How to cite: Ross AE. Androgen Receptor Signaling Inhibitors: Evidence, Indications, and Side Effects in HSPC. Grand Rounds in Urology. October 2025. Accessed Mar 2026. https://grandroundsinurology.com/androgen-receptor-signaling-inhibitors-evidence-indications-and-side-effects-in-hspc/
Summary
Ashley E. Ross, MD, PhD, Associate Professor of Urology, Clinical Director, Polsky Urologic Cancer Institute, Northwestern University, Chicago, Illinois, outlines how androgen receptor pathway inhibitors (ARPIs) influence outcomes in hormone-sensitive prostate cancer (HSPC). He explains that advanced prostate cancer remains androgen-dependent even after castration level testosterone suppression. He describes mechanisms that sustain androgen signaling, such as androgen receptor amplification, intratumoral androgen production, and androgen receptor splice variants. These findings support further targeting of the androgen receptor pathway.
Dr. Ross reviews how ARPIs work: abiraterone acetate blocks androgen synthesis, and enzalutamide, apalutamide, and darolutamide inhibit ligand binding, nuclear translocation, and DNA binding of the androgen receptor. He explains that structural differences between these agents may affect metabolism, drug interactions, efficacy, and toxicity.
He presents dosing details for each agent and reviews side effects. Abiraterone may cause hypertension, hypokalemia, transaminitis, and arrhythmia. Apalutamide may cause rash and hypothyroidism. Darolutamide may show decreased fatigue compared to placebo. Enzalutamide may cause falls, fractures, seizures, and fatigue. He emphasizes that hormonal therapy as a whole affects cardiovascular health, metabolic function, bone strength, sexual function, and cognition.
Dr. Ross shares data from trials studying ARPIs combined with androgen deprivation therapy (ADT) in synchronous metastatic HSPC that shows a 20% absolute reduction in progression at two years and a roughly 30% improvement in overall survival, with virtually all patients in the combination group showing some benefit.
Dr. Ross highlights additional uses for ARPIs, including triplet therapy with docetaxel, use in very high-risk or node-positive disease, and potential biomarker-driven strategies.
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ABOUT THE AUTHOR
Ashley E. Ross, MD, PhD, is an Associate Professor of Urology and Clinical Director for the Polsky Urological Oncology Center at Northwestern Feinberg School of Medicine in Chicago, Illinois. Dr. Ross specializes in prostate cancer, genomics, immunology, targeted therapies, and clinical trials. His research primarily aims to enhance the diagnosis and treatment of clinically significant prostate cancer, including the identification of prognostic and predictive biomarkers and the initiation of clinical trials.
