Can enzalutamide be used instead of abiraterone in metastatic castration‑resistant prostate cancer?

Can Enzalutamide Replace Abiraterone in Metastatic Castration-Resistant Prostate Cancer?

Yes, enzalutamide can be used instead of abiraterone as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC), as both are equally recommended Grade A standard options by major guidelines. 1 However, the choice between them should be guided by specific clinical factors including prior treatment exposures, side effect profiles, drug interactions, and practical dosing considerations.

Initial Treatment Selection for Treatment-Naïve mCRPC

Both agents are endorsed as equivalent first-line options for patients with good performance status and no prior docetaxel:

• ASCO guidelines recommend enzalutamide 160 mg daily with ADT as a strong recommendation based on high-quality evidence from ENZAMET and ARCHES trials showing survival benefits. 1

• AUA guidelines designate both abiraterone plus prednisone and enzalutamide as standard treatments for mCRPC patients with good performance status who have received prior docetaxel. 1

• NCCN guidelines list both as category 1 treatment options without preference for one over the other in treatment-naïve patients. 1

Key Factors Favoring Enzalutamide Over Abiraterone

Dosing Simplicity

• Enzalutamide requires no fasting requirements and no concurrent steroid administration, making it significantly easier for patient compliance. 2, 3
• Abiraterone must be taken on an empty stomach (1,000 mg daily) or requires careful low-fat breakfast coordination (250 mg daily), with unpredictable bioavailability when taken with food. 1, 3

Drug Interaction Profile

• Enzalutamide is a potent CYP3A4 inducer, which can reduce levels of many concomitant medications—this is a critical consideration in polypharmacy patients. 4
• Abiraterone has minimal drug-drug interaction potential compared to enzalutamide. 4

Hepatic Dysfunction

• Both agents require dose adjustment or alternative selection in hepatic impairment, but abiraterone carries higher hepatotoxicity risk requiring monthly liver function monitoring. 5, 3

Efficacy in Sequential Use

• If both agents will eventually be used, starting with abiraterone followed by enzalutamide provides superior outcomes compared to the reverse sequence (median time to second PSA progression: 19.3 vs 15.2 months, HR 0.66, p=0.036). 2, 6
• Enzalutamide shows meaningful second-line activity after abiraterone (36% PSA response rate), whereas abiraterone after enzalutamide shows minimal activity (4% PSA response rate). 7, 6

Key Factors Favoring Abiraterone Over Enzalutamide

Side Effect Profile

• Enzalutamide carries significantly higher fatigue risk (OR 0.46, p<0.00001) and overall adverse event rates compared to abiraterone. 8
• Enzalutamide has seizure risk (though rare, not reported in some studies), making it contraindicated in patients with seizure history. 7
• Abiraterone's main toxicities are mineralocorticoid excess (hypertension, hypokalemia, fluid retention) which are predictable and manageable with monitoring. 5, 3

Cost Considerations

• Abiraterone is available as a generic formulation, potentially offering cost savings. 1
• Alternative dosing of abiraterone 250 mg with low-fat breakfast can reduce financial toxicity, though this requires careful patient education and is not FDA-approved for all indications. 1, 3

Critical Sequencing Principle: Avoid Cross-Resistance

Never switch from enzalutamide to abiraterone or vice versa in patients who have progressed on one agent for mCRPC—this demonstrates significant cross-resistance. 1, 2

• After progression on either agent plus docetaxel, cabazitaxel is the preferred next option (radiographic PFS 8.0 vs 3.7 months for switching between the two agents, HR 0.54, p<0.0001). 2

• The NCCN reorganized mCRPC treatment recommendations based on prior therapeutic exposures specifically to address this cross-resistance issue. 1

Combination Therapy: Not Recommended

Do not combine enzalutamide and abiraterone together—the Alliance A031201 trial demonstrated no OS benefit (HR 0.89, p=0.03, not meeting significance threshold) despite longer rPFS. 9

• Drug-drug interactions result in 2.2- to 2.9-fold higher abiraterone clearance when combined with enzalutamide, reducing abiraterone efficacy. 9
• The combination increases toxicity without meaningful survival benefit. 9

Practical Algorithm for Selection

Choose Enzalutamide if:

• Patient has difficulty with fasting requirements or medication timing 3
• Patient does not want concurrent steroid therapy 2
• Patient has hepatic dysfunction concerns 4
• This will be the only novel hormonal agent used (no sequential therapy planned) 2

Choose Abiraterone if:

• Patient is on multiple medications with potential CYP3A4 interactions 4
• Patient has seizure history or risk factors 7
• Patient has significant fatigue concerns 8
• Sequential therapy with both agents is planned (use abiraterone first) 2, 6
• Cost is a major barrier and generic formulation is available 1

Common Pitfalls to Avoid

• Do not use micronized abiraterone formulation in non-castrate settings—it is only FDA-approved for mCRPC and has different dosing/indications. 1, 3
• Do not use abiraterone 250 mg with low-fat breakfast outside carefully monitored settings, as ASCO does not support this in routine practice due to unpredictable bioavailability. 1, 3
• Do not switch between these agents after progression on one—move to cabazitaxel, radium-223, or other non-cross-resistant therapies. 1, 2
• Monitor appropriately: Monthly LFTs, electrolytes, and blood pressure for abiraterone 5, 3; fatigue assessment and seizure precautions for enzalutamide 7, 8