Introduction
Enzalutamide is a second-generation nonsteroidal antiandrogen medication used in the treatment of prostate cancer. Marketed under the brand name Xtandi®, it represents a significant advancement in the management of castration-resistant prostate cancer (CRPC). Approved by the FDA in 2012, enzalutamide has demonstrated substantial efficacy in improving overall survival and delaying disease progression in patients with advanced prostate cancer.
Mechanism of Action
Enzalutamide exerts its therapeutic effects through multiple mechanisms targeting the androgen receptor pathway:
- Competitive inhibition of androgen binding to androgen receptors
- Inhibition of nuclear translocation of activated androgen receptors
- Impairment of DNA binding and interaction with androgen response elements
- Inhibition of androgen receptor-mediated transcription
Unlike first-generation antiandrogens, enzalutamide does not exhibit agonist activity when androgen receptor overexpression occurs, making it more effective in preventing cancer progression.
Indications
FDA-approved indications:
- Metastatic castration-resistant prostate cancer (mCRPC)
- Non-metastatic castration-resistant prostate cancer (nmCRPC) at high risk of metastasis
- Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy
Dosage and Administration
Standard dosing: 160 mg (four 40 mg capsules) orally once daily Administration: Take with or without food at approximately the same time each day Special populations:- Renal impairment: No dosage adjustment necessary
- Hepatic impairment:
- Mild to moderate (Child-Pugh Class A-B): No dosage adjustment - Severe (Child-Pugh Class C): Not recommended
- Geriatric patients: No dosage adjustment required
Pharmacokinetics
Absorption: Well absorbed with time to peak concentration (Tmax) of 1 hour (fasted) or 4 hours (fed) Distribution: Volume of distribution ~49 L; >97% protein bound (primarily albumin) Metabolism: Extensive hepatic metabolism primarily via CYP2C8 and CYP3A4 Elimination: Half-life approximately 5.8 days; excreted primarily via urine (71%) and feces (14%) Active metabolite: N-desmethyl enzalutamide (achieving similar plasma concentrations to parent drug)Contraindications
- Pregnancy (may cause fetal harm)
- History of hypersensitivity to enzalutamide or any component of the formulation
- Concomitant use with strong CYP2C8 inhibitors (unless benefits outweigh risks)
Warnings and Precautions
Seizure risk: 0.5% incidence in clinical trials; permanently discontinue if seizure occurs Posterior reversible encephalopathy syndrome (PRES): Rare but serious neurologic syndrome Cardiovascular events: Increased risk of hypertension, ischemic heart disease, and heart failure Falls and fractures: Increased risk, particularly in elderly patients Embryo-fetal toxicity: May cause fetal harm; men with female partners of reproductive potential should use effective contraceptionDrug Interactions
Strong CYP2C8 inhibitors: Increased enzalutamide exposure (avoid combination) Strong CYP3A4 inducers: Decreased enzalutamide exposure (avoid combination) CYP3A4 substrates: Decreased exposure to drugs metabolized by CYP3A4 (e.g., midazolam, simvastatin) CYP2C9 substrates: Decreased exposure to drugs metabolized by CYP2C9 (e.g., warfarin) CYP2C19 substrates: Decreased exposure to drugs metabolized by CYP2C19 P-gp substrates: Decreased exposure to P-gp substrates (e.g., digoxin)Adverse Effects
Very common (≥10%):- Fatigue (50%)
- Hot flashes (20%)
- Hypertension (15%)
- Nausea (12%)
- Diarrhea (11%)
- Falls (11%)
- Headache (9%)
- Dizziness (7%)
- Insomnia (7%)
- Anxiety (6%)
- Seizure (0.5%)
- Seizures
- Posterior reversible encephalopathy syndrome
- Cardiovascular events
- Pathological fractures
Monitoring Parameters
Baseline:- Complete blood count
- Comprehensive metabolic panel (including liver function tests)
- PSA level
- Cardiovascular assessment (blood pressure, ECG if indicated)
- Bone health assessment (DEXA scan if appropriate)
- PSA every 3 months
- Blood pressure regularly (especially first 3 months)
- Liver function tests periodically
- Monitor for neurological symptoms (seizures, headache, visual disturbances)
- Assessment of fall risk and bone health
- Regular imaging for disease assessment
Patient Education
- Take medication at the same time each day with or without food
- Do not stop treatment without consulting your healthcare provider
- Swallow capsules whole; do not crush or open
- Report any seizures, falls, dizziness, or visual changes immediately
- Monitor blood pressure regularly as recommended
- Use effective contraception if partner is pregnant or of reproductive potential
- Be aware of potential drug interactions; inform all healthcare providers about enzalutamide use
- Report any new medications, including over-the-counter drugs and supplements
- Maintain regular follow-up appointments for monitoring
References
1. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197. 2. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. 3. Xtandi® (enzalutamide) [package insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2023. 4. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. 5. National Comprehensive Cancer Network. Prostate Cancer Guidelines. Version 4.2023. 6. European Association of Urology Guidelines on Prostate Cancer. 2023 Update.