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, Tomasz M. Beer, MD, of OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, and colleagues 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.¹ The trial was stopped after demonstration of benefit at the first overall survival interim analysis.

Study Details

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 at 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 age (median, 72 and 71 years; 21% < 65 years in both), ethnicity (77% white in both, 10% Asian in both), Eastern Cooperative Oncology Group performance status (0 in 67% and 69%, 1 in 33% and 31%), prostate-specific antigen (PSA) level (median, 54 vs 42 µg/L), history of cardiovascular disease (21% vs 20%), Gleason score (≤ 7 in 49% and 48%, ≥ 8 in 51% and 52%), time from diagnosis or first treatment (median, 63 and 65 months), and type of disease progression at study entry (PSA only in 43% and 44%, PSA and radiographic in 40% and 41%, radiographic only in 15% and 13%).

The two group were similarly balanced for disease localization (bone only in 40% in both, soft tissue only in 14% and 18%, bone and soft tissue in 45% and 42%), distribution of disease (bone in 85% and 82%, lymph nodes in 50% and 51%, lung or liver visceral disease in 11% and 13%), use of prior antiandrogens (87% and 86%), number of prior antiandrogens (1 for 66% in both, 2 in 19% and 18%), and number of bone metastases (0 in 15% and 18%, 1–9 in 52% and 49%, 10–20 in 16% and 14%, > 20 in 17% and 18%).

Survival Benefits

At 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. Hazard ratios for radiographic progression-free survival were significant in favor of enzalutamide in all subgroup analyses, consisting of those according to ECOG performance status 0 and 1, age < 75 and ≥ 75 years, geographic region, and Gleason score at diagnosis of ≤ 7 and ≥ 8, PSA progression only and radiographic progression with or without PSA progression at study entry, presence and absence of visceral disease, PSA value above and below median, lactate dehydrogenase level above and below median, hemoglobin level above and below median, and presence and absence of baseline bisphosphonate or denosumab (Xgeva) use. Risk reduction with enzalutamide was not affected by prior exposure to antiandrogens.

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 overall survival, with hazard ratios being significant in favor of enzalutamide for most. The overall survival benefit was also not affected by previous exposure to antiandrogens.

In an updated overall survival analysis (including 116 additional deaths), 82% vs 73% of patients in the enzalutamide and placebo groups, respectively, remained alive at 18 months; median overall survival was estimated at not reached vs 31.0 months (HR = 0.73, P < .001).

Subsequent anticancer therapy was taken by 44% of the enzalutamide group and 76% of the placebo group, including treatments associated with survival benefit in metastatic prostate cancer by 40% and 70%, respectively; the most commonly used of the latter were docetaxel (33% and 57%), abiraterone (Zytiga, 21% and 46%), and cabazitaxel (Jevtana, 6% and 13%). This difference was largely a reflection of the difference in the percentage of participants still receiving their assigned study treatment at the time of the analysis, Dr. Beer explained to The ASCO Post.

Improved Secondary Endpoints

Enzalutamide treatment was associated with significant reduction in the risk of all secondary endpoints (P < .001 for all), as reflected in prolongation of median time to initiation of cytotoxic chemotherapy, median time to first skeletal-related event, and median time to PSA progression. The drug was also associated with significantly greater rates (P < .001 for all) of complete or partial soft-tissue response in patients with measurable disease at baseline (59%, including complete response in 20%, vs 5%, including complete response in 1%) and achievement of PSA decline of ≥ 50% (78% vs 3%) and ≥ 90% (47% vs 1%).

In an exploratory quality of life analysis using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale, enzalutamide treatment was associated with a significantly greater time to decline in FACT-P global score (median, 11.3 vs 5.6 months, HR = 0.63, P < .001).

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 or higher occurred in 43% vs 37% of patients, with the median time until the 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 in the enzalutamide and placebo groups, respectively, 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.” n

Disclosure: The study was funded by Medivation and Astellas Pharma. Dr. Beer has received research grants from Astellas Pharma, and Medivation. For full disclosures of all study authors, visit www.nejm.org.

Reference

1. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. June 1, 2014 (early release online).