Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2- mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2 , while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non– BRCA -associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay. This article is featured in Highlights of This Issue, [p. 6067][1] [1]: /lookup/volpage/27/6067?iss=22

中文翻译：

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具有双等位基因 BRCA1/2 失活的患者对不同组织学肿瘤类型的奥拉帕尼治疗有反应

目的：评估 olaparib（一种 PARP 抑制剂（PARPi））在 BRCA1/2 突变肿瘤患者中的疗效，无论组织学肿瘤类型如何。患者和方法：治疗难治性 BRCA1/2 突变癌症患者被纳入标签外奥拉帕尼 300 mg 每日两次治疗，直至疾病进展或出现不可接受的毒性。在药物再发现方案 (DRUP) 中，治疗难治性实体恶性肿瘤患者接受基于肿瘤分子谱的标签外药物，同时对基线肿瘤活检进行全基因组测序 (WGS)。主要终点是临床获益（CB；根据 RECIST 1.1 定义为客观缓解或疾病稳定≥ 16 周）。根据方案，患者使用类似西蒙的两阶段模型进行登记。结果：纳入了 24 名具有 9 种不同肿瘤类型且携带 BRCA1/2 突变的可评估患者，58% 的患者因奥拉帕尼治疗而出现 CB。在 BRCA1/2 完全丧失功能 (LoF) 的患者中观察到 CB，而 73% 的双等位基因 BRCA LoF 患者有 CB。在 17 名患者和 7 名没有当前标记适应症的患者中，分别有 10 名和 4 名患者患有 CB。四名双等位基因丢失患者的治疗抗性可能是由 WGS 在三种肿瘤类型中发现的额外致癌驱动因素解释的，包括 Wnt 通路激活、FGFR 扩增和 CDKN2A 丢失。结论：这些数据表明，对于具有双等位基因 BRCA LoF 的非 BRCA 相关组织学患者，使用 PARPis 是一种很有前景的治疗策略。WGS 允许使用单一检测准确检测 BRCA 的完整 LoF 和同源修复缺陷 (HRD) 特征以及可能导致耐药性的致癌驱动因素。这篇文章被收录在本期的亮点中，[p. 6067][1][1]：/lookup/volpage/27/6067?iss=22