Orlando, FL—Treatment with enzalutamide (Xtandi) after progression with androgen-deprivation therapy (ADT) led to a significant improvement in survival for men with metastatic castration-resistant prostate cancer (mCRPC), according to a new randomized trial reported at the 2014 American Urological Association annual meeting.
Patients randomized to placebo had a median radiographic progression-free survival (PFS; primary end point) of 3.9 months, whereas the median had not been reached in the enzalutamide group, said Christopher P. Evans, MD, Chair, Department of Urology, University of California, Davis, Sacramento.
“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 Dr Evans. “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,” he added.
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 radiographic PFS (Scher HI, et al. N Engl J Med. 2012;367:1187-1197).
Phase 3 Clinical Trial: PREVAIL
The data came from the multicenter international phase 3 clinical trial PREVAIL involving 1717 patients with mCRPC who had progressed with ADT but who had not yet received chemotherapy. The 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 to placebo. The coprimary end points were radiographic PFS and overall survival (OS).
A final OS analysis was planned to take place after 765 events had occurred, but the trial ended prematurely after a planned interim analysis demonstrated significant advantages in the coprimary end points in favor of enzalutamide.
The total patient population included 204 patients with visceral involvement. The median age was approximately 71 years, and approximately 50% of patients had a Gleason score of ≥8 at diagnosis; almost 90% had previous antiandrogen exposures, and approximately 25% had undergone radical prostatectomy.
Overall, approximately 80% of the patients had bone metastases, and more than 50% 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 Dr Evans.
At the interim analysis, the 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.
Enzalutamide more than doubled the time to chemotherapy versus placebo (28 vs 10.8 months, respectively; HR, 0.349; P <.001), although that analysis is ongoing.
Enzalutamide was associated with slightly more adverse events (AEs), including serious events (31.6% vs 26.2%, respectively) and grade ≥3 (42.3% vs 37.3%, respectively). The time to a first grade ≥3 AE was prolonged in the enzalutamide arm versus placebo (22.7 vs 13.7 months, respectively), and discontinuation related to AEs and fatal AEs occurred in a similar proportion of patients in each group.