Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer

Abstract

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.

PARP inhibitors in ovarian cancer: overcoming resistance with combination strategies

“…The ComPAKT trial (NCT02338622) evaluated the combination in patients with advanced solid tumors, of the evaluable patients, 44.6% achieved clinical benefit (RECIST complete/partial response or stable disease ≥4 months), including BRCA1/2 mutant cancers and BRCA1/2 wildtype cancers with or without DDR and PI3K/AKT pathway alterations [ 65 ]. A second study in patients with endometrial, ovarian, and triple-negative breast cancers demonstrated a similar clinical benefit rate of 41% [ 66 ]. Provisional analysis of tumor samples from this study determined that markers of DNA damage checkpoint activation and decreased mTOR activity were associated with response, whereas resistance to the combination was associated with high receptor tyrosine kinase activity levels and mTOR activation [ 66 ].…”

“…A second study in patients with endometrial, ovarian, and triple-negative breast cancers demonstrated a similar clinical benefit rate of 41% [ 66 ]. Provisional analysis of tumor samples from this study determined that markers of DNA damage checkpoint activation and decreased mTOR activity were associated with response, whereas resistance to the combination was associated with high receptor tyrosine kinase activity levels and mTOR activation [ 66 ]. The authors conclude that these putative biomarkers could improve patient selection for this combination, although it is unclear whether these markers of resistance were dependent on prior PARPi exposure or varied between malignancies.…”

Therapeutic Targeting of DNA Damage Response in Cancer

“…The combination was both tolerable and effective, especially in epithelial ovarian cancer (N = 28), with 10 patients (36%) achieving a partial response and 50% showing stable disease [154]. In two phase 1 trials, the combination of olaparib with capivasertib, an AKT inhibitor, demonstrated tolerability and antitumor efficacy in both germline BRCA1/2-mutant and wild-type disease [155,156]. Further studies are ongoing (NCT04729387, NCT03660826) to validate the combination of PI3K-AKT pathway inhibitors and PARP inhibitors in various clinical situations.…”

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

“…While combination therapy required a dose attenuation of the pan-PI3Ki BKM120 in one study [ 77 ], the combination of olaparib with the PI3Ki alpelisib was shown to be safe and effective [ 78 ]. Similarly, olaparib combination appeared to be safe with the protein kinase B inhibitor capivasertib [ 79 , 80 ]. Additionally, there were no clinically relevant interactions between olaparib and endocrine therapy including anastrozole, letrozole, or tamoxifen [ 81 ].…”