评估奥拉帕尼联合曲妥珠单抗治疗 HER2 阳性晚期乳腺癌 (ABC) 和生发 BRCA 突变 (gBRCAm) 患者的疗效和安全性。 OPHELIA (NCT03931551) 是一项单组、开放标签、2 期临床审判。年龄≥18岁的诊断为HER2阳性ABC且具有BRCA1或BRCA2生发有害突变且之前接受过至少一种晚期疾病全身治疗方案的患者被纳入研究。患者接受奥拉帕尼加曲妥珠单抗治疗，直至疾病进展、出现不可接受的毒性或撤回同意。主要终点是研究者根据 RECIST v.1.1 评估的至少 24 周的临床获益率。主要次要终点包括总体缓解率 (ORR) 和安全性。共筛选了 68 名接受过治疗的 HER2 阳性 ABC 患者。由于进展缓慢，试验在招募了 5 名患者（而不是计划的 20 名患者）后停止。四名患者获得了临床获益（80.0%，95% CI；28.​​4-99.5，p < 0.001），并且达到了主要终点。 ORR 为 60.0%（95% CI；14.7-94.7），包括一项完全缓解。四名 (80.0%) 患者经历了至少一种与治疗相关的治疗突发不良事件 (TEAE)。大多数 TEAE 为 1 级或 2 级。没有发生与治疗相关的死亡，也没有发现新的安全信号。这项研究表明，奥拉帕尼加曲妥珠单抗的联合治疗对于既往治疗过的 HER2 阳性 gBRCAm ABC 患者可能是有效且安全的。应进一步研究该 ABC 患者群体，不应预先将其排除在 BRCA1/2 驱动癌症靶向治疗的临床试验之外。版权所有 © 2024。由 Elsevier Ltd 出版。

To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm).OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile.A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified.This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.Copyright © 2024. Published by Elsevier Ltd.