Preventing and Overcoming Resistance to PARP Inhibitors: A Focus on the Clinical Landscape

SIMPLE SUMMARY: PARP inhibitors (PARPi) are current treatment options for patients with ovarian, breast, pancreatic or prostate cancer. Although PARPi have transformed the patient journey in these disease settings, resistance eventually develops, leaving them with limited therapeutic opportunities. In this review, we summarize the mechanisms of resistance to PARPi described in pre-clinical models, focusing on the most clinically relevant and proposing ways to tackle them. ABSTRACT: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are now a first-line maintenance treatment in ovarian cancer and have been approved in other cancer types, including breast, pancreatic and prostate. Despite their efficacy, and as is the case for other targeted therapies, resistance to PARPi has been reported clinically and is generating a growing patient population of unmet clinical need. Here, we discuss the mechanisms of resistance that have been described in pre-clinical models and focus on those that have been already identified in the clinic, highlighting the key challenges to fully characterise the clinical landscape of PARPi resistance and proposing ways of preventing and overcoming it.