恩杂鲁胺用于未经化疗、转移性去势抵抗性前列腺癌的日本患者：安慰剂对照PREVAIL试验的事后分析

Enzalutamide in Japanese patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer: A post-hoc analysis of the placebo-controlled PREVAIL trial.

作者信息

Kimura Go, Yonese Junji, Fukagai Takashi, Kamba Tomomi, Nishimura Kazuo, Nozawa Masahiro, Mansbach Hank, Theeuwes Ad, Beer Tomasz M, Tombal Bertrand, Ueda Takeshi

机构信息

Department of Urology, Nippon Medical School, Tokyo, Japan.

Department of Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

出版信息

Int J Urol. 2016 May;23(5):395-403. doi: 10.1111/iju.13072. Epub 2016 Mar 27.

DOI:10.1111/iju.13072

PMID:27018069

Abstract

OBJECTIVES

To evaluate the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients.

METHODS

This was a post-hoc analysis of the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naïve patients with metastatic castration-resistant prostate cancer progressing on androgen deprivation therapy were randomized one-to-one to 160 mg/day oral enzalutamide or placebo until discontinuation on radiographic progression or skeletal-related event and initiation of subsequent antineoplastic therapy. Coprimary end-points were centrally assessed radiographic progression-free survival and overall survival. Secondary end-points were investigator-assessed radiographic progression-free survival, time to initiation of chemotherapy, time to prostate-specific antigen progression, prostate-specific antigen response (≥50% decline) and time to skeletal-related event.

RESULTS

Of 1717 patients, 61 were enrolled in Japan (enzalutamide, n = 28; placebo, n = 33); hazard ratios (95% confidence interval) of 0.30 for centrally assessed radiographic progression-free survival (0.03-2.95), 0.59 for overall survival (0.20-1.8), 0.46 for time to chemotherapy (0.22-0.96) and 0.36 for time to prostate-specific antigen progression (0.17-0.75) showed the treatment benefit of enzalutamide over the placebo. Prostate-specific antigen responses were observed in 60.7% of enzalutamide-treated men versus 21.2% of placebo-treated men. Plasma concentrations of enzalutamide were higher in Japanese patients: the geometric mean ratio of Japanese/non-Japanese patients was 1.126 (90% confidence interval 1.018-1.245) at 13 weeks. Treatment-related adverse events grade ≥3 occurred in 3.6% of enzalutamide- and 6.1% of placebo-treated Japanese patients.

CONCLUSION

Treatment effects and safety in Japanese patients were generally consistent with the overall results from PREVAIL.

摘要

目的

评估恩杂鲁胺在日本患者中的治疗效果、安全性及药代动力学。

方法

这是一项对3期双盲、安慰剂对照的PREVAIL试验的事后分析。无症状或症状轻微、未接受过化疗且在雄激素剥夺治疗期间病情进展的转移性去势抵抗性前列腺癌患者被一对一随机分配至口服160毫克/天恩杂鲁胺组或安慰剂组，直至因影像学进展或骨骼相关事件停药并开始后续抗肿瘤治疗。共同主要终点为中心评估的影像学无进展生存期和总生存期。次要终点为研究者评估的影像学无进展生存期、开始化疗的时间、前列腺特异性抗原进展时间、前列腺特异性抗原反应（下降≥50%）以及骨骼相关事件发生时间。

结果

1717例患者中，61例来自日本（恩杂鲁胺组，n = 28；安慰剂组，n = 33）；中心评估的影像学无进展生存期的风险比（95%置信区间）为0.30（0.03 - 2.95），总生存期为0.59（0.20 - 1.8），开始化疗时间为0.46（0.22 - 0.96），前列腺特异性抗原进展时间为0.36（0.17 - 0.75），表明恩杂鲁胺相对于安慰剂具有治疗益处。接受恩杂鲁胺治疗的男性中60.7%观察到前列腺特异性抗原反应，而接受安慰剂治疗的男性中这一比例为21.2%。日本患者中恩杂鲁胺的血浆浓度较高：在第13周时，日本/非日本患者的几何平均比值为1.126（90%置信区间1.018 - 1.245）。接受恩杂鲁胺治疗的日本患者中3.6%发生≥3级治疗相关不良事件，接受安慰剂治疗的日本患者中这一比例为6.1%。