安斯泰来前列腺癌新药Xtandi III期PREVAIL达主要终点

安斯泰来（Astellas）和Medivation制药10月22日宣布，独立数据监测委员会（IDMC）已告知双方，对前列腺癌药物Xtandi（enzalutamide）全球性III期PREVAIL研究的一项既定中期分析取得了积极结果。该项试验在1700多例经雄激素剥夺疗法治疗后病情恶化且还未接受化疗的转移性前列腺癌患者中开展。

鉴于该试验中所观察到的共同主要终点——影像学无进展生存期（radiographic PFS）和总生存期（OS）的临床利益，以及所观察到的安全属性，IDMC得出结论称，enzalutamide表现出了良好的利益-风险比（benefit-risk ratio）。IDMC建议终止PREVAIL试验，同时明确建议向安慰剂组提供enzalutamide治疗。III期PREVAIL试验的数据，以及安全性数据，将提交至即将召开的医学会议。

安斯泰来和Medivation将于2014年初向各地监管机构提交enzalutamide的监管文件。

IDMC中期分析的数据如下：

—与安慰剂组相比，enzalutamide治疗组总生存期（OS）表现出了统计学意义的显着优势（p＜0.0001），死亡风险降低30%（HR=0.70，95% CI:0.59-0.83）。

—与安慰剂组相比，enzalutamide治疗组影像学无进展生存期（radiographic PFS）表现出了统计学意义的显着优势（p＜0.0001），影像学进展或死亡风险降低81%（HR=0.19，95% CI:0.15-0.23）。

—在中期数据分析截止时间，enzallutamide治疗组患者患者存活率为72%，计算点估计中位总生存期为32.4个月（95% CI，31.5个月上限尚未达到）；安慰剂组患者存活率为65%，计算点估计中位总生存期为30.2个月（95% CI，28.0个月上限尚未达到）。因为实验将提前终止，同时大多患者仍然存活，估计的总生存期不会与HR一样精确。

—enzalutamide治疗组中位影像学无进展生存期（radiographic PFS）数据尚未取得（95% CI，13.8个月上限尚未达到），安慰剂组影像学无进展生存期为3.9个月（95% CI，3.7-5.4）。

—鉴于整体存活率利益和所观察到的安全性，IDMC认为整体利益-风险比利于enzalutamide治疗组，同时明确建议对安慰剂组患者提供enzalutamide治疗。

Xtandi（enzalutamide）是一种口服、日服一次的雄激素受体抑制剂，旨在干扰睾酮结合前列腺癌细胞的能力，该药于2012年8月31日获FDA批准用于既往接受过多西紫杉醇化疗的转移性阉割性前列腺癌患者的治疗。睾酮是一种男性激素，能够激化前列腺癌细胞的生长。

英文原文：Medivation, Astellas prostate cancer drug meets trial goals

Medivation and Astellas Announce the Phase 3 PREVAIL Trial of Enzalutamide Meets Both Co-Primary Endpoints of Overall Survival and Radiographic Progression-Free Survival in Chemotherapy-Naive Patients With Advanced Prostate Cancer

Study Will Be Stopped Early and Enzalutamide Will Be Offered to All Qualified Study Participants; 30% Reduction in the Risk of Death, Hazard Ratio=0.70 (p < 0.0001); 81% Reduction in the Risk of Radiographic Progression or Death, Hazard Ratio=0.19 (p < 0.0001); Medivation to Hold Conference Call at 8:30 a.m. Eastern Time Today

SAN FRANCISCO, CA and TOKYO, JAPAN -- (Marketwired) -- 10/22/13 -- Medivation, Inc. (NASDAQ: MDVN) and Astellas Pharma Inc. (TSE: 4503) today announced that the Independent Data Monitoring Committee (IDMC) has informed the companies of positive results from a planned interim analysis of the global Phase 3 PREVAIL trial of enzalutamide in more than 1,700 men with metastatic prostate cancer that has progressed despite androgen deprivation therapy and who have not yet received chemotherapy. Given the observed benefits in the trial's co-primary endpoints of overall survival and radiographic progression-free survival, and considering the observed safety profile, the IDMC concluded enzalutamide demonstrated a favorable benefit-risk ratio. The IDMC recommended the study be stopped and patients treated with placebo be offered enzalutamide. Additional data from the Phase 3 PREVAIL results, including safety data, will be submitted for presentation at an upcoming medical conference.

