Centre Hospitalier de l'Université de Montréal/CRCHUM, Montréal, QC, Canada.
Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
Lancet Oncol. 2015 Mar;16(3):338-48. doi: 10.1016/S1470-2045(15)70027-6. Epub 2015 Feb 18.
Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.
In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244.
From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone.
In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer.
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
奥特尔酮是雄激素信号通路中 CYP17、20-裂解酶的一种部分选择性抑制剂，是转移性去势抵抗性前列腺癌的一种经过验证的治疗靶点。我们评估了奥特尔酮在化疗初治的转移性去势抵抗性前列腺癌患者中的疗效。
这是一项 3 期、双盲、安慰剂对照试验，我们从 43 个国家的 324 个研究中心（即医院或大型泌尿科或集团门诊）招募了转移性去势抵抗性前列腺癌且无既往化疗的进展性患者。符合条件的患者以 1:1 的比例随机分配接受 400mg 奥特尔酮加 5mg 泼尼松每日两次或安慰剂加 5mg 泼尼松每日两次。随机分组采用交互式语音应答系统进行，患者按区域（欧洲、北美和非欧洲或北美）以及基线时是否存在影像学疾病进展进行分层。主要终点是影像学无进展生存期和总生存期，在意向治疗人群中进行评估。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01193244。
从 2010 年 10 月 31 日至 2012 年 6 月 29 日，对 2353 名患者进行了入组评估。其中，1560 名患者被随机分配接受奥特尔酮加泼尼松（n=781）或安慰剂加泼尼松（n=779）。最终分析的临床截止日期为 2014 年 1 月 15 日（死亡 611 例）。影像学无进展生存期的中位随访时间为 8.4 个月（IQR 3.7-16.6）。影像学无进展生存期的中位值为奥特尔酮加泼尼松组 13.8 个月（95%CI 13.1-14.9），安慰剂加泼尼松组 8.7 个月（8.3-10.9）（HR 0.71，95%CI 0.63-0.80；p<0.0001）。在中位随访 20.7 个月（IQR 14.2-25.4）后，奥特尔酮加泼尼松组的中位总生存期为 31.4 个月（95%CI 28.6-不可估计），安慰剂加泼尼松组为 29.5 个月（27.0-不可估计）（HR 0.92，95%CI 0.79-1.08；p=0.31）。最常见的 3 级或更高级别的不良事件是脂肪酶升高（奥特尔酮加泼尼松组 784 例中有 137 例[17%]，安慰剂加泼尼松组 770 例中有 14 例[2%]）、淀粉酶升高（奥特尔酮加泼尼松组 77 例[10%]，安慰剂加泼尼松组 9 例[1%]）、疲劳（奥特尔酮加泼尼松组 50 例[6%]，安慰剂加泼尼松组 14 例[2%]）和肺栓塞（奥特尔酮加泼尼松组 40 例[5%]，安慰剂加泼尼松组 27 例[4%]）。奥特尔酮加泼尼松组 358 例（46%）患者和安慰剂加泼尼松组 292 例（38%）患者报告了严重不良事件。
在化疗初治的转移性去势抵抗性前列腺癌患者中，与安慰剂加泼尼松相比，奥特尔酮加泼尼松可延长影像学无进展生存期。然而，其他主要终点，即总生存期，没有改善。与安慰剂加泼尼松相比，奥特尔酮加泼尼松与更多的毒性作用相关。基于这些和其他数据，奥特尔酮在转移性去势抵抗性前列腺癌中不再进一步开发。
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