FDA Agrees to Review Supplemental NDA for Enzalutamide in Metastatic Prostate Cancer

The FDA has accepted, for review, a supplemental new drug application (sNDA) for enzalutamide (Xtandi) capsules in patients with metastatic castration-resistant prostate cancer (mCRPC) that includes findings from the head-to-head studies, TERRAIN and STRIVE. The sNDA updates the section of the label that discusses the clinical studies. Astellas Pharma, Inc reports that no change in indication is being sought. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is October 22, 2016.

The randomized TERRAIN trial, which enrolled 375 patients in North America and Europe, compared the efficacy of the two single agents, enzalutamide and bicalutamide. In preclinical studies, enzalutamide demonstrated efficacy because it was tested against bicalutamide-resistant cells. The primary endpoint of the TERRAIN trial was progression-free survival (PFS), with secondary endpoints being change in prostate-specific antigen (PSA) and quality-of-life indicators.

PFS was defined as time from randomization to centrally confirmed radiographic progression, skeletal-related event, and initiation of new anti-neoplastic therapy or death, whichever occurred first. The trial evaluated enzalutamide at a dose of 160 mg taken orally once daily versus bicalutamide at a dose of 50 mg taken once daily, the approved dose in combination with a luteinizing hormone-releasing hormone (LHRH) analogue.

The study achieved its primary objective of a statistically significant increase in PFS for enzalutamide compared with bicalutamide. The median PFS for patients in the enzalutamide arm was 9.9 months longer compared with patients who received bicalutamide (15.7 vs 5.8 months, respectively) with a HR of 0.44 (95% CI, 0.34-0.57). The median time to PSA progression was 13.6 months longer with enzalutamide (19.4 months) relative to bicalutamide treatment (5.8 months) with an HR of 0.28 (82% of enzalutamide-treated patients achieved ≥ 50% PSA reduction from baseline by week 13 versus 21% of bicalutamide-treated patients). The median time on enzalutamide treatment was 11.7 months compared with 5.8 months on bicalutamide. In summary, enzalutamide demonstrated a higher efficacy rate than bicalutamide.

In the topline study results from TERRAIN, the incidence of grade 3 adverse events were 5.5% and 2.1% in the enzalutamide and bicalutamide arms, respectively. In addition, diarrhea, fatigue, hot flush, hypertension, pain in extremities, and weight loss all occurred more frequently in the enzalutamide arm.

The STRIVE trial enrolled 396 CRPC patients in the United States. The trial randomized 257 patients with metastatic prostate cancer and 139 patients with non-metastatic prostate cancer whose disease progressed despite treatment with an LHRH analogue therapy or following surgical castration. The primary endpoint of the trial was PFS, defined as time from randomization to radiographic (bone or soft tissue) progression, PSA progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurs first.

Among men with M0 and M1 CRPC, the median PFS was reported as 19.4 months in patients administered enzalutamide and 5.7 months in patients given bicalutamide. Overall, 70 patients with M0 disease and 128 with M1 CRPC were treated with enzalutamide. The median baseline PSA level was 12 ng/mL. Specifically, in those with M1 disease (n = 257), the median PFS was 16.5 months for those treated with enzalutamide and 5.5 months with bicalutamide.

In those men with M0 CRPC, the median PFS was not yet reached with enzalutamide versus 8.6 months with bicalutamide. The median duration of treatment was 14.7 months with enzalutamide and 8.4 months with bicalutamide. The median time to PSA progression in patients with M0 disease treated with enzalutamide was not reached compared with 11.1 months in the bicalutamide arm. In the M1 arm, PSA progression was seen at 24.9 months with enzalutamide versus 5.7 months with bicalutamide. Overall, 29.4% of patients treated with enzalutamide experienced a serious adverse event compared with 28.3% with bicalutamide.