恩杂鲁胺用于未经化疗的转移性去势抵抗性前列腺癌患者的随机安慰剂对照PREVAIL试验中对东亚患者的事后分析。
Post hoc analyses of East Asian patients from the randomized placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer.
作者信息
Kim Choung Soo, Choi Young Deuk, Lee Sang Eun, Lee Hyun Moo, Ueda Takeshi, Yonese Junji, Fukagai Takashi, Chiong Edmund, Lau Weber, Abhyankar Sarang, Theeuwes Ad, Tombal Bertrand, Beer Tomasz M, Kimura Go
机构信息
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine Department of Urology, Yonsei University College of Medicine Department of Urology, Seoul National University Bundang Hospital Department of Urology, Samsung Medical Center, Seoul, Korea Prostate Center and Division of Urology, Chiba Cancer Center, Chiba Department of Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research Department of Urology, Showa University Koto Toyosu Hospital, Tokyo, Japan Department of Urology, National University Health System Urology Centre, Singapore General Hospital, Singapore Medical Affairs, Medivation, Inc., San Francisco, CA [Medivation was acquired by Pfizer Inc in September 2016] Biostatistics, Astellas Pharma Europe B.V., Leiden, The Netherlands Division of Urology, Cliniques universitaires Saint-Luc, Brussels, Belgium OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR Department of Urology, Nippon Medical School, Tokyo, Japan.
出版信息
Medicine (Baltimore). 2017 Jul;96(27):e7223. doi: 10.1097/MD.0000000000007223.
BACKGROUND
Enzalutamide is an androgen receptor (AR) inhibitor that acts on different steps in the AR signaling pathway. In PREVAIL, an international, phase III, double-blind, placebo-controlled trial, enzalutamide significantly reduced the risk of radiographic progression by 81% (hazard ratio [HR], 0.19; P < .0001) and reduced the risk of death by 29% (HR, 0.71; P < .0001) compared with placebo in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.
METHODS
To evaluate treatment effects, safety, and pharmacokinetics of enzalutamide in East Asian patients from the PREVAIL trial, we performed a post hoc analysis of the Japanese, Korean, and Singaporean patients. PREVAIL enrolled patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer who had progressed on androgen deprivation therapy. During the study, patients received enzalutamide (160 mg/d) or placebo (1:1) until death or discontinuation because of radiographic progression or skeletal-related event and initiation of subsequent therapy. Centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS) were coprimary endpoints. The secondary endpoints of the PREVAIL trial were investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, and PSA response (≥50% decline).
RESULTS
Of 1717 patients, 148 patients were enrolled at sites in East Asia (enzalutamide 73, placebo 75). Treatment effect of enzalutamide versus placebo was consistent with that for the overall population as indicated by the HRs (95% confidence interval) of 0.38 (0.10-1.44) for centrally assessed rPFS, 0.59 (0.29-1.23) for OS, 0.33 (0.19-0.60) for time to chemotherapy, and 0.32 (0.20-0.50) for time to PSA progression. In East Asian patients, PSA responses were observed in 68.5% and 14.7% of enzalutamide- and placebo-treated patients, respectively. The enzalutamide plasma concentration ratio (East Asian:non-Asian patients) was 1.12 (90% confidence interval, 1.05-1.20) at 13 weeks. Treatment-related adverse events grade ≥ 3 occurred in 1.4% and 2.7% of enzalutamide- and placebo-treated East Asian patients, respectively.
CONCLUSIONS
Treatment effects and safety of enzalutamide in East Asian patients were generally consistent with those observed in the overall study population from PREVAIL. CLINICALTRIALS.
GOV NUMBER
NCT01212991.
背景
恩杂鲁胺是一种雄激素受体（AR）抑制剂，作用于AR信号通路的不同环节。在PREVAIL试验中，这是一项国际III期双盲、安慰剂对照试验，与安慰剂相比，恩杂鲁胺使初治转移性去势抵抗性前列腺癌男性患者的影像学进展风险显著降低81%（风险比[HR]，0.19；P<0.0001），死亡风险降低29%（HR，0.71；P<0.0001）。
方法
为评估恩杂鲁胺在PREVAIL试验东亚患者中的治疗效果、安全性和药代动力学，我们对日本、韩国和新加坡患者进行了事后分析。PREVAIL纳入了无症状或症状轻微、初治转移性去势抵抗性前列腺癌且在雄激素剥夺治疗后病情进展的患者。在研究期间，患者接受恩杂鲁胺（160mg/天）或安慰剂（1:1）治疗，直至死亡或因影像学进展或骨相关事件以及开始后续治疗而停药。中心评估的影像学无进展生存期（rPFS）和总生存期（OS）是共同主要终点。PREVAIL试验的次要终点包括研究者评估的rPFS、开始化疗的时间、前列腺特异性抗原（PSA）进展时间和PSA反应（下降≥50%）。
结果
在1717例患者中，148例在东亚地区的研究点入组（恩杂鲁胺组73例，安慰剂组75例）。恩杂鲁胺与安慰剂相比的治疗效果与总体人群一致，中心评估的rPFS的HR（95%置信区间）为0.38（0.10 - 1.44），OS为0.59（0.29 - 1.23），开始化疗时间为0.33（0.19 - 0.60），PSA进展时间为0.32（0.20 - 0.50）。在东亚患者中，恩杂鲁胺治疗组和安慰剂治疗组的PSA反应率分别为68.5%和14.7%。13周时，恩杂鲁胺血浆浓度比（东亚患者：非亚洲患者）为1.12（90%置信区间，1.05 - 1.20）。恩杂鲁胺治疗组和安慰剂治疗组的东亚患者中，≥3级治疗相关不良事件的发生率分别为1.4%和2.7%。
结论
恩杂鲁胺在东亚患者中的治疗效果和安全性总体上与PREVAIL总体研究人群中观察到的一致。临床试验。
美国国立医学图书馆临床试验注册号
NCT01212991。
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