Mechanism of Action of Enzalutamide
Enzalutamide is a potent androgen receptor (AR) inhibitor that works through multiple mechanisms: it competitively inhibits androgen binding to the AR with 5- to 8-fold higher affinity than bicalutamide, blocks nuclear translocation of the AR, prevents DNA binding, and inhibits coactivator recruitment. 1, 2
Multi-Step AR Signaling Pathway Inhibition
Enzalutamide acts on different steps in the androgen receptor signaling pathway, distinguishing it from first-generation antiandrogens 2:
Competitive androgen binding inhibition: Enzalutamide binds to the ligand-binding domain of the AR with substantially greater affinity (5- to 8-fold higher) compared to bicalutamide, preventing testosterone and dihydrotestosterone from activating the receptor 1
Nuclear translocation blockade: Unlike older antiandrogens, enzalutamide prevents the AR from translocating into the cell nucleus after androgen binding, keeping the receptor in the cytoplasm 1, 2
DNA binding inhibition: Even if the AR reaches the nucleus, enzalutamide inhibits its ability to bind to androgen response elements on DNA 1, 2
Coactivator recruitment prevention: Enzalutamide blocks the recruitment of coactivator proteins necessary for AR-mediated gene transcription 1, 2
Active Metabolite Contribution
The major metabolite N-desmethyl enzalutamide exhibits similar in vitro activity to the parent compound, contributing to the overall therapeutic effect 2
This metabolite is formed primarily through CYP2C8 metabolism and has a terminal half-life of approximately 7.8 to 8.6 days 2
Reduced Agonist Activity
A critical distinguishing feature is that enzalutamide has reduced agonist activity compared to other non-steroidal AR antagonists used in clinical practice 1. This means it is less likely to paradoxically activate the AR under certain conditions, a phenomenon observed with first-generation antiandrogens like bicalutamide.
Cellular and Tumor Effects
In vitro effects: Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in laboratory studies 2
In vivo effects: The drug decreased tumor volume in mouse prostate cancer xenograft models 2
Clinical PSA suppression: Once-daily dosing of 160 mg enzalutamide in addition to androgen deprivation therapy reduced PSA levels to undetectable levels (<0.2 ng/mL) in 68% of patients with metastatic castration-sensitive prostate cancer 2
Pharmacokinetic Considerations
Enzalutamide requires steady-state trough concentrations (Cmin) >10 µg/mL for therapeutic efficacy, which is achieved after approximately 28 days of daily dosing with an 8.3-fold accumulation relative to a single dose 2, 3. The mean terminal half-life is 5.8 days (range 2.8 to 10.2 days), allowing for once-daily dosing 2.
Common Pitfall
Do not confuse enzalutamide's mechanism with that of abiraterone—enzalutamide directly blocks the AR at multiple steps, while abiraterone inhibits androgen synthesis by blocking CYP17A1 1. These are complementary but distinct mechanisms in the androgen signaling axis.