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

by Selleckchem | Jun 23 2023

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.

Comments:

The purpose of the study described is to investigate the addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to poly-ADP ribose polymerase inhibitors (PARPi) as a potential strategy to overcome PARPi resistance in high-grade serous ovarian cancer (HGSOC). The study involved both cell and mouse models as well as patients with acquired PARPi-resistant HGSOC.

The patients included in the study had recurrent, platinum-sensitive HGSOC with BRCA1/2 mutations or homologous recombination (HR) deficiency. These patients had previously benefited from PARPi treatment, as determined by either a positive response on imaging/CA-125 or a prolonged duration of maintenance therapy (more than 12 months for first-line or more than 6 months for second-line). The study excluded patients who had received intervening chemotherapy. The treatment regimen consisted of olaparib (a PARPi) administered at a dose of 300mg twice daily and ceralasertib (an ATRi) at a dose of 160mg daily on days 1-7 of a 28-day cycle.

The primary objectives of the study were to assess the safety of the combination therapy and determine the objective response rate (ORR). Thirteen patients were enrolled in the study, with 12 patients evaluated for efficacy and safety. The majority of patients (62%) had germline BRCA1/2 mutations, while others had somatic BRCA1/2 mutations (23%) or HR-deficient tumors (15%). The prior indications for PARPi treatment varied, with the most common being treatment for recurrence (54%) and second-line maintenance (38%).

The results showed that the combination of olaparib and ceralasertib was tolerable and demonstrated activity in HR-deficient platinum-sensitive recurrent HGSOC that had initially benefited from PARPi but then progressed. The objective response rate (ORR) was 50%, with six patients achieving partial responses. The median treatment duration was 8 cycles, ranging from 4 to 23 or more. Grade 3/4 toxicities were observed in 38% of patients, including anemia, thrombocytopenia, and neutropenia. Four patients required dose reductions, but no patients discontinued treatment due to toxicity.

In conclusion, the study suggests that the combination of olaparib and ceralasertib has the potential to re-sensitize PARPi-resistant HGSOC to olaparib. The findings warrant further investigation of this combination therapy in larger clinical trials.