PARP inhibitors in ovarian cancer: Mechanisms of resistance and implications to therapy.

Advanced epithelial ovarian cancer of the high-grade serous subtype (HGSOC) remains a significant clinical challenge due to the development of resistance to current platinum-based chemotherapies. PARP1/2 inhibitors (PARPi) exploit the well-characterised homologous recombination repair deficiency (HRD) in HGSOC and offer an effective targeted approach to treatment. Several clinical trials demonstrated that PARPi (olaparib, rucaparib, niraparib) significantly improved progression-free survival (PFS) in HGSOC in the recurrent maintenance setting. However, 40-70 % of patients develop Resistance to PARPi presenting an ongoing challenge in the clinic. Therefore, there is an unmet need for novel targeted therapies and biomarkers to identify intrinsic or acquired resistance to PARPi in ovarian cancer. Understanding the mechanisms of resistance to PARPi is crucial for identifying molecular vulnerabilities, developing effective biomarkers for patient stratification and guiding treatment decisions. Here, we summarise the current landscape of mechanisms associated with PARPi resistance such as restored homologous recombination repair functionality, replication fork stability and alterations to PARP1 and PARP2 and the DNA damage response. We highlight the role of circulating tumour DNA (ctDNA) in identifying acquired resistance biomarkers and its potential in guiding 'real-time' treatment decisions. Moreover, we explore other innovative treatment strategies aimed at overcoming specific resistance mechanisms, including the inhibition of ATR, WEE1 and POLQ. We also examine the role of PARPi rechallenge in patients with acquired resistance.