Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial
Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial
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DOI：
10.1016/s1470-2045(20)30447-2
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发表时间：
2020-10-01
期刊：
影响因子：
51.1
通讯作者：
Arun, Banu K.
中科院分区：
文献类型：
--
作者：
Dieras, Veronique;Han, Hyo S.;Arun, Banu K.
背景 BRCA1 或 BRCA2 突变乳腺癌由于 DNA 损伤同源重组修复缺陷而对聚（ADP-核糖）聚合酶（PARP）抑制剂和铂类药物敏感。在这项试验中，我们对 HER2 阴性晚期乳腺癌和种系 BRCA1 或 BRCA2 突变患者，比较了 veliparib 与安慰剂联合卡铂和紫杉醇的情况，如果卡铂和紫杉醇在疾病进展前停用，则继续作为单一疗法。 方法 BROCADE3 是一项随机、双盲、安慰剂对照的 3 期试验，于 147 年完成 36 个国家的医院。符合条件的患者（年龄 >= 18 岁）患有有害种系 BRCA1 或 BRCA2 突变相关、组织学或细胞学证实的晚期 HER2 阴性乳腺癌，东部肿瘤合作组表现状态为 0-2，并且之前接受过最多两线转移性疾病化疗。通过交互响应技术，通过层内排列块（块大小为 3 或 6）将患者随机分配（2:1），在 21 天周期的第 1 天使用卡铂（静脉注射每分钟 6 mg/mL 的浓度曲线下面积），在第 1、8 和 15 天使用紫杉醇（静脉注射 80 mg/m(2)），并联合 veliparib（两次口服 120 mg） 每天，第-2至5天）或匹配的安慰剂。如果患者在疾病进展前停用卡铂和紫杉醇，则可以继续使用加强剂量的 veliparib 或安慰剂（连续 300 mg 每日两次，如果耐受，可逐步增加至 400 mg 每日两次）直至疾病进展。对照组患者在疾病进展后可以接受开放标签 veliparib 单药治疗。随机分组根据既往铂类使用情况、中枢神经系统转移史以及雌激素和孕激素受体状态进行分层。主要终点是研究者根据实体瘤反应评估标准 1.1 版评估的无进展生存期。疗效分析按意向治疗进行，其中包括所有随机分配的具有集中确认的 BRCA 突变的患者，安全性分析包括所有接受至少一剂 velilparib 或安慰剂的患者。这项研究正在进行中，并已在 ClinicalTrials.gov 注册，NCT02163694。调查结果 2014 年 7 月 30 日至 2018 年 1 月 17 日期间，对 2202 名患者进行了筛查，其中 513 名符合条件的患者被纳入并随机分配。在意向治疗人群 (n=509) 中，337 名患者被分配接受 veliparib 加卡铂-紫杉醇治疗（veliparib 组），172 名患者被分配接受安慰剂加卡铂-紫杉醇治疗（对照组）。数据截止时（2019年4月5日），veliparib组的中位随访时间为35.7个月（IQR 24.9-43.6），对照组为35.5个月（23.1-45.9）。 veliparib 组的中位无进展生存期为 14.5 个月（95% CI 12.5-17.7），而对照组为 12.6 个月（10.6-14.4）（风险比 0.71 [95% CI 0.57-0.88]，p=0.0016）。最常见的3级或更严重不良事件是中性粒细胞减少症（veliparib组336例患者中272例[81%] vs 对照组171例患者中143例[84%]）、贫血（142例[42%] vs 68例[40%]）和血小板减少症（134例[40%] vs 48例[28%]）。 veliparib 组中有 115 名患者（34%）发生严重不良事件，而对照组有 49 名患者（29%）发生严重不良事件。没有出现与研究药物相关的死亡。 解释 将 veliparib 添加到高活性铂双药中，如果双药停药则继续作为单一疗法，导致生殖系 BRCA 突变相关晚期乳腺癌患者的无进展生存期显着且持久的改善。这些数据表明铂类药物和 PARP 抑制剂联合治疗在该患者群体中的效用。版权所有 (C) 2020 爱思唯尔有限公司。保留所有权利。
Background BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.Methods BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged >= 18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m(2) intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.Findings Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35.7 months (IQR 24.9-43.6) in the veliparib group and 35.5 months (23.1-45.9) in the control group. Median progression-free survival was 14.5 months (95% CI 12.5-17.7) in the veliparib group versus 12.6 months (10.6-14.4) in the control group (hazard ratio 0.71 [95% CI 0.57-0.88], p=0.0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.Interpretation The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population. Copyright (C) 2020 Elsevier Ltd. All rights reserved.