From dual inhibition to precision selectivity: the molecular rationale and clinical evolution of next-generation...

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized Homologous recombination deficient (HRD) solid tumors by using the synthetic lethality which BRCA 1/2 mutated cancer cells depend on for DNA repair. Standard PARP inhibitors such as olaparib, rucaparib, niraparib, and talazoparib have been shown to inhibit both PARP1 and PARP2, and have shown significant clinical efficacy in breast, ovarian, prostate, and pancreatic cancers. However, their clinical efficacy is limited by their hematological toxicities such as anemia, thrombocytopenia, and neutropenia that requires reduction in dose and treatment discontinuation which compromises their therapeutic efficacy and long-term use. This review focuses on molecular mechanism, preclinical and clinical evidence highlighting the shift from standard dual PARP 1/2 inhibitors into selective PARP1 inhibitors. Molecular and preclinical evidence has shown that inhibition of PARP1 is sufficient to induce synthetic lethality in HRD tumors, while inhibition of PARP2 causes hematopoietic stem and progenitor cell (HSPC) toxicity via impairment of erythropoiesis. These limitations led to the use of next-generation selective PARP1 inhibitors, such as saruparib (AZD5305), with approximately 500-fold higher selectivity for PARP1 over PARP2 with potent antitumor activity and reduced hematological toxicity. The clinical efficacy and tolerability of selective PARP1 inhibitors provides a significant opportunity to use them as combination therapy which was previously limited due to combined myelosuppression. Collectively PARP1 inhibitors have demonstrated clinically impactful advancement that exhibits anticancer effect without causing significant hematological toxicity. They have potential of treating patients who benefit from PARP1 inhibitor-based precision oncology.