/disagreement in other references about whether a lower level should be used, such as <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 (BIDMC)
• AUA Symptom Score (OR) (local backup); AUA Symptom Score (UCF) (local backup). Also known as International Prostate Symptom Score (I-PSS/IPSS) or AUASS