Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy

BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy.

METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival.

RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.

CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM number, NCT00974311).

New England Journal of Medicine. 2012 Aug 15 [Epub ahead of print]

Howard I. Scher, M.D.,1,2 Karim Fizazi, M.D., Ph.D.,3 Fred Saad, M.D.,4 Mary-Ellen Taplin, M.D.,5 Cora N. Sternberg, M.D.,6 Kurt Miller, M.D.,7 Ronald de Wit, M.D.,8 Peter Mulders, M.D., Ph.D.,9 Kim N. Chi, M.D.,10 Neal D. Shore, M.D.,11 Andrew J. Armstrong, M.D.,12 Thomas W. Flaig, M.D.,13 Aude Fléchon, M.D., Ph.D.,14 Paul Mainwaring, M.D.,15 Mark Fleming, M.D.,16 John D. Hainsworth, M.D.,17 Mohammad Hirmand, M.D.,18 Bryan Selby, M.S.,18 Lynn Seely, M.D.,18 and Johann S. de Bono, M.B., Ch.B., Ph.D.19 for the AFFIRM Investigators

1. Memorial Sloan-Kettering Cancer Center, New York, New York
2. Weill Cornell Medical College, New York, New York
3. Institut Gustave Roussy, University of Paris Sud, Villejuif, France
4. University of Montreal Hospital Center, Montreal, Canada
5. Dana–Farber Cancer Institute, Boston, Massachusetts
6. San Camillo–Forlanini Hospital, Rome, Italy
7. Charité Universitätsmedizin, Berlin, Germany
8. Erasmus University Medical Center, Rotterdam, Netherlands
9. Radboud University Medical Center, Nijmegen, Netherlands
10. British Columbia Cancer Agency, Vancouver, Canada
11. Carolina Urologic Center, Myrtle Beach, South Carolina
12. Duke Cancer Institute, Duke University, Durham, North Carolina
13. University of Colorado Cancer Center, Aurora, Colorado
14. Centre Léon Bérard–Centre Régional de Lutte contre le Cancer Rhône-Alpes, Lyon, France
15. Mater Private Hospital, South Brisbane, Australia
16. Virginia Oncology Associates, Norfolk, Virginia
17. Sarah Cannon Research Institute, Nashville, Tennessee
18. Medivation, San Francisco, California
19. Institute for Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom


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