Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) trial in acquired PARP-inhibitor-resistant homologous recombination deficient ovarian cancer.

Abstract

Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to poly-ADP ribose polymerase inhibitors (PARPi) overcomes PARPi-resistance in high grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi(olaparib) and ATRi(ceralasertib) in patients with acquired PARPi-resistant HGSOC. Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR) deficient HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; >12 months 1st-line or >6 months ≥2nd-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300mg twice daily and ceralasertib 160mg daily on days 1-7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). Thirteen patients enrolled were evaluable for safety and 12 for efficacy. 62%(n=8) had germline BRCA1/2 mutations, 23% (n=3) somatic BRCA1/2 mutations, and 15%(n=2) HR-deficient tumors. Prior PARPi indication was treatment for recurrence (54%, n=7), 2nd line-maintenance (38%, n=5), and frontline treatment with carboplatin/paclitaxel (8%, n=1). There were 6 partial responses yielding an ORR of 50% (95% CI:0.15, 0.72). Median treatment duration was 8 cycles (range 4-23+). Grade(G) 3/4 toxicities were 38%(n=5); 15%(n=2) G3 anemia, 23%(n=3) G3 thrombocytopenia, 8% (n=1) G4 neutropenia. Four patients required dose-reductions. No patient discontinued treatment due to toxicity. Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib re-sensitizes PARPi resistant HGSOCs to olaparib, warranting further investigation.