Mary Linton Bounetheau Peters

Purpose: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 who 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 [10 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% confidence interval (CI), 13%–41%] for the overall population, exceeding the preestablished threshold of 17%. The median PFS for the entire population was 2 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.

Supplementary Figure S1: CONSORT diagram indicating patient disposition.

Supplementary Figure S6: Genomic characterization of BRCA2 reversion mutations

Supplementary Figure S2: Kaplan-Meier estimates of overall survival (OS) in patients treated with niraparib across the entire trial population

Supplementary Figure S3: Outcomes based on chemotherapy sensitivity

Representativeness of Study Participants

DNA Repair Gene Inclusion Variant

Supplementary Figure S5: Outcomes based on cell-free DNA tumor fraction

Summary of Treatment Emergent Adverse Events