Saruparib (AZD-5305): A Comprehensive Clinical and Scientific Review of a First-in-Class PARP1-Selective Inhibitor

Executive Summary

Saruparib (AZD-5305) is a first-in-class, orally bioavailable, investigational targeted therapy representing a significant evolution in the class of poly(ADP-ribose) polymerase (PARP) inhibitors. Developed by AstraZeneca, it is a highly potent and selective inhibitor and trapper of PARP1, an enzyme critical to the repair of single-strand DNA breaks. The foundational scientific hypothesis for Saruparib's development was to uncouple the established antitumor efficacy of PARP inhibition from the dose-limiting hematologic toxicities associated with first-generation, dual PARP1/2 inhibitors. Preclinical and clinical evidence suggests that while PARP1 inhibition is sufficient for inducing synthetic lethality in cancers with homologous recombination repair (HRR) deficiencies, the co-inhibition of PARP2 is a primary driver of myelosuppression.

Preclinical studies in patient-derived xenograft models demonstrated that Saruparib possesses superior antitumor activity compared to the first-generation PARP inhibitor olaparib, achieving higher rates of complete response and a significantly longer duration of progression-free survival. These studies also validated the safety hypothesis, showing minimal hematologic toxicity at clinically relevant exposures.