The role of PARPis and HRD testing in advanced ovarian cancer

High grade serous ovarian cancer is characterized by genomic instability, with ~50% of advanced tumors harboring homologous recombination repair (HRR) pathway deficiency (HRD). HRD results in irreparable DNA damage and increased sensitivity to platinum chemotherapy, as well as increased susceptibility to poly-ADP ribose polymerase (PARP) inhibitors. PARPis are able to induce synthetic lethality in cells with HRD by binding to and trapping PARP1 and PARP2 to single-stranded DNA breaks, which generates double-stranded breaks. The lack of high-fidelity HRR in these cells leads to reliance on error-prone DNA repair pathways (e.g.: non-homologous end joining), further genomic instablity and cell death. The presence of HRD leads to detectable signature or genomic scar which can be scored by different tools. Available tools have computed the following: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions to derive a summated HRD score. The HRD score has come to the fore as important individualised information in patients with advanced ovarian cancer, due to its correlation with response to maintenance PARPis in the first-line therapeutic setting. In this session, we discuss the role of PARPis in the treatment of advanced ovarian cancer, with particular focus on the use of HRD testing to better define optimal therapy for front-line treatment of these patients.

Learning Objectives:
1. To understand the role of PARPis in the treatment of advanced ovarian cancer
2. Understanding biomarkers to select patients for PARPi therapy