Researchers at Sutter’s California Pacific Medical Center (CPMC) in San Francisco, Calif. have discovered early signs of clinical benefit while testing niraparib, a PARP inhibitor, in patients with advanced melanoma whose tumors 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 Center, 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 tumor-infiltrating lymphocyte therapy for advanced melanoma in patients who have previously received anti-programmed cell death 1 (PD-1) antibody therapy and, if their tumors 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 tumors have HR mutations,” says Dr. Kashani-Sabet.
The trial also included circulating tumor DNA (ctDNA) monitoring, allowing the researchers to track tumor-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 tumors 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.
About Sutter Health
Sutter Health is a not-for-profit healthcare system dedicated to providing comprehensive care throughout California. Committed to health equity, community partnerships, and innovative, high-quality patient care, Sutter Health is pursuing a bold new plan to reach more people and make excellent healthcare more connected and accessible. Currently serving nearly 3.5 million patients, thanks to our dedicated team of more than 57,000 employees and clinicians, and 12,000+ affiliated physicians, with a unified focus on expanding care to serve more patients.
Sutter delivers exceptional and affordable care through its hospitals, medical groups, ambulatory surgery centers, urgent care clinics, telehealth, home health, and hospice services. Dedicated to transforming healthcare, at Sutter Health, getting better never stops.
Learn more about how Sutter Health is transforming healthcare at sutterhealth.org and vitals.sutterhealth.org.
Journal
JCO Precision Oncology