Division of Cancer Studies, University of Birmingham, Birmingham, UK.
BJU Int. 2010 Oct;106(7):966-73. doi: 10.1111/j.1464-410X.2010.09638.x.
To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration-resistant prostate cancer (CRPC).
Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once-daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety.
In total, 312 patients were randomized (placebo, n= 107; zibotentan 10 mg, n= 107; zibotentan 15 mg, n= 98). The median duration of study treatment and median follow-up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61-0.94; P= 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67-1.02; P= 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion.
The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme.
报告一项Ⅱ期临床试验的最终分析结果，该试验旨在研究特定的内皮素 A 受体拮抗剂齐索坦（阿斯利康，英国麦克尔斯菲尔德）在转移性去势抵抗性前列腺癌（CRPC）患者中的安全性和疗效。
无疼痛或轻度疼痛的 CRPC 伴骨转移患者随机接受每日口服齐索坦 10mg、15mg 片剂或安慰剂治疗。主要终点为进展时间，次要终点包括总生存期、骨转移数量变化以及安全性。
共有 312 例患者被随机分组（安慰剂组 107 例，齐索坦 10mg 组 107 例，齐索坦 15mg 组 98 例）。研究治疗的中位持续时间和中位随访时间分别为 4 个月和 22 个月。在最终分析时，各组间进展时间的主要结局无统计学差异，尽管与安慰剂组相比，齐索坦组的总生存期有所改善。与总生存期的先前分析一致，齐索坦 15mg 组（风险比[HR]，0.76；95%置信区间[CI]，0.61-0.94；P=0.103）和 10mg 组（HR，0.83；95%CI，0.67-1.02；P=0.254）的 HR 均小于 1。最常报告的认为与齐索坦治疗相关的不良事件是外周水肿、头痛和鼻塞。
本研究结果支持内皮素 A 受体拮抗作用作为治疗 CRPC 患者的一种方法。为了证实本研究中观察到的生存信号，齐索坦正在进一步进行 ENdoTHelin A USE（ENTHUSE）Ⅲ期临床试验研究。
