Olaparib plus tremelimumab in women with recurrent ovarian cancer and a germline BRCA1 or BRCA2 mutation: a phase I/II study

Response rates to immune checkpoint blockade (ICB) in ovarian cancer are low. In preclinical studies, poly(ADP-ribose) polymerase inhibition (PARPi) synergized with CTLA4 ICB to achieve long-term survival in Brca1-deficient ovarian cancer models. Here we evaluated the safety and efficacy of combined treatment with the PARPi olaparib and the CTLA4 ICB tremelimumab for recurrent epithelial ovarian cancer in a multi-site single-arm phase I/II study enrolling 50 women with germline BRCA1 or BRCA2 mutations (NCT02571725). In phase I, no new toxicities were identified (n = 3). In the combined phase I and II safety cohort (n = 49), 57% of subjects experienced grade 3 or 4 non-hematologic toxicity, with tremelimumab discontinuation in 34.7%. The primary phase II endpoint, overall response rate was 32.7% (95% CI 19.5-45.8%), and disease control rate was 47.7% (95% CI 33.0-62.5%). Secondary outcomes were progression-free survival (PFS, 3.0 months, 95% CI 2.7-5.9), and overall survival (24.3 months, CI 14.9-30.4). In exploratory post-hoc biomarker analyses, low VSTM5 or IFIT1B expression was associated with treatment benefit and improved PFS (p < 0.001). Although the trial did not meet its prespecified efficacy endpoint, PFS > 12 months in 6 subjects among this heavily pre-treated cohort highlight the need for biomarkers to select regimens for patients with recurrent ovarian cancer. Response rate to immune checkpoint blockade (ICB) in ovarian cancer remains low and combinatorial strategies are needed. Here the authors report the results of a phase I/II study of the PARP inhibitor olaparib and the anti-CTLA4 antibody tremelimumab in women with recurrent epithelial ovarian cancer and a germline BRCA1 or BRCA2 mutation.