Importance Poly(adenosine diphosphate–ribose) polymerase inhibitor and anti–programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC).

Objective To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC.

Design, Setting, and Participants This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019.

Interventions Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.

Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival.

Results Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected.

Conclusions and Relevance Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation.

Trial Registration ClinicalTrials.gov identifier: NCT02657889

重要性 聚（二磷酸腺苷-核糖）聚合酶抑制剂和抗程序性死亡受体 1 抑制剂单药治疗在晚期三阴性乳腺癌 (TNBC) 患者中的临床活性有限。

目的 评价尼拉帕尼和派姆单抗联合治疗晚期或转移性TNBC患者的临床活性（主要）和安全性（次要）。

设计、设置和参与者 这项开放标签、单臂、2 期研究在美国 34 个地点招募了 55 名符合条件的晚期或转移性 TNBC 患者，无论BRCA突变状态或程序性死亡配体 1 (PD-L1) 表达如何。数据收集时间为 2017 年 1 月 3 日至 2018 年 10 月 29 日，分析时间为 2018 年 10 月 29 日至 2019 年 2 月 27 日。

干预 在每个 21 天周期的第 1 天，患者每天一次口服 200 mg niraparib 和 200 mg 静脉注射 pembrolizumab。

主要结果和措施 主要终点是根据实体瘤反应评估标准 1.1 版的客观反应率 (ORR)。次要终点是安全性、疾病控制率（DCR；完全缓解+部分缓解+疾病稳定）、缓解持续时间（DOR）、无进展生存期（PFS）和总生存期。

结果 在 55 名女性（中位年龄，54 岁 [范围，32-90 岁]）的完整研究人群中，5 名患者确认完全缓解，5 名确认部分缓解，13 人病情稳定，24 人病情进展。在疗效可评估人群（n = 47）中，ORR 包括 10 名患者（21%；90% CI，12%-33%），DCR 包括 23 名患者（49%；90% CI，36%-62%）。数据截止时未达到中位 DOR，有 7 名患者在分析时仍在接受治疗。在 15 名可评估的肿瘤BRCA突变患者中，ORR 包括 7 名患者（47%；90% CI，24%-70%），DCR 包括 12 名患者（80%；90% CI，56%-94%），中位 PFS 为8.3 个月（95% CI，2.1 个月至不可估计）。在 27 名可评估的BRCA患者中野生型肿瘤，ORR 包括 3 名患者（11%；90% CI，3%-26%），DCR 包括 9 名（33%；90% CI，19%-51%），中位 PFS 为 2.1 个月（95 % CI，1.4-2.5 个月）。最常见的 3 级或更高级别的治疗相关不良事件是贫血 (10 [18%])、血小板减少 (8 [15%]) 和疲劳 (4 [7%])。8 名患者 (15%) 报告了免疫相关不良事件，2 名患者 (4%) 为 3 级；没有检测到新的安全信号。

结论和相关性 niraparib 联合 pembrolizumab 在晚期或转移性 TNBC 患者中提供了有希望的抗肿瘤活性，在肿瘤BRCA突变患者中具有更高的响应率。联合治疗是安全的，具有可耐受的安全性，值得进一步研究。

试验注册 ClinicalTrials.gov 标识符：NCT02657889