Poly(ADP-Ribose) Polymerase Inhibition in Melanoma: Biological Rationale, Emerging Clinical Evidence, and Biomarker Selection

Immune checkpoint inhibitors and other targeted therapies have substantially improved outcomes for patients with advanced melanoma; however, effective treatment options remain limited following treatment resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are an established therapeutic strategy in several malignancies with defects in homologous recombination repair, and emerging evidence suggests a potential role for PARP inhibition in melanoma. Alterations in homologous recombination repair and other DNA damage response pathways occur in a subset of melanomas and may create therapeutic vulnerabilities to PARP inhibition. In addition to their direct effects on DNA repair, PARP inhibitors have immunomodulatory properties that provide a biologic rationale for combination with immune checkpoint blockade. Preclinical melanoma models have demonstrated activity of PARP inhibition alone and in combination with chemotherapy, while early clinical studies have shown preliminary activity in selected patients with advanced melanoma. However, the presence of a homologous recombination repair/DNA damage response gene alteration does not necessarily indicate functional homologous recombination deficiency or predict sensitivity to PARP inhibition. This review examines the biologic rationale, preclinical and clinical evidence, and emerging combination strategies for PARP inhibition in melanoma, with particular emphasis on the challenges of biomarker selection and priorities for future clinical investigation.