866 Preclinical Study of Pamiparib, a CNS Penetrant PARP Inhibitor, in IDH1/2 Mutated Gliomas

Abstract

INTRODUCTION: Our group demonstrated IDH1/2-mutated gliomas harbor intrinsic homologous recombination (HR) defects mediated by 2-HG, conferring sensitivity to PARP-inhibitors. We studied pamiparib, a CNS-penetrant PARP-inhibitor with potent PARP-trapping ability, in combination with TMZ and radiation in IDH1/2-mutated gliomas and its pharmacokinetics to demonstrate CNS penetrance. METHODS: We performed DNA-repair functional studies with in-vitro short- and long-term viability assays, and in-vivo studies utilizing an intracranial rat glioma model with bioluminescence imaging. Pharmacokinetics was measured with LCMS/MS from harvested tumor, normal brain, and blood. RESULTS: In-vitro viability assays in paired isogenic IDH1-wildtype and mutant U87 cells showed the IDH1 mutation conferred several-fold enhanced sensitivity to TMZ, as expected. Differential TMZ sensitivity was less pronounced in HCT116 cells, as expected given higher MGMT expression. ELISA confirmed PARylation inhibition by pamiparib at the nanomolar range in a dose-dependent manner. Enhanced pamiparib sensitivity was seen in IDH-mutant U87 and HCT116 cells compared to wildtype. Pamiparib and TMZ demonstrated synergistic interactions in U87 cells, dependent upon IDH1 mutation status. In HCT116 cells, TMZ resistance was overcome with pamiparib in wildtype and mutant cells but notably at lower doses in mutant cells. Synergy was observed with pamiparib and radiation in U87-mutant, compared to wildtype cells. Pharmacokinetics demonstrated favorable CNS penetration with tumor:plasma ratios (>0.20) with 3 mg/kg and 6 mg/kg doses of pamiparib, orally administered BID to rats harboring RG2-cell intracranial tumors. These levels persisted between 2- and 8-hours after last dosing. Pamiparib selectively penetrated tumors over normal brain with normal brain:plasma ratios <0.20. CONCLUSIONS: Pamiparib may selectively target IDH1/2-mutated gliomas and act synergistically with TMZ and radiation to exploit intrinsic HR defects. Pharmacokinetics suggest favorable CNS penetration after BID oral administration.