What is the difference between Abiraterone (abiraterone acetate) and Enzalutamide in the treatment of castration-resistant prostate cancer?

Abiraterone vs Enzalutamide in Castration-Resistant Prostate Cancer

Both abiraterone acetate plus prednisone and enzalutamide are equally recommended as Grade A standard first-line options for metastatic castration-resistant prostate cancer (mCRPC) in chemotherapy-naïve patients, though recent real-world evidence suggests enzalutamide may provide modest survival advantages in specific patient subgroups. 1

Mechanism of Action Differences

Abiraterone acetate inhibits CYP17 enzyme, blocking androgen biosynthesis at the level of the testes, adrenal glands, and prostate tumor tissue itself, thereby reducing circulating and intratumoral testosterone. 1, 2 This upstream blockade requires concurrent prednisone 5 mg twice daily to prevent mineralocorticoid excess from ACTH elevation. 1

Enzalutamide directly targets the androgen receptor with 5-8 fold higher binding affinity than bicalutamide, inhibits nuclear translocation of the receptor, blocks DNA binding, prevents coactivator recruitment, and has minimal agonist activity. 1, 3 This multi-mechanistic approach does not require corticosteroid co-administration. 1

Efficacy Comparison

Guideline-Level Evidence

Both agents demonstrated Grade A evidence for improving overall survival and radiographic progression-free survival in chemotherapy-naïve mCRPC patients in their pivotal trials (COU-AA-302 for abiraterone, PREVAIL for enzalutamide). 1 Expert consensus panels were nearly equally divided on preference: 39% favored abiraterone, 27% enzalutamide, and 33% considered them equivalent. 1

Recent Real-World Data

A 2024 multicenter Veterans Affairs study of 5,779 patients found enzalutamide initiation associated with statistically significant but modest improvements compared to abiraterone: 4

• Overall survival: 0.90 months longer restricted mean survival time at 4 years (24.29 vs 23.38 months) 4
• Time to next treatment: 1.95 months longer 4
• Time to PSA response: 3.57 months shorter 4

Critical subgroup findings: The survival advantage with enzalutamide was more pronounced in patients without prior docetaxel (1.14 months longer) and those with PSA doubling time ≥3 months (2.23 months longer), but disappeared in patients with prior docetaxel or PSA doubling time <3 months. 4

Clinical Decision-Making Algorithm

First-Line Selection Factors

Choose Abiraterone when:

• Patient has visceral metastases (lung/liver), as COU-AA-302 demonstrated activity in this population post-chemotherapy, and expert consensus (88%) supports extrapolation to chemotherapy-naïve patients 1
• Patient takes multiple concomitant medications, as abiraterone has smaller drug-drug interaction potential 5
• Cost is a primary concern and low-fat breakfast dosing (250 mg daily with food vs 1,000 mg fasting) is acceptable 3, 6
• Patient has seizure history or risk factors, as enzalutamide carries 0.6% seizure risk 1

Choose Enzalutamide when:

• Patient is chemotherapy-naïve with PSA doubling time ≥3 months (strongest survival benefit) 4
• Patient has cardiovascular disease, hypertension, or hypokalemia requiring intensive monitoring, as abiraterone causes mineralocorticoid excess 1
• Patient has hepatic impairment (abiraterone requires dose reduction to 250 mg in Child-Pugh B; enzalutamide has no specific hepatic dosing adjustments in labeling) 2
• Patient adherence concerns exist with fasting requirements, as enzalutamide has simpler once-daily dosing without food restrictions 3

Adverse Event Profile Comparison

Abiraterone-specific toxicities requiring monthly monitoring: 1, 2

• Hypertension, hypokalemia, fluid retention/edema (mineralocorticoid excess)
• Hepatotoxicity (can be severe/fatal; requires liver function monitoring)
• Cardiac events
• Overall discontinuation rate: 12% 6

Enzalutamide-specific toxicities: 1

• Fatigue/asthenia (most common)
• Seizures (0.6% incidence; contraindicated in seizure-prone patients) 1
• QTc prolongation
• Diarrhea and hot flashes

Critical Sequencing Considerations

Never switch from one agent to the other after progression. 3, 7 Expert consensus strongly opposes this strategy: 1, 7

• 55% of experts do not recommend switching after primary resistance (no PSA decline, no radiological response) 1
• 53% recommend switching only in minority of selected patients even after acquired resistance 1

If sequential AR pathway inhibition is planned, start with abiraterone followed by enzalutamide, as NCCN guidelines indicate this sequence provides superior outcomes compared to the reverse. 3

After progression on either agent plus docetaxel, cabazitaxel is strongly preferred over switching AR pathway inhibitors, with radiographic PFS of 8.0 vs 3.7 months (HR=0.54, p<0.0001). 3, 7

Cross-Resistance Evidence

Sequential use demonstrates substantial cross-resistance: 8, 9

• Abiraterone after enzalutamide progression: median time to progression 15.4 weeks, only 10% achieved ≥30% PSA decline 8
• Enzalutamide after abiraterone progression: median treatment duration 4.9 months, 28.6% achieved ≥50% PSA decline, 48.6% showed primary resistance 9
• Response more likely if initial sensitivity to first agent (43.8% vs 15.8% PSA response rate) 9

Practical Dosing and Administration

Abiraterone: 1,000 mg once daily on empty stomach (1 hour before or 2 hours after food) with prednisone 5 mg twice daily, OR alternative 250 mg once daily with low-fat breakfast. 3, 6, 2 Tablets must not be crushed or chewed. 2

Enzalutamide: 160 mg once daily without food restrictions. 1, 3

Both require continuation of GnRH analog or prior bilateral orchiectomy. 2

Common Pitfalls to Avoid

• Do not discontinue abiraterone based on early PSA fluctuations before 12 weeks, as some responding patients experience initial PSA flares 7
• Do not combine either agent with radium-223, as this increases fractures and mortality 2
• Monitor blood glucose closely in diabetic patients on thiazolidinediones or repaglinide when starting abiraterone, as severe hypoglycemia has been reported 2
• Recognize enzalutamide as a potent CYP3A4 inducer that can reduce efficacy of concomitant medications 5
• Do not use abiraterone in patients unable to take corticosteroids, as prednisone is mandatory to prevent ACTH-driven side effects 1