Mechanisms and markers of resistance to androgen signaling inhibitors in patients with metastatic castration-resistant prostate cancer

Next-generation androgen signaling inhibitors such as abiraterone and enzalutamide are widely used for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, baseline and acquired resistance to these treatments is commonly observed. In the last few years, significant effort has been devoted to uncover the molecular mechanisms and predictive markers of resistance. These analyses identified various DNA (single nucleotide variations, amplifications) and RNA variants (e.g., the splice variant AR-V7) of androgen receptor in association with resistance to abiraterone and enzalutamide therapies. Additionally, androgen receptor independent resistance mechanisms were also described. Some of these alterations can be detected in tumor tissues and/or in liquid biopsies of prostate cancer patients and therefore may serve as predictive biomarkers. According to the diversity of potential resistance mechanisms, it appears that a combination of markers representing various resistance mechanisms may provide better performance as single markers. In the present review, we summarize the most important androgen receptor dependent and independent resistance mechanisms and pay attention to methodological details. Recent data has highlighted that some of the resistance mechanisms to next-generation antiandrogen agents are associated with a better response to other therapies, we give an overview on currently ongoing clinical studies evaluating this promising aspect. © 2021 The Author(s)