Princess Margaret Cancer Centre, Toronto, Canada.
Lancet Oncol. 2013 Jul;14(8):760-8. doi: 10.1016/S1470-2045(13)70184-0. Epub 2013 Jun 4.
Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone.
VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group.
Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy.
Sanofi and Regeneron Pharmaceuticals Inc.
多西他赛联合泼尼松是转移性去势抵抗性前列腺癌患者的标准一线化疗方案。阿柏西普是一种重组人融合蛋白，可结合 VEGF 和胎盘生长因子的 A 和 B 异构体，从而抑制血管生成。我们评估了与多西他赛联合泼尼松加安慰剂相比，阿柏西普联合多西他赛和泼尼松是否能改善转移性去势抵抗性前列腺癌男性患者的总生存期。
VENICE 是一项在 31 个国家（187 个地点）进行的 3 期、多中心、随机、双盲、安慰剂对照平行组研究。转移性去势抵抗性前列腺癌、足够的器官功能且无既往化疗的男性患者接受多西他赛（75mg/m2，静脉注射，每 3 周一次）和口服泼尼松（5mg，每日 2 次）治疗，并随机（1:1）接受阿柏西普（6mg/kg）或安慰剂，每 3 周静脉注射一次。通过使用计算机生成的序列，采用大小为 4 的随机块分层，根据东部合作肿瘤组表现状态（0-1 与 2），通过交互式语音应答系统进行中央随机分配。患者、研究者和负责研究实施和数据分析的其他人员对治疗分配进行了屏蔽。阿柏西普或安慰剂小瓶以相同的盒子供应。主要终点是使用意向治疗分析的总生存期。这是已完成试验的主要分析。该研究在 ClinicalTrials.gov 上注册，编号为 NCT00519285。
2007 年 8 月 17 日至 2010 年 2 月 11 日期间，共有 1224 名男性患者被随机分配到治疗组：每组 612 名。在最终分析时，中位随访时间为 35 个月（IQR 29-41），873 名男性死亡。阿柏西普组的中位总生存期为 22.1 个月（95.6%CI 20.3-24.1），安慰剂组为 21.2 个月（19.6-23.8）（分层危险比 0.94，95.6%CI 0.82-1.08；p=0.38）。我们记录了更高的 3-4 级胃肠道疾病发生率（182[30%]比 48[8.0%]）、出血事件发生率（32[5.2%]比 10[1.7%]）、高血压发生率（81[13%]比 20[3.3%]）、疲劳发生率（97[16%]比 46[7.7%]）、感染发生率（123[20%]比 60[10%]）和与治疗相关的致命不良事件发生率（21[3.4%]比 9[1.5%]）在阿柏西普组比安慰剂组。
阿柏西普联合多西他赛和泼尼松作为转移性去势抵抗性前列腺癌的一线化疗方案，与安慰剂相比，并未改善总生存期，并增加了毒性。对于需要一线化疗的此类男性患者，多西他赛联合泼尼松仍然是标准治疗方法。
赛诺菲和再生元制药公司。
