Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective.

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a paradigm-shifting therapeutic strategy in oncology, demonstrating significant synthetic lethality in tumors characterized by homologous recombination deficiency. Due to their substantial efficacy, PARP inhibitors (PARPi) have received approval for the treatment of four malignancies: ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer. However, the specific clinical indications and optimal utilization settings vary among these types of cancers. Identifying novel biomarkers is thus essential for accurately predicting patients’ responses to PARPi, therefore enhancing effective patient stratification. Notably, the emergence of acquired resistance to PARPi presents a considerable challenge to their practical implementation in clinical practice. Both preclinical and clinical studies have elucidated numerous molecular alterations contributing to this resistance, offering valuable insights into potential strategies for overcoming it. This review comprehensively summarizes landmark clinical trials involving both PARPi monotherapy and various combination strategies, and outlines future research directions. We compare existing predictive tools for resistance to PARPi, aiming to refine future clinical applications and identify critical gaps requiring further investigation. This review also presents new insights into primary and acquired resistance by updating mechanisms of PARPi action and summarizing the biological processes involved in PARPi resistance. Additionally, we discuss potential strategies designed to overcome these mechanisms.