PARP Inhibitors in the Neoadjuvant Setting; A Comprehensive Overview of the Rationale for their Use, Past and Ongoing Clinical Trials.

Abstract

Purposeof review: Poly (ADP-ribose) polymerases (PARPs) are enzymes essential for detecting and repairing DNA damage through poly-ADP-ribosylation. In cancer, cells with deficiencies in homologous recombination repair mechanisms often become more dependent on PARP-mediated repair mechanisms to effectively repair dsDNA breaks. As such, PARP inhibitors (PARPis) were introduced into clinical practice, serving as a key targeted therapy option through synthetic lethality in the treatment of cancers with homologous recombination repair deficiency (HRD). Though PARPis are currently approved in the adjuvant setting for several cancer types such as ovarian, breast, prostate and pancreatic cancer, their potential role in the neoadjuvant setting remains under investigation. This review outlines the rationale for using PARPi in the neoadjuvant setting and evaluates findings from early and ongoing clinical trials.

Recent findings: Our analysis indicates that numerous studies have explored PARPi as a neoadjuvant treatment for HRD-related cancers. The majority of neoadjuvant PARPi trials have been performed in breast and ovarian cancer, while phase II/III evidence supporting efficacy in prostate and pancreatic cancers remains limited. Studies are investigating PARPi in the neoadjuvant setting of HRD-related cancers. Future research should prioritize combination strategies with immune checkpoint inhibitors and expand outcome measures to include patient satisfaction and quality-of-life metrics.