Expanding the therapeutic window of PARP inhibitors by co-administering PARG inhibitors

Background: Homologous recombination (HR) deficiency sensitizes tumors to PARP inhibitors (PARPi), which are standard-of-care for HR-deficient cancers. Despite their efficacy, clinical use of PARPi is limited by on-target toxicity, particularly anemia, leading to dose reductions and drug holidays in about half of treated patients. To address these limitations and expand the therapeutic window of PARPi, we investigated co-administration with selective PARG inhibitors (PARGi). Methods: Cell survival assays were used to evaluate the interaction between potent PARP inhibitors (talazoparib, saruparib), less potent PARP inhibitors (niraparib, olaparib, rucaparib), and selective PARG inhibitors in HR-deficient cell lines. Bone marrow toxicity was assessed in mice and rats treated with talazoparib (0.2-0.25 mg/kg) or saruparib (0.1 mg/kg), administered alone or in combination with selective PARG inhibitors undergoing clinical development, using a 4-days-on/2-days-off/4-days-on regimen. Red blood cell counts, hematocrit, and body weight were measured one day after treatment. Antitumor efficacy was evaluated in DLD1-BRCA2-knockout cell line-derived xenografts (CDX) using a 3-days-on/4-days-off dosing schedule, administered alone or in combination with PARG inhibitors. Results: In cell survival assays, PARG inhibitors did not antagonize the cytotoxicity of potent PARPi in HR-deficient cells. In vivo, PARPi monotherapy induced anemia, weight loss, and mortality. Co-administration of PARG inhibitors rescued anemia, attenuated weight loss, and prevented treatment-related deaths. CDX studies demonstrated that tumor growth inhibition by PARPi was maintained or enhanced in combination with PARG inhibitors, allowing higher PARPi dosing without compromising safety. In rats, anemia induced by PARPi was similarly rescued by a PARG inhibitor. Overall, the combination improved the therapeutic window, enabling enhanced efficacy at higher PARPi doses. Conclusions: PARG inhibition selectively mitigates PARPi-induced toxicity without compromising anticancer efficacy in HR-deficient tumors, thereby expanding the therapeutic window. This approach enables higher PARPi dosing for improved tumor control or equivalent efficacy with fewer adverse events, particularly anemia. By reducing PARPi-associated toxicity, PARG inhibition may also facilitate combination therapies, warranting further investigation.