Treatment with enzalutamide after progression with androgen deprivation therapy (ADT) led to a significant improvement in survival for men with metastatic castration-resistant prostate cancer (mCRPC). Patients randomized to placebo had a median radiographic progression-free survival (rPFS; primary end point) of 3.9 months, whereas the median had not been reached in the enzalutamide group, as reported at the 2014 American Urological Association Annual Meeting..
“In both the intention-to-treat population and in the subgroup of patients with nonvisceral disease, treatment with enzalutamide significantly delayed the progression of metastatic disease, reduced the risk of death, and delayed the time to initiation of cytotoxic chemotherapy,” said Christopher P. Evans, MD, chair, department of urology, UC Davis, Sacramento. “Consistent benefits also were seen in the visceral disease group.”
“Enzalutamide added to androgen deprivation therapy at progression provides meaningful clinical benefit to men with metastatic castration-resistant prostate cancer.”
Enzalutamide disrupts androgen signaling by affecting 3 activities involving the androgen receptor. The drug inhibits binding of androgens to the androgen receptor, inhibits androgen receptor nuclear translocation, and inhibits androgen receptor–mediated DNA binding. In the postdocetaxel setting, enzalutamide treatment resulted in improved survival and rPFS (Scher HI, et al. N Engl J Med. 2012;367:1187-1197).
Evans reported data from the phase 3 PREVAIL trial involving men with mCRPC who had progressed with ADT but who had not yet received chemotherapy. Inclusion criteria limited enrollment to patients who were asymptomatic or who had only mild symptoms. Patients continued ADT and were randomized to enzalutamide 160 mg daily or placebo. The trial had coprimary end points: rPFS and overall survival (OS).
Investigators in the multicenter international trial enrolled and randomized 1717 patients. A final OS analysis was planned to occur after 765 events had occurred. The trial ended prematurely after a planned interim analysis demonstrated statistically significant advantages in favor of enzalutamide.
The total patient population included 204 patients with visceral involvement. The men had a median age of approximately 71 years, and approximately 50% had a Gleason score of ?8 at diagnosis. Almost 90% of the patients had had previous antiandrogen exposure, and approximately one-fourth had undergone radical prostatectomy.
Overall, approximately 80% of the patients had bone metastases, and more than 50% of them had soft-tissue disease.
The median treatment duration was almost 17 months in the enzalutamide arm versus 4.7 months in the placebo group (P=.001), and the magnitude of benefit was similar in patients with and without visceral involvement. Treatment duration in the subgroup with visceral disease was 14 months with enzalutamide and 3.7 months with placebo. Almost 70% of patients in the enzalutamide arm completed at least 12 months of treatment, said Evans.
At the interim analysis, median OS was 32.4 months (upper confidence interval not yet reached) with enzalutamide and 30.2 months with placebo, representing a 30% reduction in the hazard ratio (HR; P<.001). Patients without visceral disease also had significant improvement in OS (not yet reached vs 30.2 months with placebo; HR 0.692; P=.001). In the patients with visceral involvement, OS at the interim analysis favored enzalutamide (27.8 vs 22.8 months), but the upper limit of the confidence intervals had yet to be reached in either treatment arm.
Approximately 70% of patients in the placebo group received at least 1 additional therapy versus 40% in the enzalutamide arm. Treatment with enzalutamide more than doubled the time to chemotherapy (28.0 vs 10.8 months; HR 0.349; P<.001), although that analysis is ongoing.
Enzalutamide was associated with slightly more adverse events, including serious adverse events (31.6% vs 26.2%) and grade ?3 adverse events (42.3% vs 37.3%). The time to a first grade ?3 adverse event was prolonged in the enzalutamide arm (22.7 vs 13.7 months), and discontinuation related to adverse events (5.6% vs 5.3%) and fatal adverse events (3.5% vs 3.7%) occurred in a similar proportion of each group.
