Prostate Cancer Hormone Therapy - How Androgen Receptor Targeted Agents (ARTAs) Work

How the hormone treatments for prostate cancer work, drug by drug: LHRH agonists and antagonists, bicalutamide, abiraterone, and the second-generation antagonists enzalutamide, apalutamide and darolutamide. This video covers the mechanism of action and the side effects that follow from it. It does not cover trials, doses or when to use each drug — those get their own videos. 0:00 Intro 0:06 Introduction: one pathway 0:29 The androgen axis 2:06 Castration: LHRH agonists and antagonists 4:57 Castration resistance 6:04 First-generation antiandrogens: bicalutamide 7:45 Abiraterone and the steroid pathway 9:46 Enzalutamide, apalutamide, darolutamide 11:12 Resistance mechanisms 12:14 Summary Key points 👉 Androgen signalling has four steps a drug can block: synthesis, receptor binding, nuclear translocation, DNA binding. 👉 LHRH agonists desensitise the pituitary after an initial flare; antagonists block the receptor directly with no flare. Both leave adrenal and intratumoural androgens untouched. 👉 Castration-resistant disease is usually still driven by the androgen receptor, running on adrenal androgens, intratumoural synthesis and an amplified receptor. 👉 Bicalutamide is a competitive, reversible antagonist that covers the flare, but can act as a partial agonist when the receptor is overexpressed or mutated. 👉 Abiraterone inhibits CYP17A1 at both the 17α-hydroxylase and 17,20-lyase steps, so androgens and cortisol both fall; ACTH rises and drives deoxycorticosterone, giving hypertension, hypokalaemia and fluid retention. Prednisolone replaces cortisol. 👉 Enzalutamide, apalutamide and darolutamide bind with higher affinity, have no agonist activity, and impair nuclear entry and DNA binding. Darolutamide crosses the blood–brain barrier much less. Resistance: receptor amplification, AR-V7, pocket mutations, glucocorticoid receptor bypass and neuroendocrine change. Reference: HERO trial, Shore ND et al., N Engl J Med 2020;382:2187–2196. This is not medical advice. It is educational content.