Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival

SIMPLE SUMMARY: Synthetic lethality approaches to cancer therapy involves combining events to cause cancer cell death. Using this strategy, major advances have occurred in the treatment of women with ovarian cancer who have defects in the Homologous Recombination Repair (HRR) pathway. When the HRR pathway is defective, due to mutations or epigenetic changes in genes such as BRCA1 or BRCA2, cells can no longer accurately repair double strand breaks (DSBs). Capitalising on this weakness, pharmacological inhibition of poly (ADP-ribose) polymerase (PARP) that function to repair single strand breaks (SSBs) leads to synthetic lethality in cells with defective HRR. PARP inhibitors (PARPis) including olaparib, niraparib and rucaparib are approved for the clinical management of women with ovarian cancer. Understanding and overcoming issues of acquired resistance to PARPis, extending these strategies to benefit more patients and combining PARPis with other drugs, including immunotherapies, are of high priority in the field today. ABSTRACT: The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% displaying defective HRR. Poly ADP ribose polymerases (PARPs) are a family of enzymes that catalyse the transfer of ADP-ribose to target proteins, functioning in fundamental cellular processes including transcription, chromatin remodelling and DNA repair. In cells with deficient HRR, PARP inhibitors (PARPis) cause synthetic lethality leading to cell death. Despite the major advances that PARPis have heralded for women with ovarian cancer, questions and challenges remain, including: can the benefits of PARPis be brought to a wider range of women with ovarian cancer; can other drugs in clinical use function in a similar way or with greater efficacy than currently clinically approved PARPis; what can we learn from long-term responders to PARPis; can PARPis sensitise ovarian cancer cells to immunotherapy; and can synthetic lethal strategies be employed more broadly to develop new therapies for women with ovarian cancer. We examine these, and other, questions with focus on improving outcomes for women with ovarian cancer.