Researchers at Sutter’s California Pacific Medical Centre (CPMC) in San Francisco, Calif.

have discovered early signs of clinical benefit while testing niraparib, a PARP inhibitor, in patients with advanced melanoma whose tumours had specific genetic changes impacting DNA repair.

The single-arm, investigator initiated phase II trial—led by Kevin Kim, M.D., principal investigator and medical oncologist at CPMC, and Mohammed Kashani-Sabet, M.D., principal investigator and medical director of CPMC’s Cancer Centre, and colleagues at CPMC—examined the effectiveness of niraparib in a select group of patients whose disease previously progressed after standard treatment such as immunotherapy, and BRAF/MEK-targeted therapies.

Results of the study were presented at the 2024 ESMO Congress and were published this month in JCO Precision Oncology.

The U.S. Food and Drug Administration approved tumour-infiltrating lymphocyte therapy for advanced melanoma in patients who have previously received anti-programmed cell death 1 (PD-1) antibody therapy and, if their tumours are V600 BRAF-mutant, a combination of BRAF and MEK inhibitors.

“Despite these available, approved combination therapies, many patients’ disease progresses or recurs, reinforcing the critical need for new, targeted treatments,” says Dr. Kim.

“Our goal is to advance this research to help guide and inform the care of patients who have limited therapeutic options.”

When a cancer cell already has impaired damage repair, such as in patients with homologous recombination (HR) pathway gene mutations, the cancer cell cannot fix DNA damage.

PARP inhibitors like niraparib further block the cancer cell from repairing its damaged DNA.

As a result, the cancer cell cannot divide and ultimately dies.

Of the 14 patients who participated in the trial, 2 (14%) achieved a confirmed response, and 7 (50%) experienced stable disease lasting at least 16 weeks, resulting in a disease control rate of 64%.

In the subgroup of 10 patients with non-uveal melanoma, the response rate and disease control rate of at least 16 weeks were 20% and 70%, respectively.

“There is much more we seek to learn. Despite the small sample size, our findings suggest niraparib may offer hope to a select group of melanoma patients whose tumours have HR mutations,” says Dr Kashani-Sabet.

The trial also included circulating tumour DNA (ctDNA) monitoring, allowing the researchers to track tumour-related mutations in blood over a period of time.

In one case, a mutation in the gene ARID1A became undetectable during treatment in patients whose tumours shrunk, suggesting ctDNA could serve as a potential biomarker of treatment response.

The study builds on prior work highlighting that HR-deficient melanomas may be more sensitive to PARP inhibitors.

As of April 2025, researchers at CPMC aim to conduct a separate phase II trial testing the combination of PARP inhibitors (such as olaparib) with immunotherapy to produce improved outcomes for this genetically defined group of patients.

“Early results suggest biopsies and DNA sequencing are the essential start towards discovery, innovation and curiosity to advance more effective melanoma treatment,” says Dr. Kim.

Source: Sutter Health