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Clinical Trial
. 2014 Jul 31;371(5):424-33.
doi: 10.1056/NEJMoa1405095. Epub 2014 Jun 1.

Enzalutamide in metastatic prostate cancer before chemotherapy

Tomasz M Beer  1 , Andrew J Armstrong, Dana E Rathkopf, Yohann Loriot, Cora N Sternberg, Celestia S Higano, Peter Iversen, Suman Bhattacharya, Joan Carles, Simon Chowdhury, Ian D Davis, Johann S de Bono, Christopher P Evans, Karim Fizazi, Anthony M Joshua, Choung-Soo Kim, Go Kimura, Paul Mainwaring, Harry Mansbach, Kurt Miller, Sarah B Noonberg, Frank Perabo, De Phung, Fred Saad, Howard I Scher, Mary-Ellen Taplin, Peter M Venner, Bertrand Tombal; PREVAIL Investigators
Collaborators, Affiliations
Clinical Trial

Enzalutamide in metastatic prostate cancer before chemotherapy

Tomasz M Beer et al. N Engl J Med. .

Abstract

Background: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.

Methods: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.

Results: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.

Conclusions: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

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Figures

Figure 1
Figure 1. Kaplan–Meier Estimates of Radiographic Progression-free Survival and Overall Survival
Shown are data for the coprimary end points of radiographic progression-free survival (Panel A) and overall survival (Panel B). The dashed horizontal lines indicate medians. Hazard ratios are based on unstratified Cox regression models with treatment as the only covariate, with values of less than 1.00 favoring enzalutamide.
Figure 2
Figure 2. Kaplan–Meier Estimates for the Times until the Initiation of Cytotoxic Chemotherapy and an Increased Level of Prostate-Specific Antigen
Shown are secondary efficacy end points that include the time until the initiation of cytotoxic chemotherapy (Panel A) and the time until an increased level of prostate-specific antigen (PSA) (Panel B). The horizontal dashed lines indicate medians. Hazard ratios are based on unstratified Cox regression models with treatment as the only covariate, with values of less than 1.00 favoring enzalutamide. The full definition of PSA progression is provided in Table S1 in the Supplementary Appendix.
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