“Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy” in an international phase III, double-blind, placebo-controlled trial, investigators reported in The New England Journal of Medicine. Median overall survival, the primary endpoint, was 18.4 months among the 800 men randomly assigned to receive oral enzalutamide at 160 mg per day vs 3.6 months among 399 patients receiving placebo (P < .001). The men were stratified according to Eastern Cooperative Oncology Group performance status score (0 or 1 vs 2) and pain intensity (no pain to mild pain vs moderate to severe pain).
The study was stopped after a planned interim analysis showed a 37% reduction in the risk of death with enzalutamide vs placebo. “On the basis of these results, an independent data and safety monitoring committee recommended that the study be halted and unblinded, with eligible patients in the placebo group offered treatment with enzalutamide,” the authors wrote.
“The superiority of enzalutamide over placebo was shown with respect to all secondary endpoints,” the investigators stated. These included the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs 2%, P < .001); time to PSA progression (8.3 vs 3.0 months, HR = 0.25, P < .001); radiographic progression-free survival (8.3 vs 2.9 months, HR = 0.40, P < .001); soft-tissue response rate (29% vs 4%, P < .001); time to first skeletal-related event (16.7 vs 13.3 months, HR = 0.69, P < .001); and quality-of-life response rate (43% vs 18%, P < .001).
Formerly known as MDV3100, enzalutamide “targets multiple steps in the androgen receptor–signaling pathway, the major driver of prostate-cancer growth,” according to the AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) investigators.
Compared with the placebo group, men in the enzalutamide group had a lower incidence of grade 3 or higher adverse events (45.3% vs 53.1%) and a longer median time to the first such adverse event (12.6 vs 4.2 months). Fatigue, diarrhea, and hot flashes were reported more frequently in the enzalutamide group. Seizures were not reported in the placebo group, but were reported in 5 (0.6%) of the men receiving enzalutamide, and the drug was discontinued.
“Caution should be used in administering enzalutamide to patients with a history of seizure or who have other predisposing factors, including underlying brain injury, stroke, brain metastases, or alcoholism, or to patients receiving concomitant medication that may lower the seizure threshold,” the investigators noted.
The authors anticipated that enzalutamide would “join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy. Clinical trials of enzalutamide in earlier-stage prostate cancer are ongoing.” ■
Scher HI, et al: N Engl J Med. August 15, 2012 (early release online).