Researchers may have uncovered early indications of the clinical benefit of niraparib in patients with advanced melanoma whose tumors have specific genetic changes impacting DNA repair, according to a recent study published by Kim et al in JCO Precision Oncology.
Background
The U.S. Food and Drug Administration approved tumor-infiltrating lymphocyte therapy for patients with advanced melanoma who have previously received anti–PD-1 antibody therapy and a combination of BRAF/MEK inhibitors among those with BRAF V600–mutated tumors.
“Despite these available, approved combination therapies, many patients’ disease progresses or recurs, reinforcing the critical need for new, targeted treatments,” stressed lead study author Kevin Kim, MD, a medical oncologist at the Sutter California Pacific Medical Center. “Our goal is to advance this research to help guide and inform the care of patients who have limited therapeutic options,” he added.
When a cancer cell already has impaired damage repair, such as in patients with homologous recombination pathway gene mutations, the cancer cell is unable to fix the DNA damage. PARP inhibitors such as niraparib further block the cancer cell from repairing its damaged DNA. As a result, the cancer cell cannot divide and ultimately dies.
Study Methods and Results
In the single-arm, investigator-initiated phase II trial, the researchers examined the effectiveness of niraparib in a select group of 14 patients with advanced melanoma whose disease previously progressed after standard treatment (eg, immunotherapy as well as BRAF/MEK inhibition).
The researchers found that two of the patients who participated in the trial achieved a confirmed response, and seven of them experienced stable disease lasting at least 16 weeks—resulting in a disease control rate of 64%. In the subgroup of 10 patients with nonuveal melanoma, the response rate and disease control rate of at least 16 weeks were 20% and 70%, respectively.
Further, the researchers included circulating tumor DNA (ctDNA) monitoring, allowing them to track tumor-related mutations in the blood. In one case, a mutation in the ARID1A gene became undetectable during treatment in patients whose tumors shrank, suggesting ctDNA may serve as a potential biomarker of treatment response.
Conclusions
“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 [patients with] melanoma whose tumors have [homologous recombination] mutations,” emphasized senior study author Mohammed Kashani-Sabet, MD, Medical Director of the Cancer Center at the Sutter California Pacific Medical Center.
The research built on prior work highlighting that homologous recombination–deficient melanomas may be more sensitive to PARP inhibitors. The researchers plan to conduct a separate phase II trial assessing outcomes following the combination of PARP inhibitors such as olaparib and immunotherapy among this patient population.
“Early results suggest biopsies and DNA sequencing are the essential start toward discovery, innovation, and curiosity to advance more effective melanoma treatment,” Dr. Kim concluded.
Disclosure: For full disclosures of the study authors, visit ascopubs.org.
