Niraparib Shows Early Promise in Treating Advanced Melanoma

Researchers from Sutter's California Pacific Medical Center (CPMC) in San Francisco have reported encouraging preliminary results from their investigation into niraparib, a PARP inhibitor, for patients suffering from advanced melanoma with specific genetic alterations affecting DNA repair.

This phase II clinical trial, which was led by Dr. Kevin Kim and Dr. Mohammed Kashani-Sabet, focused on a cohort of patients whose melanoma had progressed despite receiving standard therapies, including immunotherapy and targeted treatments involving BRAF and MEK inhibitors. The findings were shared during the 2024 ESMO Congress and were published recently in JCO Precision Oncology.

Current treatment options for advanced melanoma include tumor-infiltrating lymphocyte therapy, which is available for patients who have previously undergone anti-PD-1 antibody therapy, particularly if their tumors are V600 BRAF-mutant. However, many patients experience disease progression or recurrence, highlighting the urgent need for new targeted therapies.

Dr. Kim emphasized the importance of advancing research to provide better treatment options for patients with limited alternatives. In cases where cancer cells have compromised DNA damage repair mechanisms, like those with homologous recombination (HR) pathway mutations, PARP inhibitors such as niraparib can further inhibit the cancer cell's ability to mend damaged DNA, ultimately leading to cell death.

In the trial, which included 14 participants, 2 patients (14%) achieved a confirmed response, while 7 patients (50%) maintained stable disease for a minimum of 16 weeks, resulting in a disease control rate of 64%. Notably, among the subgroup of 10 patients with non-uveal melanoma, the response rate rose to 20%, with a disease control rate of 70% over the same period.

Dr. Kashani-Sabet remarked on the significance of these early findings, suggesting that niraparib may provide hope for a specific group of melanoma patients with HR mutations. The trial also incorporated monitoring of circulating tumor DNA (ctDNA), enabling the researchers to track tumor-related mutations in the blood over time. In one case, a mutation in the ARID1A gene became undetectable during treatment in a patient whose tumor shrank, indicating that ctDNA could potentially serve as a biomarker for treatment response.

This study builds on previous research indicating that melanomas deficient in HR may respond more favorably to PARP inhibitors. Moving forward, CPMC researchers are planning a separate phase II trial to evaluate the efficacy of combining PARP inhibitors, such as olaparib, with immunotherapy to enhance outcomes for this genetically defined patient population.

In conclusion, the early results of this study underscore the necessity of biopsies and DNA sequencing as foundational steps in the pursuit of innovation and more effective treatments for melanoma.