一项研究者发起的1B期试验：niraparib导入治疗，随后niraparib联合dostarlimab用于转移性BRCA1/2突变型乳腺癌、输卵管-卵巢癌及胰腺癌

Objective: To determine activity of the combination of niraparib and dostarlimab, following a 4-week niraparib priming lead-in in patients with documented somatic or germline pathogenic variants in BRCA1/2 breast (BC), ovary (OC) and pancreas (PC) cancer and identify translational determinants of improved response. Methods: Planned enrollment was 18 patients. Patients could have received prior PARP inhibitor (PARPi) or prior PD-1/PD-L1 inhibitor, but not both. Patients underwent a biopsy before treatment and again after 4 weeks of niraparib-alone (200mg or 300 mg daily) treatment. They then received a combination of niraparib 200 mg po daily and dostarlimab 500 mg iv q 3 weeks x 4, then 1000 mg q 6 weeks until disease progression. Primary outcomes were the objective response rate (ORR), duration of response (DOR), and rate of durable (≥18 months) response. Secondary outcomes included safety and tolerability of the combined treatment and the ORR in patients whose disease had progressed on prior PARPi. Planned translational studies include 2-D and 3-D mapping of the tumor immune microenvironment (TME) before and after niraparib therapy. Results: 18 patients were enrolled: 7 BC ( 3 BRCA1 , 4 BRCA2 ), 6 OC (4 BRCA1 , 2 BRCA2 ), and 5 PC (4 BRCA2 , 1 BRCA1 ); 2 with somatic and 16 with germline BRCA 1/2 pathogenic variants. Racial distribution was 1 (5.6%) AIAN, 3 (16.7%) Asian, 1 Black (5.6%), 13 (72.2%) White. The median number of prior lines of therapy was 3 (range 1-10). 9 (50%) patients had prior PARPi and none had prior PD-1 inhibitor. 17 patients were evaluable for toxicity and 15 for response. In the 15 patients assessable for response, the best ORR was partial response (PR) in 4 (26.7%), stable disease (SD) in 5 (33.3%), and progressive disease (PD) in 6 (40%). 2 (33%) of 6 evaluable BC had PR and 2 (33%) of 6 OC had PR, and 0 of 3 PC had an objective response. DOR ranged from 5.6 to 11.0 months with no durable (≥18 months) response. Of 2 patients with OC and prior PARPi exposure without progression, both had PR with PFS of 11 and 13 months In contrast, 5 (4OC, 1 BC) evaluable patients with prior PARPi progression, 1 (20%) had SD, and 4 (80%) had PD. Median PFS was 2.4 mos (95% CI 2.0-7.7 mos) and median OS was 11.0 mos (95% CI 5.8-27.7 mos). 9 of 17 (52.9%) patients had one or more grade 3 or 4 toxicity, which included grade 3 hypertension (n=4), grade 3 neutropenia, (n=2), grade 4 thrombocytopenia (N=2), and grade 4 transaminitis (n=1). No patients came off trial for toxicity. Conclusion: A niraparib lead-in followed by combined niraparib and dostarlimab therapy demonstrated moderate clinical activity, achieving an objective response rate (ORR) of 33% in patients with recurrent BRCA1/2-mutated breast and ovarian cancers, while showing minimal activity in pancreatic cancer and in tumors with prior progression on PARPi. Translational correlatives are in progress for paired pre- and on-treatment biopsies. No unexpected toxicities were identified for the combination.