9 Oral - NCI10329: Phase Ib Sequential Trial of Agents against DNA Repair (STAR) Study to investigate the sequential combination of the Poly (ADP-Ribose) Polymerase inhibitor (PARPi) olaparib (ola) and WEE1 inhibitor (WEE1i) adavosertib (ada) in patients (pts) with DNA Damage Response (DDR)-aberrant advanced tumors, enriched for BRCA1/2 mutated and CCNE1 amplified cancers

Abstract

Background: Combination PARPi plus WEE1i (PARPi + WEE1i) induces replication stress (RS), DNA damage, and abrogates the G2 cell cycle checkpoint. Concurrent PARPi + WEE1i administration effectively inhibits tumor growth but is poorly tolerated. Sequential PARPi+WEE1i administration in vivo mirrors concurrent dosing in cells with high basal RS, while normal cells with low basal RS are protected from DNA damage, improving tolerability while preserving efficacy (Fang et al., Cancer Cell 2019). Based on these compelling preclinical data, the NCI CTEP-sponsored STAR study investigated sequential ola+ada in pts with DDR aberrant advanced tumors (NCT04197713).