Targeted therapies and PARPi therapy response following ICI therapy failure in advanced melanoma: a case series

Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown efficacy in treating cancers with homologous recombination deficiency (HRD), including subsets of melanoma. However, the potential synergy between PARPi and standard melanoma therapies remains understudied. Here, we report two cases of advanced metastatic melanoma refractory to standard-of-care treatment that demonstrated durable partial responses following the addition of PARPi in combination with immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors. Both patients exhibited homologous recombination repair (HRR) pathway mutations and tolerated the combinatory regimens well, achieving progression-free survival of more than 11 months. Mechanistically, PARPi may enhance immunogenicity to ICI therapy via activation of the cyclic GMP-AMP synthase-stimulator of interferon (cGAS-STING) pathway and modulation of programmed death ligand 1 (PD-L1) expression. Preclinical studies also support synergism between PARPi and BRAF/MEK-targeted therapies. This report highlights the potential for PARPi to be integrated into advanced melanoma treatment, particularly in HRD tumors and in combination with ICI and targeted therapies. Although limited by the small sample size, our findings support the rationale for ongoing clinical trials evaluating PARPi-based combinations and underscore the need for further studies to clarify the optimal sequencing and combinations of therapy. PARP inhibition (PARPi) offers a mechanistically rational option for advanced melanoma with homologous recombination deficiency (HRD).Two heavily pretreated metastatic melanoma patients achieved durable partial responses after PARPi-based combination therapy.Durable disease control was achieved with PARPi plus immune checkpoint inhibitors (ICI), and with triple therapy (PARPi + ICI + BRAF/MEK inhibition).Mechanistic data support synergy between PARPi and ICI. PARP inhibition (PARPi) offers a mechanistically rational option for advanced melanoma with homologous recombination deficiency (HRD). Two heavily pretreated metastatic melanoma patients achieved durable partial responses after PARPi-based combination therapy. Durable disease control was achieved with PARPi plus immune checkpoint inhibitors (ICI), and with triple therapy (PARPi + ICI + BRAF/MEK inhibition). Mechanistic data support synergy between PARPi and ICI.