Novel Therapeutic Approaches to Overcome Acquired Resistance to Enzalutamide in Patients with Advanced Prostate Cancer

Abstract

The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the standard of care treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. Despite significant improvements in clinical outcomes in the setting of castration sensitivity and castration resistance, the durability of clinical response to enzalutamide, apalutamide, and darolutamide is limited by inevitable acquired resistance. Clinically relevant biomarkers of resistance to SG-ARAs have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K/AKT, and WNT/βcatenin pathways. To combat resistance, clinical investigators have explored approaches to optimize the utility of available treatments, while venturing into the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2, and HIF-1 . Ongoing research to establish predictive biomarkers for the treatment of tumors with resistance to SG-ARAs has led to the recent approvals of the PARP inhibitors, olaparib and rucaparib. Results from ongoing studies will help shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes. This review will discuss relevant biomarkers of acquired resistance to SG-ARA therapy and newer therapeutic approaches to further improve clinical outcomes in advanced prostate cancer.