Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2021 Sep 1;27(17):4710-4716. doi: 10.1158/1078-0432.CCR-21-1279. Epub 2021 Jun 15.
Checkpoint kinase 1 (CHK1) plays a central role in the response to replication stress through modulation of cell-cycle checkpoints and homologous recombination (HR) repair. In BRCA-deficient cancers with or acquired PARP inhibitor resistance, the addition of the CHK1 inhibitor prexasertib to the PARP inhibitor olaparib compromises replication fork stability, as well as HR proficiency, allowing for sensitization to PARP inhibition.
This study followed a 3+3 design with a 7-day lead-in of olaparib alone, followed by 28-day cycles with prexasertib administered on days 1 and 15 in combination with an attenuated dose of olaparib on days 1-5 and 15-19. Pharmacokinetic blood samples were collected after olaparib alone and following combination therapy. Patients enrolled to the expansion phase of the study underwent paired tumor biopsies for pharmacodynamic (PD) assessments.
Twenty-nine patients were treated. DLTs included grade 3 neutropenia and grade 3 febrile neutropenia. The MTD/recommended phase 2 dose (RP2D) was prexasertib at 70 mg/m i.v. with olaparib at 100 mg by mouth twice daily. Most common treatment-related adverse events included leukopenia (83%), neutropenia (86%), thrombocytopenia (66%), and anemia (72%). Four of 18 patients with -mutant, PARP inhibitor-resistant, high-grade serous ovarian cancer (HGSOC) achieved partial responses. Paired tumor biopsies demonstrated reduction in RAD51 foci and increased expression of γ-H2AX, pKAP1, and pRPA after combination exposure.
Prexasertib combined with olaparib has preliminary clinical activity in -mutant patients with HGSOC who have previously progressed on a PARP inhibitor. PD analyses show that prexasertib compromises HR with evidence of induction of DNA damage and replication stress.
检查点激酶 1（CHK1）通过调节细胞周期检查点和同源重组（HR）修复，在复制应激反应中发挥核心作用。在 BRCA 缺陷型癌症中，或获得 PARP 抑制剂耐药性后，添加 CHK1 抑制剂 prexasertib 到 PARP 抑制剂奥拉帕利中，会破坏复制叉稳定性以及 HR 效率，从而使 PARP 抑制作用敏感化。
该研究采用 3+3 设计，先单独使用奥拉帕利进行 7 天的导入期，然后在第 1 天和第 15 天联合使用 prexasertib，同时在第 1 天至第 5 天和第 15 天至第 19 天减少奥拉帕利的剂量，进行 28 天的周期治疗。在单独使用奥拉帕利和联合治疗后采集药代动力学血样。参加研究扩展阶段的患者进行配对肿瘤活检以进行药效学（PD）评估。
共治疗了 29 名患者。剂量限制性毒性（DLT）包括 3 级中性粒细胞减少症和 3 级发热性中性粒细胞减少症。MTD/推荐的 2 期剂量（RP2D）为 70mg/m 的 prexasertib 静脉注射，每日两次口服 100mg 的奥拉帕利。最常见的治疗相关不良事件包括白细胞减少症（83%）、中性粒细胞减少症（86%）、血小板减少症（66%）和贫血（72%）。18 名 -突变、PARP 抑制剂耐药、高级别浆液性卵巢癌（HGSOC）患者中有 4 名获得部分缓解。配对肿瘤活检显示，联合暴露后 RAD51 焦点减少，γ-H2AX、pKAP1 和 pRPA 的表达增加。
在先前接受过 PARP 抑制剂治疗的 -突变 HGSOC 患者中，prexasertib 联合奥拉帕利具有初步的临床活性。PD 分析表明，prexasertib 通过诱导 DNA 损伤和复制应激来破坏 HR。
