Resistance to second-generation androgen receptor antagonists in prostate cancer

Abstract

The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K–AKT–mTOR and Wnt–β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes. Survival of patients with metastatic prostate cancer has improved with the approval of second-generation androgen receptor antagonists. This Review discusses common genomic alterations leading to inevitable resistance to this therapy, and potential alternative therapeutic targets for treatment. Second-generation androgen receptor antagonists (SG-ARAs) have substantially improved outcomes in patients with advanced and/or metastatic prostate cancer. Acquired resistance to SG-ARA treatment limits the effectiveness of therapy and can be conferred through multiple mechanisms, including genomic alterations of the androgen receptor (AR), DNA damage repair (DDR), phosphoinositide 3-kinase–protein kinase B–mammalian target of rapamycin (PI3K–AKT–mTOR), Wnt–β-catenin and neuroendocrine differentiation pathways. Novel therapies targeting the AR have sought to overcome numerous mechanisms of resistance, including AR amplification, AR splice variation, AR point mutations and AR bypass facilitated via the glucocorticoid receptor. Alternative therapeutic approaches to AR targeting to overcome SG-ARA resistance include investigational agents targeting cell-signalling pathways (e.g. PI3K–AKT–mTOR), DNA damage repair, angiogenesis, epithelial–mesenchymal transition and AR-independent lineage plasticity. To minimize SG-ARA resistance, optimization of available and investigational treatments in a patient-specific manner are being considered to maximize clinical outcomes in patients with prostate cancer.