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April 5, 2026

Abstract 245: Expanding the therapeutic window of PARP inhibitors by co-administering PARG inhibitors.

GRGiacomo RossettiUniversity of Bern MPMichalis PetropoulosUniversity of Bern TRTheodoros Rampias

Key Points

The aim is to expand the therapeutic window of PARP inhibitors by co-administering PARG inhibitors to mitigate toxicity without losing efficacy.
Cell survival assays evaluated interactions between PARP and PARG inhibitors in HR-deficient cell lines.
In vivo toxicity was assessed in mice and rats treated with PARP inhibitors alone or with PARG inhibitors.
Measurements included red blood cell counts, hematocrit, and body weight after treatments.
Antitumor efficacy was tested using xenograft models with varying dosing schedules.
PARG inhibitors did not decrease the effectiveness of potent PARP inhibitors in cell assays.
Co-administration rescued anemia and weight loss caused by PARP inhibitors in animal models.
Tumor growth inhibition was maintained or enhanced when combining PARG inhibitors with PARP inhibitors.
Higher doses of PARP inhibitors could be used safely with the addition of PARG inhibitors.

Abstract

Abstract 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. Citation Format: Giacomo G. Rossetti, Michalis Petropoulos, Theodoros Rampias, Thanos D. Halazonetis. Expanding the therapeutic window of PARP inhibitors by co-administering PARG inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 245.

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