Phase II Study of Niraparib in Patients With Advanced Melanoma With Homologous Recombination Pathway Gene Mutations

Patients with metastatic melanoma who progress on checkpoint inhibitors and BRAF-targeting drugs have limited therapeutic options. Up to one third of melanomas harbor at least one molecular aberration in the homologous recombination (HR) pathway, leading to HR deficiency.

In this single-arm trial, we assessed the overall response rate to niraparib in patients with metastatic melanoma, harboring a genetic alteration in the HR pathway (ARID1A/B, ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRE11A, RAD50, RAD51, RAD54B, or PALB2) who had disease progression after PD-1 blockade or BRAF/MEK inhibition if BRAF-mutant. Niraparib was administered orally at 300 mg or 200 mg daily, based on body weight and platelet count.

Fourteen patients were accrued to the trial, which was discontinued because of slow accrual. The median age was 71 years. Nine patients had an Eastern Cooperative Oncology Group performance status of 1. Eleven patients had elevated lactate dehydrogenase levels. Ten patients had nonuveal melanoma and four had uveal melanoma. Two (14%) had a partial response and seven (50%) had stable disease, with a disease control rate of 64%. The median progression-free survival was 16 weeks. Among the patients with nonuveal melanoma, two (20%) achieved partial response with a time to progression of 32 and 24 weeks, while five (50%) had stable disease lasting 16-98 weeks. None of the four patients with uveal melanoma responded. There were no unexpected adverse events related to niraparib treatment. Notably, one responder with an ARID1A mutation had detectable circulating tumor DNA at baseline, which became undetectable during treatment.

Despite the small sample size, our results indicate a promising signal for single agent niraparib in patients with pretreated nonuveal metastatic melanoma with HR gene mutations.