Can enzalutamide or apalutamide be used with androgen‑deprivation therapy instead of abiraterone in men with metastatic or high‑risk non‑metastatic castration‑sensitive prostate cancer?

Can Enzalutamide or Apalutamide Replace Abiraterone in Castration-Sensitive Prostate Cancer?

Yes, both enzalutamide and apalutamide are equally valid alternatives to abiraterone when combined with ADT for castration-sensitive prostate cancer, with ASCO guidelines providing strong recommendations for all three agents based on high-quality evidence demonstrating survival benefits. 1

Guideline-Based Recommendations for Metastatic Disease

All Three Agents Have Strong Evidence Support

For men with metastatic castration-sensitive prostate cancer, ASCO 2021 guidelines provide strong recommendations (high evidence quality) for:

• ADT + abiraterone (1,000 mg daily with prednisone 5 mg once daily) 1
• ADT + enzalutamide (160 mg daily) 1
• ADT + apalutamide (240 mg daily) 1

All three combinations demonstrated significant improvements in overall survival and radiographic progression-free survival compared to ADT alone, with benefits outweighing harms 1.

Key Trial Evidence Supporting Each Agent

• Enzalutamide: The ENZAMET and ARCHES trials showed significant benefits in PSA progression-free survival, clinical progression-free survival, and overall survival, including in patients with high-volume disease and those previously treated with docetaxel 1, 2

• Apalutamide: The TITAN trial demonstrated significantly longer radiographic progression-free survival (HR 0.48) and overall survival (HR 0.67) at 22.7 months follow-up 1

• Abiraterone: The STAMPEDE and LATITUDE trials established survival benefits, though abiraterone requires concurrent prednisone administration 1

Non-Metastatic High-Risk Disease

For non-metastatic castration-sensitive prostate cancer with high-risk features:

• ADT + abiraterone is specifically recommended by ASCO for locally advanced non-metastatic disease based on STAMPEDE data showing failure-free survival benefit (strong recommendation, high evidence quality) 1

• Enzalutamide data for this population remains pending from the EMBARK trial, with no current recommendation available 1

• Apalutamide is FDA-approved for non-metastatic castration-resistant (not castration-sensitive) prostate cancer 1

Comparative Effectiveness Considerations

Real-World Evidence Suggests Nuanced Differences

A 2024 real-world comparative study found that enzalutamide and apalutamide demonstrated superior efficacy compared to bicalutamide in delaying disease progression, while abiraterone did not show significant advantages over enzalutamide and apalutamide in this analysis 3. However, this contradicts guideline-level evidence showing equivalent survival benefits.

A 2022 network meta-analysis examining benefit-harm balance found high probabilities (>60%) for net clinical benefit with ADT + abiraterone, ADT + enzalutamide, and ADT + apalutamide, with all three appearing superior to docetaxel-containing regimens when considering quality of life 4.

Quality of Life Differences

• Abiraterone showed potential HRQoL benefit up to 24 months (moderate certainty) 4
• Enzalutamide and apalutamide showed no significant HRQoL differences compared to ADT alone (low-high certainty) 4
• All agents maintained baseline quality of life without significant deterioration 1, 4

Practical Selection Algorithm

For metastatic castration-sensitive prostate cancer:

1. All three agents are appropriate first-line choices when combined with ADT 1

2. Consider abiraterone if:

   • Patient can tolerate steroid therapy (prednisone 5 mg daily required) 1
   • Monitoring for mineralocorticoid effects (hypertension, hypokalemia) is feasible 5

3. Consider enzalutamide or apalutamide if:

   • Patient has contraindications to chronic steroid use 1, 5
   • Simplified dosing without steroid co-administration is preferred 1

4. Monitor for agent-specific toxicities:

   • Enzalutamide: seizure risk (0.6% overall, 2.2% in predisposed patients), fatigue, falls 1, 5
   • Apalutamide: rash, fractures, falls 1
   • Abiraterone: hypertension, hypokalemia, hepatotoxicity 4

For non-metastatic locally advanced disease:

• Prioritize ADT + abiraterone as this has specific guideline support with strong evidence 1
• Enzalutamide and apalutamide lack definitive evidence in this specific population 1

Critical Caveats

Continue ADT Indefinitely

All patients must continue ADT (GnRH analog or bilateral orchiectomy) to maintain castrate testosterone levels (<50 ng/dL) throughout treatment, even when adding novel hormonal agents 1, 5. This is a common pitfall to avoid.

Prior Docetaxel Subgroup

For patients previously treated with docetaxel, longer follow-up data are needed for all three agents, though early results favor their use 1. The effect on radiographic progression-free survival with apalutamide was not statistically significant in the docetaxel-pretreated subgroup, though it favored treatment 1.

Cost Considerations

ASCO guidelines explicitly note that discussions should include the cost of these agents, as all three are expensive novel hormonal therapies 1. In resource-constrained settings, first-generation antiandrogens may be considered for non-metastatic disease 1.