Enzalutamide

1. Drug Class

• Androgen receptor inhibitor (ARI)
• Oral, second-generation anti-androgen.
• Used in prostate cancer (metastatic and non-metastatic).

2. Mechanism of Action

• Potent androgen receptor signaling inhibitor:
  • Blocks androgen binding to the androgen receptor.
  • Inhibits nuclear translocation of the androgen receptor.
  • Prevents DNA binding and transcription of androgen-responsive genes.
• Unlike first-generation antiandrogens (e.g., bicalutamide), it has no agonist activity, even in the setting of AR overexpression.

3. Indications (FDA/Health Canada)

• Metastatic castration-resistant prostate cancer (mCRPC) – with or without prior chemotherapy (docetaxel).
• Metastatic castration-sensitive prostate cancer (mCSPC) – in combination with androgen deprivation therapy (ADT).
• Non-metastatic castration-resistant prostate cancer (nmCRPC).

4. Dosing

• 160 mg orally once daily (4 × 40 mg capsules), with or without food.
• Continue ADT (LHRH agonist/antagonist) or surgical castration.

5. Pharmacokinetics

• Oral bioavailability: good.
• Highly protein bound (~97–98%).
• Metabolized primarily by CYP2C8 and CYP3A4.
• Active metabolites contribute to activity.
• Half-life: ~5.8 days → steady state reached after 1 month.

6. Toxicities / Adverse Effects

Common:

• Fatigue, asthenia
• Hot flashes
• Hypertension
• Diarrhea, constipation
• Peripheral edema

Serious:

• Seizures (low but significant risk; avoid in patients with seizure history or on drugs lowering seizure threshold).
• Posterior reversible encephalopathy syndrome (PRES) – rare.
• Falls and fractures (bone health risk).

7. Drug Interactions

• Strong CYP3A4 inducer, moderate CYP2C9/2C19 inducer → ↓ levels of warfarin, phenytoin, some statins, anticoagulants, and many oral drugs.
• Substrate of CYP2C8 and CYP3A4 → caution with inhibitors/inducers.
• P-gp interactions possible.

8. Monitoring

• PSA: efficacy monitoring.
• Blood pressure: risk of hypertension.
• Neurologic status: seizures, dizziness.
• Fall risk and bone density (especially if combined with ADT).
• LFTs: although hepatotoxicity is uncommon, baseline and periodic checks may be prudent.

9. Clinical Pearls for Pharmacists

• Always ensure ongoing ADT (castrate testosterone levels) while on enzalutamide.
• Counsel patients about seizure risk, driving, and fall prevention.
• Review medication list carefully for CYP-mediated interactions.
• Fatigue is very common – supportive care may be needed.
• Unlike abiraterone, enzalutamide does not require concurrent prednisone.

Key Takeaway for Oncology Pharmacists:

Enzalutamide is a cornerstone AR-targeted therapy for advanced prostate cancer. Pharmacists play a critical role in managing drug–drug interactions, monitoring for seizures and hypertension, supporting adherence, and ensuring ongoing ADT.

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