METASTATIC CASTRATE- RESISTANT PROSTATE CANCER TREATMENT (MCRPC) Fabricio Racca GU, CNS and Sarcoma Programme, Oncology Department Vall d’Hebron University Hospital, Barcelona, Spain AGENDA First-line treatment in mCRPC patients: Standard of Care Androgen Biosynthesis Inhibitors (ABIs) Second generation antiandrogens Docetaxel Radium 223 Novel hormonal therapies Immunotherapy Targeted therapies Failed trials Conclusions Siegel RL, et al., CA Cancer J Clin 2017;67:7–30. © 2017 American Cancer Society. With permission from John Wiley and Sons. SINCE 2010 A PLETHORA OF NEW TRIALS HAVE SHOWN BENEFIT IN MCRPC Trial / agent approved Disease state Comparator Hazard ratio P value IMPACT Chemo-näive CRPC Placebo 0.77 0.032 (Provenge vaccine) 2010 COU-AA-302 Placebo Chemo-naïve CRPC UK UK (Abiraterone acetate) 2012 Prednisone Pre-docetaxel ALSYPMCA (Radium 223) 2013 BSC 0.74 <0.00046 CRPC PREVAIL (Enzalutamide) 2014 Chemo-naïve CRPC Placebo 0.71 <0.0001 Mitoxantrone TAX327 (Docetaxel) 2004 Chemo-naïve CRPC 0.76 0.009 Prednisone Mitoxantrone TROPIC (Cabazitaxel) 2010 Post-docetaxel CRPC 0.70 <0.0001 Prednisone COU-AA-301 Post-docetaxel Placebo 0.65 <0.0001 (Abiraterone acetate) 2010 CRPC Prednisone Post-docetaxel ALSYPMCA (Radium 223) 2013 BSC 0.71 <0.00046 CRPC Post-docetaxel AFFIRM (Enzalutamide) 2012 BSC 0.63 <0.0001 CRPC ANDROGEN BIOSYNTHESIS INHIBITORS (ABIS) ABIRATERONE ACETATE + PREDNISONE Cholesterol Desmolase Renin Deoxy- Pregnenolone Progesterone Corticosterone Aldosterone corticosterone CYP17 17α-hydroxylaseX 11β-Hydroxylase ACTH 17α-OH- 17α –OH- 11-Deoxy- Cortisol pregnenolone progesterone cortisol CYP17 C17,20X-lyase 5α-reductase DHEA Androstenedione Testosterone DHT CYP19: aromatase Estradiol Adapted from Attard G, et al., J Clin Oncol 26(28), 2008: 4563-71. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. ABIRATERONE: PHASE III (COU-AA-301) 1195 patients with R Efficacy endpoints (ITT) Abiraterone 1000 mg daily progressive, mCRPC A N Prednisone 5 mg BID Primary endpoint: Failed 1 or D N=797 OS (25% improvement; 2 chemotherapy O HR 0.8) regimens, one of M Secondary endpoints (ITT): which contained I docetaxel S Placebo daily TTPP E Prednisone 5 mg BID rPFS D n=398 2:1 PSA response Phase 3, multinational, multicentre, randomised, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) Stratification according to: ECOG performance status (0-1 vs. 2) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression with or without PSA progression) de Bono JS, et al., N Eng J Med 2011;364 21:1995-2005. UPDATED ANALYSIS (775 EVENTS): OS BENEFIT OF A AA INCREASED FROM 3.9 TO 4.6 MONTHS AA 100 Placebo HR (95% CI): 0.74 (0.64-0.86) 80 p < 0.0001 AA median OS (95% CI): 60 15.8 months (14.8-17.0) 40 Survival (%) Placebo median OS (95% CI): 20 11.2 months (10.4-13.1) 0 0 6 12 18 24 30 Time to death (months) AA 797 657 473 273 15 0 Placebo 398 306 183 100 6 0 Median duration of follow-up: 20.2 months Median duration of treatment: 8 months with AA vs. 4 months with placebo Reprinted from The Lancet Oncology 2012; 13 (10), Fizazi K, et al., 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, 983–92. Copyright 2012, with permission from Elsevier. ABIRATERONE: PHASE III (COU-AA-302) Efficacy endpoints Patients R A Primary: Progressive chemo-naïve N AA 1000 mg daily rPFS by central review mCRPC patients D Prednisone 5 mg BID OS (n = 1088) O (n = 546) M Secondary: Asymptomatic or mildly I symptomatic S Time to opiate use (cancer- E Placebo daily related pain) D Prednisone 5 mg BID Time to initiation of (n = 542) chemotherapy 1:1 Time to ECOG-PS deterioration TTPP Phase 3 multicentre, randomised, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs. 1 Ryan C, et al., N Engl J Med 2013;368(2)138-148. STATISTICALLY SIGNIFICANT IMPROVEMENT IN RPFS PRIMARY ENDPOINT Reprinted from Eur Urol, 66(5), Rathkopf D, et al., Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302), 815–25. Copyright 2014 with permission from the European Association of Urology. COU-AA-302: OVERALL SURVIVAL Reprinted from The Lancet Oncology 2015; 16(2), Ryan C, et al., 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; 152–60. Copyright 2015, with permission from Elsevier. SAFETY OF LONG TERM TREATMENT OF CHEMO-NAÏVE MCRPC PATIENTS WITH AA + P FOR ≥4 YEARS AEs in COU-AA-302 patients who received AA + P for ≥4 years AEs in