Fizazi Karim, Jones Robert, Oudard Stephane, Efstathiou Eleni, Saad Fred, de Wit Ronald, De Bono Johann, Cruz Felipe Melo, Fountzilas George, Ulys Albertas, Carcano Flavio, Agarwal Neeraj, Agus David, Bellmunt Joaquim, Petrylak Daniel P, Lee Shih-Yuan, Webb Iain J, Tejura Bindu, Borgstein Niels, Dreicer Robert
Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif; Stephane Oudard, Université Paris Descartes, Paris, France; Robert Jones, Institute of Cancer Sciences, University of Glasgow, Glasgow; Johann De Bono, The Institute of Cancer Research, London, United Kingdom; Eleni Efstathiou, University of Athens Medical School, Athens; George Fountzilas, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Fred Saad, University of Montreal Hospital Center, Montreal, Canada; Ronald de Wit, Erasmus University Medical Center, Rotterdam, the Netherlands; Felipe Melo Cruz, ABC Foundation School of Medicine, Santo André; Flavio Carcano, Hospital de Cancer de Barretos, Barretos, Brazil; Albertas Ulys, Institut of Oncology, Vilnius University, Vilnius, Lithuania; Neeraj Agarwal, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; David Agus, University of Southern California, Los Angeles, CA; Daniel P. Petrylak, Yale University Cancer Center, New Haven, CT; Shih-Yuan Lee, Bindu Tejura, Niels Borgstein, Takeda Pharmaceuticals International; Iain J. Webb, Millennium: The Takeda Oncology Company, Cambridge, MA; Robert Dreicer, Cleveland Clinic, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain.
J Clin Oncol. 2015 Mar 1;33(7):723-31. doi: 10.1200/JCO.2014.56.5119. Epub 2015 Jan 26.
Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy.
In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant.
The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%).
Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.
奥替诺隆（TAK - 700）是一种处于研究阶段的非甾体、可逆、选择性17,20 - 裂解酶抑制剂。本研究在多西他赛治疗后进展的转移性去势抵抗性前列腺癌患者中对奥替诺隆进行了研究。
在我们的研究中，1099名男性按2:1的比例随机分组，接受每日两次400毫克奥替诺隆加5毫克泼尼松或安慰剂加每日两次5毫克泼尼松治疗，按地区（欧洲、北美[NA]和非欧洲/北美）和简明疼痛量表 - 简表中最严重疼痛评分进行分层。主要终点是总生存期（OS）。仅在主要终点分析有显著意义时，才对关键次要终点（影像学无进展生存期[rPFS]、前列腺特异性抗原降低≥50%[PSA50]以及12周时的疼痛反应）进行统计学检验。
在跨越预先设定的OS无效边界后，研究揭盲。奥替诺隆 - 泼尼松组与安慰剂 - 泼尼松组的中位OS分别为17.0个月和15.2个月（风险比[HR]，0.886；95%置信区间，0.739至1.062；P = 0.190）。奥替诺隆 - 泼尼松组观察到rPFS有所改善（中位值，8.3对5.7个月；HR，0.760；95%置信区间，0.653至0.885；P < 0.001）。奥替诺隆 - 泼尼松在PSA50率（25%对10%，P < 0.001）和至PSA进展时间（中位值，5.5对2.9个月，P < 0.001）方面优于安慰剂 - 泼尼松，但在疼痛反应率方面无差异（12%对9%；P = 0.128）。奥替诺隆 - 泼尼松组的不良事件（所有级别）总体上更频繁，包括恶心（42%对26%）、呕吐（36%对17%）、疲劳（29%对23%）以及淀粉酶升高（14%对2%）。
我们的研究未达到OS的主要终点。奥替诺隆 - 泼尼松组更长的rPFS和更高的PSA50率表明其具有抗肿瘤活性。
