Biomarkers May Predict Sensitivity to Combined PARP and PD-1 Inhibition in Ovarian Cancer
Posted: Tuesday, May 12, 2020
The presence of mutational signature 3 or a positive immune score in ovarian tumors appears to be associated with an improved outcome with the combination of PARP and immune checkpoint inhibitors, according to Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute, Boston, and colleagues. Tumors that lacked these features did not seem to respond effectively to this combination treatment. The results were published in Nature Communications.
“Patients with advanced or metastatic ovarian cancer who are resistant to standard platinum-based chemotherapy agents often have few further options for treatment,” Dr. Konstantinopoulos commented in a Dana-Farber press release. “Our findings will help ensure that patients for whom a PARP inhibitor/checkpoint inhibitor combination won’t be beneficial can focus on other clinical trials of treatments that may be more effective for them.”
The team of investigators performed single-cell imaging and extensive immunogenic profiling on ovarian tumor samples obtained from 62 patients enrolled in a phase I/II niraparib and pembrolizumab clinical trial. The presence of mutational signature 3, resulting from homologous recombination deficiency or a positive immune score, was correlated with clinical benefit and a significantly prolonged progression-free survival (hazard ratio = 0.32). Absence of both features appeared to be associated with a lack of response to the combination of the PARP inhibitor niraparib and the PD-1 inhibitor pembrolizumab (objective response rate = 0%).
The median progression-free survival with niraparib and pembrolizumab in Sig3-positive and Sig3-negative patients was 5.0 months and 2.2 months, respectively. Sig3-positive tumors displayed increased PD-L1 expression in tumor cells and macrophages, which indicated enhanced immunogenicity. The presence of a positive immune score and Sig3 positivity resulted in increased interferon activation and CD8-positive T-cell exhaustion. Of note, based on single-cell imaging, the investigators proposed that interferon-primed exhausted CD8-positive T cells may be significantly associated with response to PARP and immune checkpoint inhibition.
Disclosure: For full disclosures of the study authors, visit nature.com.