Phase 1b dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple negative breast, and ovarian cancer.

Purpose Based on strong preclinical rationale, we sought to confirm recommended phase 2 dose for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. Experimental design We performed a safety lead in followed by expansion in endometrial, triple negative breast, or ovarian cancers. Olaparib 300mg orally twice daily (BID) and capivasertib orally BID on a four day on three day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400mg (DL1); 320mg (DL-1). Patients underwent biopsies at baseline and 28 days. Results 38 patients were enrolled. 7 (18%) had germline BRCA1/2 mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (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 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.