A patient with metastatic prostate cancer is treated with enzalutamide. Unlike older anti-androgens (flutamide), enzalutamide does not cause 'anti-androgen withdrawal syndrome'. This is because:

• A Enzalutamide inhibits multiple steps: AR binding (higher affinity than flutamide), nuclear translocation, and co-activator recruitment; mutant AR variants that convert flutamide to an agonist do not affect enzalutamide ✓
• B Enzalutamide has higher binding affinity for AR than flutamide, preventing any agonism
• C Enzalutamide additionally inhibits androgen synthesis at the adrenal level, unlike flutamide
• D Enzalutamide acts at the ligand-binding domain and DNA-binding domain simultaneously, making it a dual-site antagonist

Explanation

Flutamide is a second-generation anti-androgen that can act as a partial agonist when bound to mutant androgen receptors (e.g., AR-T877A), causing 'anti-androgen withdrawal syndrome' when flutamide is stopped. Enzalutamide is a second-generation (third-line) AR inhibitor with approximately 5–8 times higher AR binding affinity than bicalutamide; it inhibits AR-DNA binding, nuclear translocation, and co-activator recruitment. Mutant ARs that convert flutamide to agonists generally do not confer agonism for enzalutamide, reducing withdrawal syndrome risk.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.