What is the comparison between enzalutamide (generic) and abiraterone (generic) in the treatment of prostate cancer?

Enzalutamide vs Abiraterone in Prostate Cancer

For treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), both enzalutamide and abiraterone are equally recommended as Grade A standard options, but when sequencing is required, abiraterone followed by enzalutamide provides superior outcomes compared to the reverse sequence. 1

Initial Treatment Selection for mCRPC

Treatment-Naïve Patients (No Prior Docetaxel or Novel Hormone Therapy)

Both agents are Grade A standard recommendations for symptomatic mCRPC patients with good performance status and no prior docetaxel chemotherapy. 1

Key mechanistic differences:

• Enzalutamide: Binds androgen receptor with 5-8 fold higher affinity than bicalutamide, inhibits DNA binding, blocks nuclear translocation, and has reduced agonist activity 1
• Abiraterone: Inhibits CYP17 enzyme to block androgen biosynthesis throughout the body, requires concurrent prednisone 5mg daily 2

Recent real-world comparative data favors enzalutamide:

• A 2024 Veterans Affairs study of 5,779 patients showed enzalutamide initiation resulted in 0.90 months longer overall survival at 4 years (RMST: 24.29 vs 23.38 months), 1.95 months longer time to treatment switching, and 3.57 months shorter time to PSA response 3
• A 2021 VHA analysis of 3,174 patients demonstrated 16% reduced risk of death with enzalutamide (HR=0.84,95% CI 0.76-0.94, p=0.0012) 4
• Benefits were most pronounced in patients without prior docetaxel and those with PSA doubling time ≥3 months 3

Optimal Sequencing Strategy

If both agents will be used sequentially, start with abiraterone followed by enzalutamide. 5

The 2019 Canadian phase 2 crossover trial (n=202) definitively demonstrated:

• Time to second PSA progression: 19.3 months (abiraterone→enzalutamide) vs 15.2 months (enzalutamide→abiraterone), HR=0.66, p=0.036 5
• PSA response to second-line enzalutamide: 36% (26/73 patients) 5
• PSA response to second-line abiraterone: only 4% (3/75 patients) 5

Critical clinical implication: Enzalutamide retains meaningful activity after abiraterone progression, but abiraterone shows minimal activity after enzalutamide progression due to cross-resistance. 5, 6

Cross-Resistance Considerations

Avoid switching from enzalutamide to abiraterone or vice versa in patients who have already received one agent for mCRPC. 1

• NCCN guidelines downgraded both agents from Category 1 "preferred" to "other recommended" when used after the other agent, based on cross-resistance data 1
• The CARD study demonstrated cabazitaxel is superior to switching between these agents (radiographic PFS: 8.0 vs 3.7 months, HR=0.54, p<0.0001) 1
• After progression on either agent plus docetaxel, cabazitaxel is the Category 1 preferred option 1

Adverse Event Profiles

Abiraterone-specific monitoring requirements:

• Mineralocorticoid excess: hypertension (more common), hypokalemia, fluid retention 1, 2
• Hepatotoxicity requiring liver function monitoring 1, 2
• Cardiac events including atrial fibrillation (rare but increased) 1
• Overall discontinuation rate: 12% 1

Enzalutamide-specific concerns:

• Fatigue (most common) 1
• Seizure risk (5/800 patients in AFFIRM trial) 1
• Diarrhea and hot flashes 1

Age considerations for abiraterone:

• Patients ≥70 years had reduced survival benefit (HR=0.94 vs HR=0.51 in younger patients) and increased grade 3-5 adverse events (47% vs 33%) in STAMPEDE 1

Practical Dosing Considerations

Abiraterone cost-saving alternative:

• Standard: 1,000mg daily on empty stomach 2
• Alternative: 250mg daily with low-fat breakfast (reduces financial toxicity, improves adherence) 1, 2

Enzalutamide:

• 160mg once daily 1

Clinical Decision Algorithm

1. First-line mCRPC, no prior therapy: Choose enzalutamide based on superior real-world survival data, particularly if patient has no prior docetaxel and PSA doubling time ≥3 months 3, 4

2. If sequential therapy anticipated: Start abiraterone, reserve enzalutamide for second-line (provides 4.1 months longer combined treatment benefit) 5

3. After progression on either agent: Use cabazitaxel rather than switching to the other novel hormone therapy 1

4. Patients ≥70 years with comorbidities: Consider enzalutamide over abiraterone due to better tolerability profile in this population 1