What is the appropriate starting dose, administration, monitoring, and safety considerations for enzalutamide (Xtandi) in metastatic castration‑resistant prostate cancer?

Enzalutamide (Xtandi) Dosing and Management

Standard Dosing

The recommended dose of enzalutamide is 160 mg administered orally once daily, taken with or without food, and continued until disease progression or unacceptable toxicity. 1

• Capsules and tablets must be swallowed whole with sufficient water—do NOT chew, dissolve, open capsules, or cut/crush tablets 1
• No food restrictions apply, and concurrent prednisone is permitted but not required 2

Concurrent Androgen Deprivation Requirements

• Patients with castration-resistant prostate cancer (CRPC) or metastatic castration-sensitive prostate cancer (mCSPC) must continue GnRH analog therapy concurrently or have had bilateral orchiectomy 1
• Patients with non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence may receive enzalutamide with or without a GnRH analog 1
• For patients with high-risk biochemical recurrence, treatment can be suspended if PSA becomes undetectable (<0.2 ng/mL) after 36 weeks, then reinitiated when PSA rises to ≥2.0 ng/mL (post-prostatectomy) or ≥5.0 ng/mL (post-radiation) 1

Dose Modifications for Adverse Reactions

For Grade ≥3 or intolerable adverse reactions, withhold enzalutamide for one week or until symptoms improve to Grade ≤2, then resume at the same dose or reduce to 120 mg or 80 mg daily. 1

Drug Interaction Dose Adjustments

Strong CYP2C8 Inhibitors

• Avoid coadministration when possible 1
• If unavoidable, reduce enzalutamide dose to 80 mg once daily 1
• Return to prior dose when inhibitor is discontinued 1

Strong CYP3A4 Inducers

• Avoid coadministration when possible 1
• If unavoidable, increase enzalutamide dose from 160 mg to 240 mg once daily 1
• Return to 160 mg when inducer is discontinued 1

Critical Safety Monitoring

Seizure Risk

Seizure occurs in 0.6-0.9% of patients and requires permanent discontinuation of enzalutamide immediately if it occurs. 2, 1

• Seizures occurred between 13 to 2,250 days after initiation 1
• All seizure events resolved after discontinuation 1
• Patients with predisposing factors for seizure were generally excluded from clinical trials 1

Common Adverse Events Requiring Monitoring

• Fatigue (33-34%): Most common adverse event, monitor at each visit 2, 3
• Hypertension (12%): Regular blood pressure monitoring required 2, 3
• Mental impairment disorders (5%): Assess cognitive function, particularly in elderly patients 2, 3
• Diarrhea (21%) and hot flushes (20%): Supportive management 2, 3
• Major adverse cardiovascular events (5%): Monitor for cardiac symptoms 2

Age-Specific Considerations

• Patients under age 70 typically maintain full dose without reduction 4
• Adherence decreases in patients over age 70, requiring closer monitoring 4

Clinical Efficacy Benchmarks

Enzalutamide demonstrates superior efficacy compared to bicalutamide, with 76% reduction in risk of progression or death (HR 0.24). 2, 3

Expected Response Rates

• PSA decline ≥50%: 54-72% of patients 2, 4
• Median progression-free survival: 15.7-20.0 months (depending on prior treatment) 2
• Median overall survival: 35.3-67.0 months (depending on disease stage and prior treatment) 2, 5, 6

Treatment Position

The NCCN designates enzalutamide as a Category 1, preferred treatment option for patients with metastatic CRPC without prior novel hormone therapy. 2, 3

• For non-metastatic CRPC with PSA doubling time ≤10 months, enzalutamide is a Category 1, preferred option 2
• For patients with prior novel hormone therapy, enzalutamide is included in "other recommended regimens" 2
• Bone-supportive care medications should be continued 2