Prostate cancer represents a significant oncological challenge, with its natural history predominantly driven by androgen receptor (AR) signaling. The pivotal role of this pathway underscores the rationale for targeting AR activity in therapeutic strategies. However, the development of resistance mechanisms has highlighted the need for advanced therapies to address the complexity of the castration-resistant status.
We analyzed the evolving role of second-generation androgen receptor signaling inhibitors (ARSIs) in the management of non-metastatic and metastatic castration-resistant prostate cancer, we critically examine emerging combination strategies involving ARSIs, novel agents targeting resistance pathways, and the mechanisms underlying treatment resistance. The review also provides insights into future directions for enhancing outcomes. PubMed literature research using keywords related to castration-resistant prostate cancer and its treatments was performed, including the most relevant trials and reviews.
ARSIs have revolutionized the management of prostate cancer, providing substantial clinical benefits and representing the cornerstone of current treatment paradigms. However, key challenges remain, including determining optimal treatment sequencing, overcoming resistance mechanisms, and tailoring therapies to specific molecular subtypes. Biomarker-driven approaches are critical for refining patient selection and improving therapeutic outcomes. Ongoing trials investigating novel hormonal-axis-directed agents and innovative combination therapies aim to expand the arsenal of effective treatment.
Expert review of anticancer therapy. 2025 Mar 16 [Epub ahead of print]
Linda Danielli, Elisa Tassinari, Andrea Marchetti, Matteo Rosellini, Veronica Mollica, Liang Cheng, Francesco Massari
Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Department of Pathology and Laboratory Medicine, Department of Surgery (Urology), Brown University Warren Alpert Medical School, the Legorreta Cancer Center at Brown University, and Brown University Health, Providence, RI, USA.