Mechanism of Action of Apalutamide
Apalutamide is a nonsteroidal androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR, inhibits AR nuclear translocation, prevents DNA binding, and blocks AR-mediated transcription. 1
Molecular Mechanism
Apalutamide works through multiple complementary mechanisms to block androgen receptor signaling:
- Direct AR binding: Apalutamide binds directly to the ligand-binding domain of the androgen receptor with 7- to 10-fold greater affinity compared to first-generation anti-androgens like bicalutamide 2
- Nuclear translocation blockade: The drug prevents the AR from moving into the cell nucleus after androgen binding 1
- DNA binding inhibition: Apalutamide impedes the AR from binding to DNA once in the nucleus 2, 1
- Transcriptional suppression: The drug blocks AR-mediated gene transcription, preventing expression of genes that promote prostate cancer cell growth 1
Cellular and Tumor Effects
The multi-step AR blockade produces measurable anti-tumor activity:
- Decreased tumor cell proliferation: Apalutamide administration reduces cancer cell division in preclinical models 1
- Increased apoptosis: The drug triggers programmed cell death in prostate cancer cells 1
- Tumor volume reduction: These combined effects lead to decreased tumor volume in mouse xenograft models of prostate cancer 1
Active Metabolite Contribution
N-desmethyl apalutamide, the major metabolite, is also pharmacologically active but less potent:
- The metabolite exhibits one-third the AR inhibitory activity of the parent compound in transcriptional reporter assays 1
- At steady-state, the metabolite achieves similar plasma concentrations to apalutamide (AUC ratio of 1.3) 1
- Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributes to the overall clinical activity 1
Clinical Pharmacodynamic Effects
The AR inhibition translates to measurable clinical effects:
- In non-metastatic castration-resistant prostate cancer (nmCRPC), apalutamide 240 mg daily plus ADT reduced PSA to undetectable levels (<0.2 ng/mL) in 38% of patients compared to 0% with ADT alone 1
- In metastatic castration-sensitive prostate cancer (mCSPC), the combination achieved undetectable PSA in 68% of patients versus 32% with ADT alone 1