JCO：zibotentan联合多西他赛不能改善转移性去势抵抗前列腺癌患者生存

ENTHUSE (内皮素A的应用) 研究项目的组成部分之一是内皮素A受体拮抗剂zibotentan药效与安全性(ZD4054)研究(NCT00617669)，该部分研究针对转移性去势抵抗前列腺癌(CRPC)患者，旨在对zibotentan联合多西他赛的治疗方案进行考察。在2013年4月8日在线出版的《临床肿瘤学杂志》(Journal of Clinical Oncolgoy)上，法国巴黎第十一大学的Karim S. Fizazi博士等人发表了该研究的相关进展。

在该项随机、双盲、安慰剂对照临床III期研究中，患者在为期21天的治疗周期第一天时，接受75 mg/m²的多西他赛静脉注射，并每日口服10 mg的zibotentan或安慰剂治疗。研究主要终点为总生存率(OS)。次要终点则包括出现疼痛的时间以及前列腺特异性抗原(PSA)进展、疼痛以及PSA缓解率、无进展生存率、与健康相关的生活质量和安全性。

共1,052例患者在本研究中接受了治疗(多西他赛-zibotentan, n = 524; 多西他赛-安慰剂, n = 528)。数据截止时，两组中分别有277例及280例患者死亡。研究结果显示，多西他赛-zibotentan组患者与多西他赛-安慰剂治疗方案组间在OS方面并无差异(风险比, 1.00; 95% CI, 0.84至1.18; P = .963)。根据观察，在次要终点方面也无显著差异，包括出现疼痛进展的时间(中位时间 9.3 个月v 10.0个月)，或疼痛缓解率(风险比, 0.84; 95% CI, 0.61 至1.16; P = .283)方面。Zibotentan组与安慰剂组患者至出现死亡的中位时间分别为20.0 个月与 19.2个月。报告中Zibotentan组的最常见不良事件为外周性水肿(52.7%)、腹泻(35.4%)、脱发(33.9%)以及恶心(33.3%)。

研究人员最终认为，在转移性CRPC患者治疗中，与多西他赛联合安慰剂方案相比，多西他赛联合10 mg/d的zibotentan方案并不能显著改善患者OS。

与前列腺癌相关的拓展阅读：

• 地加瑞克治疗前列腺癌可降低心血管事件风险
• JNCI：PSA筛查并不能预测前列腺癌特异性死亡事件的发生
• NEJM：间歇性雄激素剥夺治疗可小幅改善前列腺癌患者生存质量
• 地加瑞克治疗前列腺癌疗效佳
• Lancet Oncol：经皮雌激素治疗前列腺癌可减少并发症的发生
• 短期雄激素阻断治疗高危前列腺癌安全有效
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Phase III, Randomized, Placebo-Controlled Study of Docetaxel in Combination With Zibotentan in Patients With Metastatic Castration-Resistant Prostate Cancer.
PURPOSE
As part of the ENTHUSE (Endothelin A Use) program, the efficacy and safety of zibotentan (ZD4054), an oral specific endothelin A receptor antagonist, has been investigated in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (CRPC).
Patients And methods
In this randomized, double-blind, placebo-controlled, phase III study, patients received intravenous docetaxel 75 mg/m2 on day 1 of 21-day cycles plus oral zibotentan 10 mg or placebo once daily. The primary end point was overall survival (OS). Secondary end points included time to pain and prostate-specific antigen (PSA) progression, pain and PSA response, progression-free survival, health-related quality of life, and safety.
Results
A total of 1,052 patients received study treatment (docetaxel-zibotentan, n = 524; docetaxel-placebo, n = 528). At the time of data cutoff, there had been 277 and 280 deaths, respectively. There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = .963). No significant differences were observed on secondary end points, including time to pain progression (median 9.3 v 10.0 months, respectively) or pain response (odds ratio, 0.84; 95% CI, 0.61 to 1.16; P = .283). The median time to death was 20.0 and 19.2 months for the zibotentan and placebo groups, respectively. The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%), and nausea (33.3%).
CONCLUSION
Docetaxel plus zibotentan 10 mg/d did not result in a significant improvement in OS compared with docetaxel plus placebo in patients with metastatic CRPC.