In a castrated man with metastatic castration‑sensitive prostate cancer and good performance status, what are the first‑line treatment options and how should I choose between enzalutamide and abiraterone?

First-Line Treatment for Metastatic Castration-Sensitive Prostate Cancer

For a castrated man with metastatic castration-sensitive prostate cancer and good performance status, offer either abiraterone plus prednisone or enzalutamide combined with continued androgen deprivation therapy (ADT), with a preference for starting abiraterone first if sequential therapy is anticipated. 1, 2

Standard First-Line Options

Both agents are Grade A, Category 1 recommendations with equivalent efficacy for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC):

• Abiraterone acetate 1000 mg daily plus prednisone 5 mg twice daily is a standard treatment option 3
• Enzalutamide 160 mg daily is equally recommended as a standard treatment 3
• Both agents demonstrated statistically significant improvements in overall survival and radiographic progression-free survival in chemotherapy-naïve patients 3

The American Society of Clinical Oncology (ASCO) gives a strong recommendation for enzalutamide 160 mg daily combined with ADT based on high-quality survival data 1. The American Urological Association (AUA) designates both as standard treatments with equivalent evidence strength 3, 1.

How to Choose Between Enzalutamide and Abiraterone

Start with Abiraterone if Sequential Therapy is Likely

If you anticipate the patient will eventually require both agents, start with abiraterone followed by enzalutamide. This sequence provides superior outcomes compared to the reverse:

• Median time to second PSA progression: 19.3 months (abiraterone→enzalutamide) versus 15.2 months (enzalutamide→abiraterone), HR 0.66, p=0.036 4
• Enzalutamide retains meaningful second-line activity after abiraterone (36% PSA response rate), whereas abiraterone after enzalutamide shows minimal benefit (4% PSA response rate) 4
• The National Comprehensive Cancer Network (NCCN) explicitly recommends this sequencing strategy 1, 2

Practical Administration Factors

Choose enzalutamide for patients with:

• Poor medication adherence or complex medication schedules (no fasting required, no concurrent steroid needed) 1
• Hepatic dysfunction requiring dose reduction (abiraterone requires monthly liver function monitoring due to hepatotoxicity risk) 1, 2

Choose abiraterone for patients with:

• Cost constraints (generic formulation available; can consider 250 mg with low-fat breakfast as cost-saving alternative, though not FDA-approved) 1, 2
• Seizure history or risk factors (enzalutamide carries seizure risk) 2

Adverse Event Profile Considerations

Abiraterone-specific monitoring requirements:

• Monthly liver function tests mandatory due to hepatotoxicity risk 1
• Monitor for mineralocorticoid excess (hypertension, hypokalemia, fluid retention) 3
• Overall discontinuation rate 12% 2
• Requires concurrent prednisone 5 mg twice daily to prevent ACTH-related side effects 3

Enzalutamide-specific concerns:

• Fatigue is the most common adverse event 3
• Seizure risk (though rare in clinical trials) 2
• No steroid requirement simplifies regimen 1
• Potent inducer of drug-metabolizing enzymes, creating significant drug-drug interaction potential 5

Critical Pharmacokinetic Consideration

Never combine enzalutamide and abiraterone. A randomized phase III trial demonstrated no overall survival benefit from combination therapy (HR 0.89, p=0.03, not meeting significance threshold), likely because enzalutamide increases abiraterone clearance 2.2- to 2.9-fold, resulting in subtherapeutic abiraterone levels despite increased toxicity 6, 5.

Cross-Resistance and Sequencing Pitfalls

Do not switch directly from enzalutamide to abiraterone (or vice versa) after progression on the first agent. Both agents exhibit significant cross-resistance through shared androgen receptor pathway mechanisms 1, 2, 7:

• After progression on either agent plus docetaxel, cabazitaxel is strongly preferred over switching to the alternate hormonal agent 1, 7
• Cabazitaxel provides radiographic PFS of 8.0 months versus 3.7 months for switching hormonal agents (HR 0.54, p<0.0001) 1, 7
• The NCCN has reorganized its algorithm specifically to address this cross-resistance issue 1

Dosing Specifics

Abiraterone:

• Standard: 1000 mg once daily on empty stomach (1 hour before or 2 hours after food) 3
• Alternative: 250 mg once daily with low-fat breakfast (not FDA-approved but reduces cost) 1, 2
• Always combine with prednisone 5 mg twice daily 3

Enzalutamide:

• 160 mg once daily, no food restrictions 3
• No concurrent steroid required 1

Performance Status Considerations

For patients with good performance status (ECOG 0-2), both agents are appropriate first-line options 3. The choice should be guided by the sequencing strategy, practical factors, and adverse event profiles outlined above.

For patients with poor performance status (ECOG 3-4), abiraterone plus prednisone or enzalutamide may be offered as options, though evidence is limited in this population 3. Palliative care should be the primary focus 3, 7.