Sig3 Mutation, Immune Score Indicate Response to PARP Inhibitor/Immune Checkpoint Inhibitor Combo in Ovarian Cancer

March 27, 2020

Ovarian cancer remains the most deadly of the gynecologic cancers. Researchers from Dana-Farber Cancer Institute may have discovered biomarkers that could predict which patients with platinum-resistant ovarian cancer would benefit from combination poly-ADP ribose polymerase (PARP) inhibitor/immune checkpoint inhibition treatment, as well as those who should pursue a different course of therapy.

Ovarian cancer remains the most deadly of the gynecologic cancers. Researchers from Dana-Farber Cancer Institute may have discovered 2 biomarkers that could predict which patients with platinum-resistant ovarian cancer would benefit from combination poly-ADP ribose polymerase (PARP) inhibitor/immune checkpoint inhibition treatment, as well as those who should pursue a different course of therapy.

“Patients with advanced or metastatic ovarian cancer who are resistant to standard platinum-based chemotherapy agents often have few further options for treatment,” stated Panagiotis Konstantinopoulos, MD, PhD, director of translational research, Gynecologic Oncology, at Dana-Farber, co—senior author of the study. “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.”

Separately, a PARP inhibitor and a checkpoint inhibitor produce minimal results in patients with ovarian cancer. The investigators of the phase 1/2 TOPACIO/Keynote-162 trial focused on biomarkers that would indicate a response to niraparib/pembrolizumab, respectively. Specifically, niraparib produces responses in a mere 3% of these patients, while pembrolizumab comes in at just 5%. Together, however, this combination ramps up the combined rate of complete (5%) and partial response (PR; 13%) 18%. In addition, the combination held disease progression at bay for over a year in 65%. However, the median (range, 4.2-14.5+ months) duration of response was not reached.

What biomarkers did the investigators find that they think will help direct PARP inhibitor/immune checkpoint inhibitor treatment in patients with ovarian cancer who haven’t responded to previous treatments?

They used single-cell spatial analysis and spatial analysis on a subset of 62 patients from the TOPACIO trial who had undergone a median of 3 (range, 1-5) prior lines of therapy, through the course of which most (76%) of the patients became platinum resistant or refractory.

Using signature multivariate analysis, they were able to determine that patients who were positive for the signature 3 (Sig3) mutation, used here as a surrogate of homologous recombination deficiency, had more of a clinical benefit, in the form of stable disease or PR (P = .02), compared with patients who had progressive disease. The median progression-free survival in these patients was 5.0 (range, 2.1-22.7) months compared with 2.2 (range, 0.5-8.6; P = .0005) months in Sig3-negative patients.

An Immune Score (IS) was then assigned, which was itself a surrogate for “interferon-primed exhausted CD8+ T cells in the tumor microenvironment.” In this study, overall response significantly correlated with IS (P = .01). According to the press release on the study results, exhausted T cells indicate tumors likely to respond to checkpoint-inhibiting drugs. Therefore, the more exhausted T cells a tumor contains, the higher its IS, or signaling activity toward the immune system.

The results demonstrate that all patients who responded to the combination treatment were positive for either Sig3 or IS or both.

“Our study highlights that careful analysis of genomic information and single-cell spatially resolved data from clinical samples can provide valuable information on the determinants of response to therapy and accelerate the development of predictive biomarkers to aid in patient stratification,” the authors concluded.

Reference

Färkkilä A, Gulhan DC, Casado J, et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer [published online March 19 2020]. Nat Commun. doi: 10.1038/s41467-020-15315-8.