2024•Unpublished venueOpen access
Data from Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) trial in acquired PARP-inhibitor-resistant homologous recombination deficient ovarian cancer
Stephanie L. Wethington, Payal Deepak Shah, Lainie P. Martin, Janos Laszlo Tanyi, Nawar Latif, Mark Aloysuis Morgan, Drew A. Torigian, Diego Rodriguez, Simon A. Smith, Emma Jane Dean, Susan M. Domchek, Ronny Drapkin, Ie‐Ming Shih, Eric J. Brown, Wei‐Ting Hwang, Deborah Kay Armstrong, Stephanie L. Gaillard, Robert Lawrence Giuntoli, Fiona A. Simpkins
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Abstract
Abstract Purpose: 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. Patients and Methods: 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). Results: 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. Conclusion: 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.