The future of androgen receptor targeting in prostate cancer: third-generation inhibitors and beyond.

The androgen receptor (AR) pathway plays a fundamental role in the treatment of prostate cancer, from the localized stage to metastatic disease, even in castration-resistant prostate cancer (CRPC). Despite the significant benefit for the earlier use of second-generation AR pathway inhibitors (ARPI), treatment resistance is still emerging. A deeper understanding of the biology of ARPI resistance is crucial for developing new therapeutic targets. In this review, we will explore the biology of second-generation ARPI resistance and discuss the evolving landscape of third-generation ARPI and steroid hormone inhibitors, which are shaping the future of prostate cancer therapeutics. Targeting the biosynthesis of steroid precursors with CYP11A1 inhibition, inducing AR degradation with proteolysis-targeting chimera degraders or restoring ARPI sensitivity with EZH2 inhibitors are among the most advanced strategies in development. Alongside these new drugs, AR genomic alterations and particularly AR mutations emerge as a promising biomarker for patient selection. These innovative therapeutics help bring more personalized approaches to patients with prostate cancer, aiming to overcome resistance and improve patient outcomes.