For those interested, here is a recent review article. I have not seen the Full Text, but it and the Reference section may be of help to those fighting this particular battle in our ongoing war.Resistance to second-generation androgen receptor antagonists in prostate cancer
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.Key points
• 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."