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 ClinicalTrials.gov number, NCT00974311.).
Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA. scherh@mskcc.org
Howard I
HI
Scher
Karim
K
Fizazi
Fred
F
Saad
Mary-Ellen
ME
Taplin
Cora N
CN
Sternberg
Kurt
K
Miller
Ronald
R
de Wit
Peter
P
Mulders
Kim N
KN
Chi
Neal D
ND
Shore
Andrew J
AJ
Armstrong
Thomas W
TW
Flaig
Aude
A
Fléchon
Paul
P
Mainwaring
Mark
M
Fleming
John D
JD
Hainsworth
Mohammad
M
Hirmand
Bryan
B
Selby
Lynn
L
Seely
Johann S
JS
de Bono
D000368:Aged; D059002:Androgen Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000601:surgery; D012640:Seizures / Q000139:chemically induced; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000627:therapeutic use
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide