Nesuparib (JPI-547) dual TNKS/PARP inhibitor + GemAbraxane hits 53.8% ORR in 1L advanced PDAC, but mFOLFIRINOX combo not tolerated

Nesuparib is an oral dual tankyrase (TNKS) and PARP inhibitor designed to induce “BRCAness” (via WNT/Hippo pathway modulation) and was combined with first-line GemAbraxane or modified FOLFIRINOX in a multicenter, open-label Phase Ib dose-escalation study (NCT05257993) in locally advanced/metastatic PDAC (n=27; GemAbraxane n=14, mFOLFIRINOX n=13; data cutoff December 31, 2025). Tolerability was acceptable with GemAbraxane at 12.5mg intermittent schedules (DL-1 5 days on/2 off; DL-2 3 on/4 off), while tolerability was not established with mFOLFIRINOX; grade 3/4 AEs were mainly hematologic (GemAbraxane: anemia 57.1%, thrombocytopenia 64.3%, neutropenia 92.9%; mFOLFIRINOX: 84.6%, 92.3%, 84.6%), with no treatment-related deaths. Efficacy looked strongest in the GemAbraxane arm (ORR 53.8%, DCR 92.3%, 1 CR; mPFS not reached; mOS 14.2 months, immature), versus the mFOLFIRINOX arm (ORR 38.5%, DCR 92.3%, mPFS 7.33 months, mOS 18.5 months); for context, historical 1L GemAbraxane yields mOS ~8.5–8.7 months in metastatic PDAC, and FOLFIRINOX-class regimens historically deliver mOS ~11.1 months in fit patients—so the GemAbraxane ORR here is above typical benchmarks, but the survival readouts are early and cross-arm comparisons are not interpretable in this small Phase Ib setting.