Phase 1b dose expansion and translational analyses of olaparib in combination with the oral AKT inhibitor capivasertib in recurrent endometrial, triple negative breast, and ovarian, primary peritoneal, or fallopian tube cancer

BackgroundCombining poly (ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and determine a recommended phase 2 dose (RP2D) for PARP inhibitor olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance. MethodsAs part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a four day on three day off schedule was evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days. Findings38 patients were enrolled. 7 (18%) patients had known germline BRCA1/2 mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting in absence of maximum supportive care. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (n=6) with no DLTs, confirming this as RP2D. Most common treatment-related grade 3 or 4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 subjects evaluable for response, 6 (19%) had partial response (PR) with a PR rate of 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlation between response and immune activity, as well as alterations in cell cycle and DNA damage response genes. Therapy resistance was associated with receptor tyrosine kinase (RTK) and RAS-MAPK pathway activity, as well as metabolism and epigenetics. InterpretationThe combination of olaparib and capivasertib is well tolerated and demonstrates evidence of durable activity in womens cancers, with particularly promising response in endometrial cancer. Importantly, tumor samples acquired pre and on-therapy can help predict patient benefit. FundingAstraZeneca, MDACC Moonshots Program, MDACC Support Grant CA016672 NCI SPOREs in Ovarian (CA217685) and Uterine (CA098258) Cancer and a kind gift from the Miriam and Sheldon Medical Research Foundation. AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).