Poly (ADP-ribose) polymerase inhibitors (PARPi) for advanced malignancies with multiple DNA-repair genetic aberrations

Abstract

ABSTRACT Introduction Poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of advanced tumors with defects in genes involved in homologous recombination repair (HRR), including cancers of the prostate, pancreas, breast, and ovary. In these advanced tumors, PARPi afford ‘synthetic lethality’ by blocking the PARP-associated repair pathway in cancer cells with HRR genetic mutations, resulting in chromosome instability and cellular apoptosis. According to the synthetic lethality theory, patients with a greater burden of genetic alterations, in proportion (relative quantity) or category, would have more satisfactory outcomes after PARPi administration. However, this issue remains obscure based on the existing sporadic evidence. Areas covered We summarize the therapeutic effects of PARPi in advanced tumors with multiple HRR genetic mutations, and attempted to compare these results with those obtained for cancers with a single mutation. Expert opinion Limited evidence has provided a possibly encouraging response to PARPi among patients carrying multiple HRR genetic mutations compared with those with a single mutation (although the treatment effect was negative in some patients). Further research is needed to understand the role of PARPi in tumor cells with multiple HRR genetic mutations.