Background Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information NCT01506609.

中文翻译：

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Veliparib 联合替莫唑胺或卡铂/紫杉醇与安慰剂联合卡铂/紫杉醇治疗 BRCA1/2 局部复发/转移性乳腺癌患者：随机 II 期研究。

背景 BRCA1/2 突变肿瘤中的同源重组缺陷导致对聚（ADP-核糖）聚合酶抑制剂敏感，从而干扰 DNA 损伤修复。Veliparib 是一种有效的聚（ADP-核糖）聚合酶抑制剂，在早期临床试验中增强了铂类药物和替莫唑胺的抗肿瘤活性。这项 II 期研究检查了间歇性 veliparib 联合卡铂/紫杉醇 (VCP) 或替莫唑胺 (VT) 在 BRCA1/2 突变乳腺癌患者中的安全性和有效性。患者和方法将≥18岁患有局部复发或转移性乳腺癌和有害BRCA1/2种系突变的合格患者按1:1:1随机分配至VCP、VT或安慰剂加卡铂/紫杉醇(PCP)组。主要终点是无进展生存期（PFS）；次要终点包括总生存期（OS）和总缓解率（ORR）。结果 290 名随机患者中，经中心实验室证实，284 名患者为 BRCA+。对于 VCP 与 PCP，中位 PFS 分别为 14.1 和 12.3 个月 [风险比 (HR) 0.789；95% CI 0.536-1.162；P = 0.227]，中期中位 OS 28.3 和 25.9 个月（HR 0.750；95% CI 0.503-1.117；P = 0.156），ORR 77.8% 和 61.3%（P = 0.027）。对于 VT（与 PCP），中位 PFS 为 7.4 个月（HR 1.858；95% CI 1.278-2.702；P = 0.001），中期中位 OS 19.1 个月（HR 1.483；95% CI 1.032-2.131；P = 0.032），并且ORR 28.6%（P < 0.001）。卡铂/紫杉醇组之间的安全性相当。与 PCP 相比，VT 治疗中中性粒细胞减少、贫血、脱发和神经病变等不良事件（所有级别）的发生率较低。结论 与 PCP 相比，接受 VCP 的 BRCA1/2 突变复发/转移性乳腺癌患者的 PFS 和 OS 均出现数字但无统计学意义的增加。在卡铂/紫杉醇中添加 veliparib 显着改善 ORR。与 PCP 相比，VCP 的毒性并未出现有临床意义的增加。VT 不如 PCP。一项正在进行的 III 期试验正在评估 VCP 与 PCP 的比较，如果在该患者群体中停止化疗而没有进展，可选择继续使用 veliparib/安慰剂单药治疗。临床试验信息NCT01506609。