Niraparib in patients with <i>BRCA</i> -mutated unresectable or recurrent biliary tract, pancreatic and other gastrointestinal cancers: An investigator-initiated phase 2 trial (NIR-B trial).

589 Background: It has been reported that there are BRCA1/2 -mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations. Methods: Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (BTC; cohort A), pancreatic cancers (PC; cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL received 200 mg of niraparib, orally once daily, until disease progression or intolerable adverse events occurred. Primary endpoint was the investigator-assessed objective response rate (ORR) in each cohort with a threshold response rate of 10% and an expected response rate of 35%. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Furthermore, pre-treatment ctDNA was collected and analyzed by Guardant360. Results: A total of 62 pts, 26 in cohort A, 26 in cohort B, and 10 in cohort C were enrolled between March 2021 and April 2023. Because one patient in cohort C did not receive protocol treatment, 61 pts were identified for primary efficacy and safety analysis. Median number of prior regimens was 1/2/2 (range, 1–2/1–2/1-6). In cohort A/B/C, the confirmed ORR was 15.4/15.4/0% [95% highest posterior density credible interval, 8.4–27.9/8.4–27.9/0.0–25.9]. The DCR, median (m) PFS, mOS were 57.7/53.8/22.2% [95% confidence interval (CI), 36.9–76.6/33.4–73.4/2.8–60.0], 2.7/1.8/1.4 months (95% CI, 1.5–4.1/1.4–9.3/1.0–2.8), 7.8/9.5/7.4 months (95% CI, 5.9–9.8/3.5–NE/2.9–8.6), respectively. In the pts with BRCA mutations by Guardant360 (cohort A/B/C were 18/21/8), ORR was 11.1/19.0/0% (95% CI, 2.0-30.2/6.5–38.3/0.0–28.3). The most common treatment-emergent adverse events were thrombocytopenia (31.1%), anemia (27.9%), neutropenia (14.8%), nausea (36.1%), fatigue (29.5%), anorexia (24.6%). Conclusions: Although niraparib had signs of clinical activity in pts with BRCA -mutated BTC and PC, the primary endpoint was not achieved statistically. No new safety signal was observed. Alternative approaches, such as evaluation in biomarker-selected patients or in combination with other agents, may demonstrate greater clinical activity of niraparib in this setting. Clinical trial information: jRCT2011200023.