Sig3 mutation and immune score determine responses to combination PARP and PD-1 inhibition in ovarian cancer
Immune checkpoint inhibitors have shown promising therapeutic outcomes in many types of cancer, but ovarian cancer has been an exception. Thus, developing new strategies to improve the efficacy of immune checkpoint inhibitors is a high priority for the treatment of ovarian cancer.
Studies have demonstrated that the combination of programmed cell death protein 1 (PD-1) and poly-ADP ribose polymerase (PARP) inhibitors has demonstrated synergistic antitumor activity in ovarian cancer. However, predictive biomarkers to identify patients who would benefit from the treatment combination are lacking.
A recent study, published in Nature Communications, identified two markers – mutational signature 3 (Sig3) and positive immune score (IS) – to determine if patients with platinum-resistant ovarian cancer will respond to the combination of immune checkpoint and PARP inhibitors.
The researchers from the Dana-Farber Cancer Institute in Boston, MA, performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (TOPACIO trial; NCT02657889).
Using multivariate analysis, researchers found that Sig3 mutation positivity, a surrogate of defective homologous recombination DNA repair, correlates with clinical benefit; significantly more Sig3-positive patients had stable disease or partial response (p = 0.02), compared to patients who had progressive disease. The median progression-free survival (PFS) in Sig3-positive patients was 5.0 months (range 2.1–22.7) compared with 2.2 months (range 0.5–8.6; p = 0.0005) in the Sig3-negative patients.
Additionally, an IS, used as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment, was assigned to each sample. According to the study, IS positivity was significantly correlated with overall response (p = 0.01).
In conclusion, the presence of one or both tumor features was associated with clinical benefit and prolonged PFS (p = 0.002; HR 0.32). Conversely, patients whose cells lacked both of these features showed absence of response to niraparib/pembrolizumab combination (objective response rate 0%).
The publication concludes that this 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’.
Written by Marta Palhas
1. Färkkilä A, Gulhan D, Casado J et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat Commun. 2020 Mar;11(1). doi:10.1038/s41467-020-15315-8