A Meta-Analysis and Indirect Comparison of Endothelin A Receptor Antagonist for Castration-Resistant Prostate Cancer

Background
Endothelin A (ET-A) receptor antagonists including zibotentan and atrasentan, have been suggested as a treatment for castration-resistant prostate cancer (CRPC). Our aim was to conduct a meta-analysis and indirect comparison to assess the efficacy and safety of ET-A receptor antagonists for treatment of CRPC.
Methods
We systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science from inception to November 2014 to identify randomized controlled trials (RCTs) which assessed ET-A receptor antagonists for treatment of CRPC. Meta-analysis was conducted by STATA version 12.0 software.
Results
Eight RCTs were identified, involving 6,065 patients. The results of direct comparison showed that compared with placebo, there was no statistically significant difference in the improvement of progression-free survival (PFS), overall survival (OS), time to disease progression (TTP), and total adverse events (AEs) with ET-A receptor antagonist treatment for CRPC. The results of ET-A receptor antagonists plus docetaxel versus docetaxel alone were similar. The indirect comparisons showed that there were no significant differences between zibotentan plus docetaxel versus atrasentan plus docetaxel when compared with docetaxel alone or zibotentan versus atrasenta compared with placebo in the improvement of PFS, OS, TTP, and total adverse events.
Conclusions
There were no significant benefits for ET-A receptor antagonists with or without docetaxel in the improvement of PFS, OS, TTP, and overall AEs. And there were no significant differences between zibotentan and atrasentan. Single-agent docetaxel should remain as one of the standard treatments.

背景 内皮素A（ET-A）受体拮抗剂（包括齐博坦与阿曲生坦）已被提议作为去势抵抗性前列腺癌（Castration-Resistant Prostate Cancer, CRPC）的治疗方案。本研究旨在通过Meta分析与间接比较，评估ET-A受体拮抗剂治疗CRPC的疗效与安全性。
方法 我们系统检索了PubMed、EMBASE、Cochrane图书馆及Web of Science数据库，检索时限从建库至2014年11月，以筛选评估ET-A受体拮抗剂治疗CRPC的随机对照试验（Randomized Controlled Trials, RCTs）。采用STATA 12.0版本软件进行Meta分析。
结果 共纳入8项RCTs，涉及6065例患者。直接比较结果显示，与安慰剂组相比，ET-A受体拮抗剂治疗CRPC对无进展生存期（Progression-Free Survival, PFS）、总生存期（Overall Survival, OS）、疾病进展时间（Time to Disease Progression, TTP）及总不良事件（Adverse Events, AEs）的改善均无统计学显著差异。ET-A受体拮抗剂联合多西他赛对比单纯多西他赛的结果亦相似。间接比较结果显示，当分别以单纯多西他赛或安慰剂为对照时，齐博坦联合多西他赛与阿曲生坦联合多西他赛之间、齐博坦与阿曲生坦之间，在PFS、OS、TTP及总不良事件的改善方面均无显著差异。
结论 无论是否联合多西他赛，ET-A受体拮抗剂在改善PFS、OS、TTP及总不良事件方面均无显著获益。且齐博坦与阿曲生坦之间亦无显著差异。多西他赛单药仍应作为标准治疗方案之一。