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

Abstract

<div>AbstractPurpose:<p>Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP 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.</p>Patients and Methods:<p>Eligible patients had recurrent, platinum-sensitive <i>BRCA1/2</i> mutated or homologous recombination (HR)–deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR).</p>Results:<p>Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (<i>n</i> = 8) had germline <i>BRCA1/2</i> mutations, 23% (<i>n</i> = 3) somatic <i>BRCA1/2</i> mutations, and 15% (<i>n</i> = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, <i>n</i> = 7), second-line maintenance (38%, <i>n</i> = 5) and first-line treatment with carboplatin/paclitaxel (8%, <i>n</i> = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15–0.72). Median treatment duration was 8 cycles (range 4–23+). Grade (G) 3/4 toxicities were 38% (<i>n</i> = 5); 15% (<i>n</i> = 2) G3 anemia, 23% (<i>n</i> = 3) G3 thrombocytopenia, 8% (<i>n</i> = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity.</p>Conclusions:<p>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 resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.</p></div>