Targeting germline or somatic DNA repair defects (beyond BRCA) in pancreatic cancer with niraparib: A phase II study (NIRA-PANC)

4156 Background: Targeting a molecular subset of pancreatic cancer (PC) may identify alternatives to perpetual chemotherapy and chemo-resistance/toxicity. Poly (ADP ribose) polymerase inhibitors (PARPi) have shown efficacy in germline BRCA mutation via synthetic lethality. Preclinical evidence suggests PARPi may target DNA repair defects beyond BRCA. We conducted a Niraparib phase II study in PC patients with germline/somatic DNA repair defects. Methods: This is an open-label, phase 2 trial in pts with locally advanced or metastatic PC with germline or somatic mutations , known or tested after consent to pre-screening tumor tissue analysis in DNA repair genes (BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A), who have progressed on or intolerant of at least one line of therapy, no prior PARPi, with evaluable disease, and ECOG PS 0-1. Eligible pts were treated with Niraparib 300mg or 200mg PO daily for 28 days (1 cycle = 28 days) (200mg dose for baseline weight is < 77 kg or baseline platelet count is < 150,000 µL) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary objective was 6-month PFS rate. The secondary objectives were OS, DCR and safety. Pts were evaluable for safety if they had received > 1 dose of Niraparib and for efficacy if they had also received > 1 follow-up imaging study. Results: As of Feb 2023, 36 (13 female, 23 male) pts were enrolled, with a mean age of 62.9 (median 64, IQR 51-73, min 41, max 83, SD 11.25), of whom 27 (8 female, 19 male) were evaluable for efficacy. After a median follow-up of 9.0 months (IQR 6.0-15.1 m), the 6-month PFS rate was 40.7% (11/27 pts; 95% CI 4.7%- 100 %). The median PFS is 4.4 m (CI 2.3 - 6.5 m), and median OS is 9.1 m (7.5 -15.1 m). The disease control rate at 8 weeks was 70.4% (19 of 27 pts; 95% CI 49.8%-86.3%). Of the 27 evaluable pts- BRCA2 mutation was seen in 10 pts, ATM (5), CHEK2 (5), BRCA1 (2), NBN (2), ARID1A (1), FANCA (1), FAM175 A (1), RAD51B (1), IDH1 (1), IDH2 (1). Among 36 pts evaluable for safety, treatment-related adverse events occurred in 75% (27/36), and Grade 3 and grade 4 treatment-related adverse events occurred in 31% (11/36). The most common treatment-related AEs were anemia (25%, 9/36), nausea (22%, 8/36), thrombocytopenia (19%, 7/36), vomiting (19%, 7/36), and fatigue (17%, 6/36). Serious treatment-emergent adverse events were reported in 11% (4/36). There were no treatment-related deaths. Conclusions: In previously treated pts with locally advanced and metastatic PC harboring DNA repair defects, niraparib monotherapy yielded a 6-month PFS rate of 40%, median PFS of 4.4 months, and median OS of 9.1 months. Clinical trial information: NCT03553004 . [Table: see text]