Can a PARP Inhibitor Plus Immunotherapy Improve Recurrent Ovarian Cancer Outcomes?

The combination of niraparib and pembrolizumab was well tolerated and showed promising antitumor activity in patients with recurrent ovarian carcinoma, according to a phase I/II trial. The combination was active across several subgroups, and researchers say it warrants further investigation.

“Preclinical models, including those for ovarian carcinoma, have demonstrated a synergistic antitumor effect with niraparib and anti–PD-1 drugs regardless of BRCA mutation status or PD-L1 expression,” wrote study authors led by Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute in Boston. This synergy could involve several mechanisms, including the ability of PARP inhibitors to upregulate PD-L1 expression.

The new study included 9 patients in a phase I portion and 53 patients in a phase II cohort, all with recurrent ovarian carcinoma, regardless of BRCA mutation status; 60 patients were available for the final efficacy analysis. The median age in the trial was 60 years, and most patients had an ECOG performance status of 0 (71%). The median number of prior lines of therapy was 3, and 63% had received prior bevacizumab. Results of the study were published in JAMA Oncology.

After a median follow-up of 12.4 months, the confirmed objective response rate of the full cohort was 18%; there were 8 partial responses, and 28 patients had stable disease, for a disease control rate of 65%. Twenty patients had progressive disease. The median duration of response was not yet reached in the trial; 8 patients had a response lasting longer than 6 months, and 4 achieved a response lasting longer than 9 months.

An analysis of subgroups found that the combination therapy showed activity regardless of BRCA mutation status or homologous recombination deficiency (HRD) status, with similar objective response rates for all biomarker-defined populations. “Although we noted that patients with fewer lines of therapy had higher response rates than those with 3 or more prior lines, the confidence intervals overlapped,” the authors pointed out. “Response rates were similar regardless of platinum status or prior bevacizumab treatment.”

The median progression-free survival (PFS) was 3.4 months. The 6-month PFS rate was 31%, and at 12 months the rate was 12%. Overall survival data were not yet mature.

The most common treatment-related adverse events included fatigue (53%), nausea (42%), and anemia (36%). For treatment-related adverse events of grade 3 or higher, anemia (21%) and thrombocytopenia (9%) were most frequent; there were no treatment-related patient deaths, nor were there any cases of myelodysplastic syndrome or acute myeloid leukemia. A total of 10 patients (19%) experienced immune-related adverse events related to treatment, with only 3 patients experiencing such events at grade 3 or higher.

“This study has shown that the combination treatment of niraparib and an anti–PD-1 antibody appears to be well tolerated and potentially provides clinical activity by tumor shrinkage and disease stabilization in patients with recurrent ovarian carcinoma,” the authors concluded.

In an accompanying editorial, Kunle Odunsi, MD, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, and Tanja Pejovic, MD, PhD, of the Oregon Health & Science University in Portland, wrote that the results are promising and the combination could offer “clinical benefits that could be superior to current standard-of-care chemotherapy and to either drug alone.”

They noted, though, that the study’s small numbers limit the interpretation of the subgroup analyses, in particular regarding varying combinations of BRCA and HRD status. “Larger confirmatory randomized clinical trials are needed that use panels of integrated biomarkers that would allow identification of patients most likely to respond,” they wrote.