Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor–Resistant Homologous Recombination–Deficient Ovarian Cancer

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