Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and Drug Administration Drug Approval Summary

Abstract

This article summarizes the regulatory evaluation that led to the full approval of enzalutamide (XTANDI, Medivation Inc.) by the U.S. Food and Drug Administration (FDA) on August 31, 2012, for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. This approval was based on the results of a randomized, placebo-controlled trial which randomly allocated 1,199 patients with mCRPC who had received prior docetaxel to receive either enzalutamide, 160 mg orally once daily (n ¼ 800), or placebo (n ¼ 399). All patients were required to continue androgen deprivation therapy. The primary endpoint was overall survival. At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for the enzalutamide arm compared with the placebo arm [HR ¼ 0.63; 95% confidence interval: 0.53-0.75; P < 0.0001]. The median overall survival durations were 18.4 months and 13.6 months in the enzalutamide and placebo arms, respectively. The most common adverse reactions (10%) included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Seizures occurred in 0.9% of patients on enzalutamide compared with no patients on the placebo arm. Overall, the FDA's review and analyses of the submitted data confirmed that enzalutamide had a favorable benefit-risk profile in the study patient population, thus supporting its use for the approved indication. The recommended dose is 160 mg of enzalutamide administered orally once daily. Enzalutamide represents the third product that the FDA has approved in the same disease setting within a period of 2 years.

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

“…The health of the mice was monitored throughout the study by measuring body weights and checking for abnormal behavior, such as lethargy, lack of hydration, and additional signs of weakness. Tumor size was measured twice weekly and tumor volume calculated using the formula: volume ¼ length  width  depth  0.5236 (mm 3 ). Mice were sacrificed 1 hour after the final dose for tissue harvesting.…”

“…Although androgen deprivation therapy (ADT), currently the treatment of choice for metastatic prostate cancer, can lead to remissions, tumors frequently return in a form that is highly resistant to ADT and other therapies, that is, metastatic castration-resistant prostate cancer (mCRPC). Although the efficacy of mCRPC treatment has recently been improved by using more powerful chemotherapeutics targeting the androgen receptor (AR) signaling axis, such as enzalutamide (3) and abiraterone (4), the overall survival of patients has only marginally increased (5)(6)(7). Moreover, it is thought that further improved versions of such drugs can promote transdifferentiation of prostatic adenocarcinoma to neuroendocrine prostate cancer, a subtype of the disease that is currently incurable (8)(9)(10).…”

Androgen receptor antagonists for prostate cancer therapy

“…In contrast to the 'classical antiandrogens', enz does not only block androgen binding, but it also inhibits translocation of the AR to the nucleus and impairs AR binding to DNA (Tran et al 2009). It has been approved by the FDA and EMA for treating patients with chemo-resistant CRPC (Ning et al 2013). Further structural optimization for inhibition of proliferation, pharmacokinetics, and in vivo efficacy resulted in the development of a compound called ARN-509 (Fig.…”

“…Enzalutamide In patients who progressed during docetaxel therapy, enz has been shown to increase overall survival in comparison with placebo in mCRPC patients in the AFFIRM trial, leading to its FDA approval (Scher et al 2012, Ning et al 2013. A recent report from the AFFIRM trial showed comparable efficacy, safety, and tolerability in patients aged O75 years as well, suggesting its possible future widespread use (Sternberg et al 2014).…”

Advanced prostate cancer &ndash; patient survival and potential impact of enzalutamide and other emerging therapies

“…Enzalutamide, a small molecule AR antagonist is a once daily second generation AR signaling inhibitor that was approved by the FDA in 2012 for the treatment of mCRPC post-chemotherapy with docetaxel 63. Given that the AR transcription program remains active despite emergence of castration resistance,64 this property has been exploited to screen for anti-androgens with specific ability to bind and inhibit the AR without the agonistic effects 65…”