ASCO 2014: Enzalutamide Before Chemotherapy Prolongs Progression-Free and Overall Survival in Metastatic Prostate Cancer
The androgen receptor inhibitor enzalutamide (Xtandi) has been shown to prolong survival in men with metastatic castration-resistant prostate cancer with progressive disease after chemotherapy. In the phase III PREVAIL trial reported in The New England Journal of Medicine, Beer et al found that enzalutamide treatment prior to chemotherapy was associated with significantly prolonged progression-free survival, overall survival, and time to chemotherapy compared with placebo in patients with metastatic disease progressing despite androgen-deprivation therapy. The trial was stopped after demonstration of benefit at the first overall survival interim analysis. These data were also presented at the 2014 ASCO Annual Meeting in Chicago (Abstract 5007).
In the double-blind trial, 1,717 patients with minimally symptomatic or asymptomatic metastatic prostate cancer who had not received chemotherapy were randomly assigned to receive oral enzalutamide 160 mg/d (n = 872) or placebo (n = 845). The coprimary endpoints were radiographic progression-free survival and overall survival. The enzalutamide and placebo groups were balanced for baseline demographics and disease characteristics.
Survival Benefits
At follow-up of 12 months, the rate of radiographic progression-free survival was 65% in the enzalutamide group vs 14% in the placebo group (hazard ratio [HR] = 0.19, P < .001). Median radiographic progression-free survival was not reached vs 3.9 months. At the planned interim analysis of overall survival (after 540 deaths), median duration of follow-up for survival was 22 months. Death had occurred in 28% of enzalutamide patients vs 35% of placebo patients (HR = 0.71, P < .001). Median overall survival was estimated at 32.4 vs 30.2 months.
The treatment effect of enzalutamide was consistent across all prespecified subgroups for both progression-free survival and overall survival, and risk reductions for both were not affected by previous exposure to antiandrogens. In an updated overall survival analysis (including 116 additional deaths), 82% vs 73% of patients remained alive at 18 months; median overall survival was estimated at not reached vs 31.0 months (HR = 0.73, P < .001).
Subsequent therapy associated with survival benefit in metastatic prostate cancer was received by 40% of the enzalutamide group and 70% of the placebo group, with the two most common treatments being docetaxel (33% and 57%) and abiraterone (Zytiga; 21% and 46%).
Improved Secondary Endpoints
Enzalutamide treatment was associated with significant prolongation (P < .001 for all) of median time to initiation of cytotoxic chemotherapy (28.0 vs 10.8 months, HR = 0.35), median time to first skeletal-related event (31.1 vs 31.3 months, HR = 0.72), and median time to prostate-specific antigen (PSA) progression (11.2 vs 2.8 months, HR = 0.17) and significantly greater rates (P < .001 for all) of complete or partial soft-tissue response (59% vs 5%) and achievement of PSA decline of ≥ 50% (78% vs 3%) and ≥ 90% (47% vs 1%).
Adverse Events
The median duration of study drug treatment was 16.6 months in the enzalutamide group and 4.6 months in the placebo group and the median reporting period for adverse events was 17.1 vs 5.4 months. Adverse events of ≥ grade 3 occurred in 43% vs 37% of patients, with the median time until first grade 3 event being longer in the enzalutamide group (22.3 vs 13.3 months). Adverse events of any grade occurring in ≥ 20% of enzalutamide patients and at a rate ≥ 2% higher than in placebo patients consisted of fatigue, back pain, constipation, and arthralgia.
After adjustment for length of exposure, events with a higher rate per 100 patient-years in the enzalutamide group were hot flush (14 vs 12), hypertension (11 vs 7), and falls (11 vs 9). Hypertension was the most common adverse event of ≥ grade 3 in the enzalutamide group (7%), and the most common cardiac event was atrial fibrillation (2% vs 1% in placebo group). Serious adverse events occurred in 32% vs 27% of patients and adverse events led to treatment discontinuation in 6% vs 6% and to death in 4% vs 4%. There was no evidence of enzalutamide-associated hepatotoxicity.
The investigators concluded, “Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.”
Tomasz Beer, MD, of the OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Medivation and Astellas Pharma. For full disclosures of the study authors, visit www.nejm.org or view the study abstract at abstract.asco.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