The IDMC informed the companies of the following results:

Patients treated with enzalutamide demonstrated a statistically significant overall survival advantage compared with patients receiving placebo (p < 0.0001). Enzalutamide provided a 30% reduction in risk of death compared with placebo (Hazard Ratio=0.70; 95% confidence interval, 0.59-0.83).

Patients treated with enzalutamide demonstrated a statistically significant radiographic progression-free survival advantage compared with patients receiving placebo (p < 0.0001). Enzalutamide provided an 81% reduction in risk of radiographic progression or death compared with placebo (Hazard Ratio=0.19; 95% confidence interval, 0.15-0.23).

The percentage of patients alive in the enzalutamide arm was 72% as compared with 65% in the placebo arm at the time of the interim analysis data cut-off date. Treatment with enzalutamide resulted in a calculated point estimate for median overall survival of 32.4 months (95% confidence interval, 31.5 months-upper limit not yet reached) versus 30.2 months (95% confidence interval, 28.0 months-upper limit not yet reached) for patients receiving placebo. Because the trial will be stopped early with the majority of patients still alive, the estimated median survivals are not as precise as the hazard ratio. The hazard ratio takes into account available information about the trial endpoint from all patients whereas the median is a single point estimate of a much smaller number of patients at risk.

The median radiographic progression-free survival was not yet reached (95% confidence interval, 13.8 months-upper limit not yet reached) in the enzalutamide arm and was 3.9 months (95% confidence interval, 3.7-5.4) in the placebo arm.

Given the overall survival benefit and the observed safety profile, the IDMC considered the overall benefit-risk ratio to favor the enzalutamide arm and recommended unequivocally that patients receiving placebo be offered treatment with enzalutamide.

Of the 1,715 patients treated in the blinded PREVAIL study, two patients were reported by investigators to have had a seizure event. The full analysis of the safety data will become available upon final database lock and unblinding.

"To my knowledge, the benefits in overall survival and radiographic progression-free survival reported in today's PREVAIL trial results are unprecedented in this patient population," said Tomasz M. Beer, M.D., F.A.C.P., professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health & Science University, and the co-principal investigator of the PREVAIL study.

"Achieving statistically-significant and clinically meaningful results in both co-primary endpoints -- overall survival and radiographic progression-free survival -- is an important outcome for patients and we are excited by the results of the Phase 3 PREVAIL trial," said David Hung, M.D., founder, president and CEO, Medivation. "I extend my sincere thanks to the patients, physicians, study teams and other collaborators around the world, who have been instrumental in helping us achieve this important milestone."

"We are very pleased about these results and will work closely with Medivation to pursue an expanded indication for enzalutamide," said Sef Kurstjens, M.D., Ph.D., Chief Medical Officer of Astellas. "We are committed to being at the forefront of the fight against prostate cancer by providing patients with treatment options to help them manage their disease."

Medivation and Astellas will initiate meetings with and submissions to regulatory agencies beginning in early 2014.

About PREVAIL

The Phase 3 PREVAIL trial is a randomized, double-blind, placebo-controlled, multi-national trial that enrolled more than 1,700 patients at sites in the United States, Canada, Europe, Australia, Russia, Israel and Asian countries including Japan. The trial enrolled patients with metastatic prostate cancer whose disease progressed despite treatment with androgen deprivation therapy and had not yet received chemotherapy. The co-primary endpoints of the trial are overall survival and radiographic progression-free survival. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken orally once daily versus placebo. Targeted enrollment was completed in May 2012 and the interim analysis was pre-specified after 516 events (patient deaths).

Enzalutamide Mechanism of Action

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

About XTANDI? (enzalutamide) capsules

XTANDI was approved by the FDA on August 31, 2012 and is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.