Empowering PARP inhibition through rational combination: Mechanisms of PARP inhibitors and combinations with a focus on the treatment of metastatic castration-resistant prostate cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of many cancers. Metastatic castration-resistant prostate cancer (mCRPC) is an area where PARP inhibitors are intensively studied; the efficacy with PARP inhibitor monotherapy in patients with homologous recombination repair mutations following novel hormonal therapy have prompted the investigation of combination therapy, with adding an androgen receptor pathway inhibitor (ARPI) being one focus of research. Data on PARP inhibitor monotherapy and combination therapy for mCRPC are accumulating, and it is important to navigate through the complex data to inform treatment decision. Here we review the mechanisms of action of PARP inhibitors, their pharmacological properties, the synergistic activity of PARP inhibitors plus other drug classes, and the clinical evidence on monotherapy and combination therapy in patients with mCRPC. We propose key considerations in the selection of agents and treatment sequence for mCRPC, such as efficacy, toxicity profiles, biomarkers, and interactions with concomitant medications.