PARP Inhibitor Shows Promise in Advanced Melanoma Treatment - EMJ

PARP Inhibitor Shows Promise in Advanced Melanoma Treatment

PATIENTS with advanced melanoma who have exhausted current standard treatments face limited options. A recent phase II study investigated the use of niraparib, a PARP inhibitor, in patients with metastatic or unresectable melanoma carrying mutations in the homologous recombination (HR) DNA repair pathway. These patients had previously progressed on anti–PD-1 therapy and, where applicable, BRAF/MEK-targeted therapies.

Among 14 participants, two (14%) showed confirmed responses and seven (50%) maintained stable disease for at least 16 weeks, resulting in a 64% disease control rate. Notably, patients with nonuveal melanoma had a 20% response rate, while none of those with metastatic uveal melanoma responded. Two patients achieved progression-free survival (PFS) exceeding one year, with gene alterations in PALB2 and ATM, suggesting that specific HR mutations may confer greater sensitivity to PARP inhibition.

The study highlights how HR pathway alterations, which affect roughly a fifth to a third of melanomas, may offer an opportunity for targeted treatment. While previous trials using PARP inhibitors in melanoma were largely ineffective, they did not focus on genetically selected patients. This study’s molecularly targeted approach yielded more encouraging outcomes.

Despite promising results, the trial was terminated early due to slow patient accrual, likely because HR-mutant melanomas often respond better to immune checkpoint inhibitors. This underlines the need for combination strategies, such as pairing PARP inhibitors with PD-1 blockers or MAPK pathway inhibitors, which have shown synergistic effects in preclinical studies.

Although the sample size was small, this trial provides early evidence that PARP inhibition may benefit a subset of melanoma patients with HR gene mutations. Further trials with larger cohorts and combination regimens are warranted to refine patient selection and treatment protocols for this high-need group.

Reference

Kim KB et al. Phase II study of niraparib in patients with advanced melanoma with homologous recombination pathway gene mutations. JCO Precis Oncol. 2025;9:e2400658.

 

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