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Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: analysis from the phase 2 TRITON2 study.

非 BRCA DNA 损伤修复基因改变和 PARP 抑制剂 Rucaparib 在转移性去势抵抗性前列腺癌中的反应: 来自 2 期 TRITON2 研究的分析。

  • 影响因子:8.32
  • DOI:10.1158/1078-0432.CCR-20-0394
  • 作者列表:"Abida W","Campbell D","Patnaik A","Shapiro JD","Sautois B","Vogelzang NJ","Voog EG","Bryce AH","McDermott R","Ricci F","Rowe J","Zhang J","Piulats JM","Fizazi K","Merseburger AS","Higano CS","Krieger LE","Ryan CJ","Feng FY","Simmons AD","Loehr A","Despain D","Dowson M","Green F","Watkins SP","Golsorkhi T","Chowdhury S
  • 发表时间:2020-02-21
Abstract

PURPOSE:Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase 2 TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. PATIENTS AND METHODS:TRITON2 enrolled patients who had progressed on 1 to 2 lines of next-generation androgen receptor (AR)-directed therapy and 1 taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and prostate-specific antigen (PSA) response (≥50% decrease from baseline). RESULTS:TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration (ATM [n = 49], CDK12 [n = 15], CHEK2 [n = 12], and other DDR genes [n = 14]). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM (2/19 [10.5%] and 2/49 [4.1%], respectively), CDK12 (0/10 [0%] and 1/15 [6.7%], respectively), or CHEK2 (1/9 [11.1%] and 2/12 [16.7%], respectively), including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2 However, patients with alterations in other DDR-associated genes (eg, PALB2) may benefit from PARP inhibition.

摘要

目的: 在转移性去势抵抗性前列腺癌 (mCRPC) 中,除 BRCA 外,DNA 损伤修复 (DDR) 基因的基因组改变可能赋予 PARP 抑制的合成致死性。为了验证这一假设,rucaparib 的 2 期 TRITON2 研究包括 mCRPC 和有害的非 BRCA DDR 基因改变的患者。 患者和方法: TRITON2 入组了接受 1 ~ 2 行新一代雄激素受体 (AR) 导向治疗和 1 例基于紫杉烷的 mCRPC 化疗的患者。关键终点是研究者根据改良 RECIST/PCWG3 评估的影像学反应和前列腺特异性抗原 (PSA) 反应 (较基线下降 ≥ 50%)。 结果: TRITON2 入选了 78 例非 BRCA DDR 基因改变的患者 (ATM [n = 49],CDK12 [n = 15],CHEK2 [n = 12], 和其他 DDR 基因 [n = 14])。在可评估每个终点的患者中,在 ATM 改变的有限数量患者中观察到影像学和 PSA 反应 (分别为 2/19 [10.5%] 和 2/49 [4.1%])。 CDK12 (分别为 0/10 [0%] 和 1/15 [6.7%]),或 CHEK2 (1/9 [11.1%] 和 2/12[分别为 16.7%]),包括 11 例确诊双等位基因 ATM 缺失或 11 例 ATM 种系突变患者无影像学或 PSA 反应。在 DDR 基因 PALB2 、 FANCA 、 BRIP1 和 RAD51B 改变的患者中观察到应答。结论: 在 mCRPC 中 rucaparib 的这项前瞻性、基因组学驱动的研究中,我们发现在 ATM 、 CDK12 或 CHEK2 改变的男性中,对 PARP 抑制的放射学/PSA 反应有限, 其他 DDR 相关基因 (如 PALB2) 发生改变的患者可能受益于 PARP 抑制。

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