Enzalutamide, used for castration-resistant prostate cancer, has a different mechanism than bicalutamide despite both being androgen receptor (AR) antagonists. Enzalutamide additionally prevents:
- A AR nuclear translocation and AR-coactivator recruitment, in addition to competitive DHT binding site blockade ✓
- B 5-alpha reductase conversion of testosterone to dihydrotestosterone in prostatic tissue
- C CYP17A1 (17alpha-hydroxylase/C17,20-lyase) activity in adrenal androgen synthesis
- D AR gene amplification by inhibiting histone deacetylase activity in prostate cancer cells
Explanation
Enzalutamide is a second-generation AR antagonist that, unlike bicalutamide, not only competitively occupies the androgen binding site but also prevents AR nuclear translocation (by occupying the ligand-binding domain in a configuration that masks the nuclear localization signal) and inhibits AR-DNA binding and AR interaction with transcriptional coactivators. Bicalutamide-resistant prostate cancers often display AR mutations that convert bicalutamide from antagonist to agonist, but enzalutamide maintains antagonism in most such cases. Abiraterone inhibits CYP17A1 (adrenal androgen synthesis). Finasteride/dutasteride inhibit 5-alpha reductase. HDACi have no AR amplification prevention activity.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.