ETX-19477 (oral PARG inhibitor) posts 29% PR rate in heavily pretreated BRCA-mut HGSOC

ETX-19477 is an oral, potent, selective poly(ADP-ribose) glycohydrolase (PARG) inhibitor designed to exploit replication-fork DNA repair vulnerabilities (mechanistically distinct from PARP inhibitors). In the first-in-human ERADIC8 Phase 1/2 dose-escalation/expansion study (NCT06395519), 45 patients with advanced solid tumors were treated across 11 dose levels; in BRCA-mutant high-grade serous ovarian cancer (HGSOC) treated at BID dose levels, 2/7 evaluable patients (29%) achieved a partial response and 3/7 (43%) had stable disease despite a median 4 prior lines (range 2–11), including platinum-resistant and prior PARP inhibitor–exposed responders. Safety was largely GI and hematologic (nausea 53%, vomiting 38%, fatigue 24%; Grade 3 neutropenia 16%, one Grade 4 neutropenia 2%); BID dosing achieved >85% PARG inhibition across the dosing interval, while typical single-agent chemo options in platinum-resistant ovarian cancer often land in the low–mid teens for ORR, and biomarker-selected mirvetuximab (FRα-high) is ~32% ORR (so this early BRCA-enriched signal looks “in range,” albeit in a tiny n and without DOR/PFS yet).