Itareparib: A potent, selective and non-trapper PARP1 inhibitor for combination therapy with DNA damaging agents in solid tumors

BACKGROUND: The poly(ADP-ribose) polymerase-1 (PARP1) enzyme is critical to DNA Damage Response. Multiple first generation non-selective, trapping PARP1/2 inhibitors have been successful as single agent cancer treatments in homologous recombination (HR)-deficient malignancies; on the other hand, first-generation PARPi such as olaparib (a strong PARP1 trapper), or veliparib (a PARP1 trapper with medium potency), have not been successful in combination with chemotherapy due to a poor therapeutic window. Recently, second generation trapper PARP1-selective inhibitors (e.g. saruparib, M9466, SNV1521 and palacaparib) have entered clinical development, based on preclinical evidence that PARP2 inhibition is associated with anemia and dispensable for anti-tumor efficacy. However, emerging clinical data suggest that these drugs display hematological effects similar to the first generation PARPi. Indeed, all these inhibitors trap PARP1 on DNA lesions, causing hematological adverse effects that are overlapping with those caused by chemotherapy agents such as temozolomide (TMZ) and topoisomerase I inhibitors (TOP1i), thus limiting their combination potential. METHODS: We used biochemical and cellular assays to evaluate itareparib potency and selectivity. Additionally, we performed cellular proliferation assays and mechanistic assays such as DNA damage markers assessment by high-content imaging and DNA combing assays, to evaluate itareparib activity in combination with DNA damaging agents (DDA). Finally, we performed in vivo experiments in tumor bearing mice and tumor free rats to assess the combination effects of itareparib plus TMZ on tumor growth inhibition and on the bone marrow. RESULTS: Itareparib is a non-trapper PARPi and showed synergistic activity in combination with TMZ and TOP1i or Antibody Drug Conjugates (ADCs) with TOP1i payloads on DNA damage markers and in proliferation assays in vitro. The combination efficacy with temozolomide was confirmed in vivo in a small cell lung cancer xenografts model. Additionally, the comparative data with trapper-PARPi suggests that the combination efficacy with TMZ and TOP1i is not dependent on the trapping potency. Importantly, itareparib combination with DDA had lower impact on bone marrow precursors both in vitro and in vivo compared to PARP1-trapping inhibitors. Consistently with literature data, in vitro studies identify SLFN11 expression as a sensitivity biomarker to the combination of itareparib with chemotherapy. CONCLUSIONS: Itareparib features are designed to expand the application of PARP1i through combination with chemotherapy, ADCs and radionuclides addressing the unmet need of patients with both HR-deficient and HR-proficient tumors. Itareparib is currently in Phase I/II clinical trials in combination with DNA-damaging agents in brain (high grade gliomas), lung and ovarian cancer.