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Xtandi (Enzalutamide) Submitted to FDA for Expanded Labeling

Approval sought for use in chemo-naïve patients with advanced prostate cancer

A supplemental new drug application (sNDA) has been submitted to the FDA seeking approval of Xtandi (enzalutamide, Astellas Pharma/Medivation Inc.) for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy. Xtandi was approved in August 2012 for the treatment of patients with mCRPC who have previously received docetaxel chemotherapy.

The sNDA application is based on results from the phase III, randomized, double-blind, placebo-controlled PREVAIL trial, which compared enzalutamide and placebo in more than 1,700 chemotherapy-naïve mCRPC patients whose disease had progressed during treatment with a luteinizing hormone-releasing hormone (LHRH) analogue or after bilateral orchiectomy. The study’s co-primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). The trial was designed to evaluate enzalutamide at a dose of 160 mg taken orally once daily versus placebo.

In this study, patients treated with enzalutamide demonstrated a statistically significant OS advantage compared with patients receiving placebo (P < 0.0001). Enzalutamide provided a 30% reduction in the risk of death compared with placebo (hazard ratio [HR], 0.70). Moreover, patients treated with enzalutamide demonstrated a statistically significant rPFS advantage compared with patients receiving placebo (P < 0.0001). The drug provided an 81% reduction in the risk of radiographic progression or death compared with placebo (HR, 0.19).

In view of the observed benefits in the trial’s co-primary endpoints of OS and rPFS, and considering the drug’s safety profile, an independent data monitoring committee (IDMC) concluded that enzalutamide demonstrated a favorable risk–benefit ratio. The IDMC recommended that the study be stopped and that patients treated with placebo be offered enzalutamide.

The percentage of patients alive in the enzalutamide arm was 72% compared with 65% in the placebo arm at the time of the data cut-off date. Treatment with enzalutamide resulted in a calculated point estimate for median OS of 32.4 months versus 30.2 months for patients receiving placebo. The median rPFS was not yet reached (95% confidence interval, 13.8 months) in the enzalutamide arm and was 3.9 months in the placebo arm.

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. The drug has been shown to competitively inhibit androgen binding to androgen receptors, and to inhibit androgen receptor nuclear translocation and interaction with DNA.

Sources: Astellas Pharma; March 18, 2014; and Medivation Inc.; October 22, 2013.

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