Purpose: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. Patients and Methods: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days. Results: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 ( n = 6); therefore, DL1 was reexplored ( n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics. Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.

中文翻译：

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奥拉帕尼联合 Capivasertib 治疗复发性子宫内膜癌、三阴性乳腺癌和卵巢癌的 Ib 期剂量扩展和转化分析

目的：基于强有力的临床前理论基础，我们试图确认 PARP 抑制剂奥拉帕尼与 AKT 抑制剂 capivasertib 联合使用的推荐 II 期剂量 (RP2D)，并评估反应和耐药的分子标志物。患者和方法：我们对子宫内膜癌、三阴性乳腺癌、卵巢癌、输卵管癌或腹膜癌进行了安全导入，然后进行了扩张。对奥拉帕尼 300 mg 每日口服两次和 capivasertib 每日口服两次（连续 4 天、休息 3 天）进行了评估。计划使用 capivasertib 的两个剂量水平 (DL)：400 mg (DL1) 和 320 mg (DL-1)。患者在基线和 28 天时接受活检。结果：共有38名患者入组。七名 (18%) 存在种系 BRCA1/2 突变。DL1 治疗的前 2 名患者出现了腹泻和呕吐的剂量限制性毒性 (DLT)。DL-1 上未观察到 DLT（n = 6）；因此，在没有 DLT 的情况下重新探索了 DL1（n = 6），确认​​ DL1 为 RP2D。最常见的与治疗相关的 3/4 级不良事件是贫血 (23.7%) 和白细胞减少症 (10.5%)。在 32 名可评估受试者中，6 名（19%）有部分缓解（PR）；子宫内膜癌PR率为44.4%。另外七名 (22%) 患者疾病稳定时间超过 4 个月。肿瘤分析表明反应与免疫活动、细胞周期改变和 DNA 损伤反应之间存在很强的相关性。治疗耐药与受体酪氨酸激酶和 RAS-MAPK 通路活性、代谢和表观遗传学相关。结论：olaparib 和 capivasertib 的组合不会产生严重不良事件，并且在卵巢癌、子宫内膜癌和乳腺癌中表现出持久的活性，在子宫内膜癌中具有良好的疗效。重要的是，治疗前和治疗中获取的肿瘤样本可以帮助预测患者的获益。