PARP Inhibitors in Melanoma-An Expanding Therapeutic Option?

Abstract

Simple SummaryMelanomas with homologous recombination DNA damage repair pathways represent a subset of melanoma that may benefit from PARP inhibitors and immunotherapy. PARP inhibitors have an established role in treating cancers with underlying BRCA mutation through synthetic lethality; however, there is increasing evidence that it can be applied to a larger population including other types of homologous recombination defects. These gene mutations can be found in 20–40% of cutaneous melanoma. To date, PARP inhibitors and immunotherapy have been overlooked in the management of melanoma. This review explores the reasons for combining PARP inhibitors and immunotherapy. There is evidence to suggest that PARP inhibitors can improve the therapeutic effect of immune checkpoint inhibitors. Therefore, this combination approach has the potential to impact future treatment of patients with melanoma, particularly those with homologous recombination DNA damage repair defects. Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.