COU-AA-302 patients who received AA + P for ≥4 years vs. <4 years either early (0-12 Months) or late (36-48 months) AA + P ≥4 years AA + P <4 years During 0-12 months of During 36-48 months (n=41) (n=505) treatment (n=41) of treatment (n=41) Any grade, n (%) 41(100) 500 (99.8) Any grade, n (%) 41(100) 39 (95) Grade 3/4, n (%) 23 (56) 267 (53) Grade 3/4, n (%) 9 (22) 6 (15) Any Grade Any Grade Any Any Grade 3b Grade 3b grade* 3-4 grade 3-4 gradea grade Fatigue 27 (66) 1 (2) 217 (43) 15 93) Fatigue 11 (27) 0 8 (20) 0 Diarrhoea 21 (51) 1 (2) 116 (23) 7 (1) Diarrhoea 6 (15) 0 7 (17) 0 Arthralgia 20 (49) 2 (5) 153 (31) 9 (2) Arthralgia 7 (17) 1 (2) 5 (12) 0 Back pain 20 (49) 1 (2) 180 (36) 17 (3) Back pain 7 (17) 1 (2) 5 (12) 0 Peripheral Peripheral 17 (42) 0 132 (26) 3 (<1) 10 (24) 0 4 (10) 0 oedema oedema *>40% cut-off. a. >15% cut-off; b.There were no grade 4 or 5 AEs. Conclusion 41 of 546 patients in COU-AA-302 continued AA + P treatment for ≥4 years As expected, efficacy measures were improved for AA + P ≥4 years vs. AA + P <4 years group There were no new safety signals or signs of cumulative toxicity over time with AA + P Carles J, et al., Ann Oncol 2016;27(6):243–65. 740P. 12 SECOND GENERATION ANTIANDROGENS ENZALUTAMIDE Reprinted from Clin Cancer Res, 2013, 19(6):1335–9, Hoffman-Censits J, Kelly WK, Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate cancer, with permission from AACR. AFFIRM A phase 3 trial of Enzalutamide vs. placebo in post-chemotherapy treated castration-resistant prostate cancer (CRPC) Patient population: R Primary endpoint: A Enzalutamide 1199 patients with progressive N Overall Survival CRPC D 160 mg daily O n = 800 *Failed docetaxel M chemotherapy I S E Placebo D n = 399 2:1 *Glucocorticoids were not required but allowed. Scher HI, et al., N Engl J Med 2012;367(13):1187-97. OVERALL SURVIVAL From N Engl J Med, Scher HI, et al., Increased survival with enzalutamide in prostate cancer after chemotherapy, 367(13):1187–97. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. TIME TO PSA PROGRESSION AND RADIOGRAPHIC PROGRESSION- FREE SURVIVAL Time to PSA progression Radiographic progression-free survival From N Engl J Med, Scher HI, et al., Increased survival with enzalutamide in prostate cancer after chemotherapy, 367(13):1187–97. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. PREVAIL A phase 3 trial of Enzalutamide vs. placebo in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) Patient population: R A Enzalutamide 1717 patients with N Co-Primary endpoints: progressive mCRPC D 160 mg daily O n = 872 Overall Survival Asymptomatic M I rPFS Chemotherapy naïve S E Placebo D n = 845 1:1 Beer TM, et al., N Engl J Med 2014;371(5),424–33. PREVAIL: CO-PRIMARY ENDPOINTS Rate of rPFS: 65% (Enza) vs.14% (Placebo) - HR 0.19 (95% CI, 0.15 to 0.23; P<0.001) Median OS: 32.4 months (Enza) vs. 30.2 (Placebo) HR 0.71 (95% CI, 0.60 to 0.84; P<0.001) From N Engl J Med, Beer TM, et al., Enzalutamide in metastatic prostate cancer before chemotherapy, 371 (5), 424–433. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. DOCETAXEL DOCETAXEL IS STANDARD IN FIRST-LINE CPRC Docetaxel plus prednisone or mitoxantrone Docetaxel and estramustine compared plus prednisone for advanced PC1 with mitoxantrone and prednisone for Median survival (mos) HR P-value advanced refractory prostate cancer2 Combination 0.83 0.04 Docetaxel q3w 18.9 0.76 0.009 Docetaxcel qw 17.4 0.91 0.36 Mitoxantrone 16.5 n/a n/a HR: 0.80 (95% CI 0.67, 0.97) 1. From N Engl J Med, Tannock IF, et al., Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer, 351:1502–12. Copyright © 2004 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; 2. From N Engl J Med, Petrylak DP, et al. Docetaxel and Estramustine Compared with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer, 351:1513–20. Copyright © 2004 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. PHASE III CLINICAL TRIALS SHOWING DOCETAXEL IMPACT ON SURVIVAL Docetaxel-based phase III trials % with Time to PSA Study Regimen ORR paliative progression Survival response response (months) SWOG Docetaxel + Estramustine 17 50 17 6 18 Mitoxantrone + PDN 10 27 11 3 16 TAX 327 Docetaxel (3w) + PDN 12 45 35 7.9 18.9 Docetaxel (w) + PDN 8 48 31 8.2 17.4 Mitoxantrone + PDN 7 32 22 7.8 16.5 Sternberg C, et al., Progress in the treatment of advanced prostate cancer.