A Phase 2 Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2

Purpose: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition has demonstrated efficacy in patients with platinum-sensitive pancreatic cancer with germline BRCA1/2 pathogenic variants (PV). Whether PARP inhibitors might be effective in a broader population of patients with pancreatic cancer remains under investigation. Patients and Methods: This multicenter, open-label phase II trial (NCT03601923) enrolled patients with advanced pancreatic cancers that harbored germline or somatic BRCA1, BRCA2, PALB2, ATM, and/or CHEK2 PVs. Patients with prior progression on platinum-based therapy were excluded. Patients were treated with niraparib 200 or 300 mg once daily, with their initial dose determined by weight and platelet count. The primary endpoint was 6-month progression-free survival (PFS). Results: Thirty-two patients (ten women [31%]; median age: 67 years) were enrolled. Patients had a PV in at least one of the following genes: ATM (n=14), BRCA2 (n=10), PALB2 (n=3), CHEK2 (n=4), or BRCA1 (n=2). The 6-month PFS was 25% (90% CI: 13–41%) for the overall population, exceeding the pre-established threshold of 17%. The median PFS for the entire population was 2.0 months (95% CI: 1.4–3.8), and the objective response rate was 14% (95% CI: 4–33%). All six patients with ≥ 6 months of PFS and evaluable tumor zygosity had biallelic inactivation of a DNA repair gene. Three patients with biallelic inactivation of ATM and no progression on prior chemotherapy received niraparib for more than 1 year. Conclusions: Niraparib demonstrated clinically meaningful benefit in a subset of patients. The prolonged PFS observed in patients with biallelic ATM loss warrants further investigation.