Introduction
Xtandi (enzalutamide) is an oral, second-generation androgen receptor inhibitor developed for the treatment of prostate cancer. It represents a significant advancement in the management of castration-resistant prostate cancer (CRPC), offering a novel mechanism of action that targets multiple steps in the androgen receptor signaling pathway. Approved by the FDA in 2012, Xtandi has become a cornerstone therapy for advanced prostate cancer patients.
Mechanism of Action
Xtandi exerts its therapeutic effects through three primary mechanisms: 1. Inhibition of androgen binding to the androgen receptor 2. Impairment of nuclear translocation of the androgen receptor 3. Disruption of DNA binding and co-activator recruitment
Unlike first-generation antiandrogens, enzalutamide does not exhibit agonist activity in the setting of androgen receptor overexpression. It competitively inhibits testosterone and dihydrotestosterone binding with a binding affinity approximately 5-8 times greater than bicalutamide.
Indications
FDA-approved indications:
- Metastatic castration-resistant prostate cancer (mCRPC)
- Non-metastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic castration-sensitive prostate cancer (mCSPC)
Dosage and Administration
Standard dosing: 160 mg (four 40 mg capsules) orally once daily Administration: Can be taken with or without food Special populations:- Hepatic impairment: Avoid use in severe hepatic impairment (Child-Pugh Class C)
- Renal impairment: No dosage adjustment necessary
- Elderly patients: No dosage adjustment required
Pharmacokinetics
Absorption: Peak plasma concentrations achieved in 1 hour (fasted) or 2.5 hours (fed) Distribution: Volume of distribution ~110 L; >97% protein bound Metabolism: Primarily via CYP2C8 and CYP3A4 Elimination: Half-life approximately 5.8 days; excreted primarily in urine (71%) and feces (14%)Contraindications
- Pregnancy (Category X)
- History of hypersensitivity to enzalutamide or any component of the formulation
- Concomitant use with strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort)
Warnings and Precautions
Seizure risk: 0.9% incidence in clinical trials; discontinue permanently if seizure occurs Posterior reversible encephalopathy syndrome (PRES): Rare cases reported Falls and fractures: Increased risk observed in clinical trials Cardiovascular events: Increased incidence of hypertension, ischemic heart disease, and heart failure Embryo-fetal toxicity: Can cause fetal harm; patients with female partners of reproductive potential must use effective contraceptionDrug Interactions
Strong CYP3A4 inducers: Avoid concomitant use (decreased enzalutamide exposure) CYP3A4 substrates: Enzalutamide is a strong inducer of CYP3A4; may decrease exposure to drugs metabolized by CYP3A4 CYP2C9 substrates: Enzalutamide is a moderate inducer of CYP2C9; may decrease exposure to drugs metabolized by CYP2C9 P-gp substrates: Enzalutamide may decrease concentrations of P-gp substrates Warfarin: Monitor INR more frequentlyAdverse Effects
Most common adverse reactions (≥10%):- Fatigue (50%)
- Hot flush (20%)
- Hypertension (15%)
- Headache (12%)
- Diarrhea (21%)
- Musculoskeletal pain (15%)
- Seizure (0.9%)
- PRES (<1%)
- Cardiovascular events (7-11%)
- Fractures (4-11%)
Monitoring Parameters
- Prostate-specific antigen (PSA) levels every 3 months
- Blood pressure regularly
- Seizure activity assessment
- Bone health monitoring (DEXA scan if indicated)
- Liver function tests periodically
- Complete blood count
- Fall risk assessment
Patient Education
- Take medication at the same time each day
- Do not interrupt or discontinue without consulting healthcare provider
- Report any seizures, falls, or neurological symptoms immediately
- Use effective contraception if partner is of reproductive potential
- Be aware of potential drug interactions with other medications
- Report any new or worsening cardiac symptoms
- Maintain adequate hydration and report significant diarrhea
- Avoid activities requiring mental alertness if experiencing fatigue
References
1. Scher HI, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197. 2. Beer TM, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433. 3. Hussain M, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. 4. Xtandi® (enzalutamide) [package insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2023. 5. Davis ID, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. 6. National Comprehensive Cancer Network. Prostate Cancer Guidelines Version 2.2023.