Why is enzalutamide (an androgen receptor inhibitor) not considered a first-line treatment for a patient with high-volume metastatic hormone-sensitive prostate cancer, when androgen deprivation therapy (ADT) plus docetaxel (a chemotherapy agent) plus abiraterone (an androgen receptor inhibitor) or darolutamide (an androgen receptor inhibitor) are recommended as first-line treatments?

Why Enzalutamide Is Not Preferred as First-Line Therapy for High-Volume Metastatic Hormone-Sensitive Prostate Cancer

Enzalutamide lacks high-quality evidence demonstrating superior overall survival when combined with ADT plus docetaxel (triplet therapy) in the metastatic hormone-sensitive setting, whereas both abiraterone and darolutamide have proven survival benefits in this specific triplet combination. 1, 2

The Evidence Hierarchy for First-Line Treatment

Triplet Therapy: The Current Standard

For patients with high-volume metastatic hormone-sensitive prostate cancer who are fit for chemotherapy, triplet therapy with ADT plus docetaxel plus either abiraterone or darolutamide represents the preferred Category 1 treatment approach. 1, 2

The NCCN explicitly states that ADT plus docetaxel doublet therapy is no longer recommended as a standalone option because triplet therapies have demonstrated superior overall survival. 1, 2 This paradigm shift is based on two landmark trials:

• PEACE-1 trial: ADT + docetaxel + abiraterone demonstrated median overall survival of 4.4 years versus 3.4 years with ADT + docetaxel alone (1-year absolute gain), with hazard ratio 0.75 (95.1% CI, 0.59–0.95; P = 0.017) in the population receiving all three therapies. 1

• ARASENS trial: ADT + docetaxel + darolutamide showed 4-year overall survival of 62.7% versus 50.4% with placebo (HR 0.68; P<0.001), representing a 23-month overall survival gain. 3, 4

Why Enzalutamide Is Not in This Category

Enzalutamide has never been studied in a phase III randomized controlled trial as part of triplet therapy (ADT + docetaxel + enzalutamide) in the metastatic hormone-sensitive setting. 1 The evidence for enzalutamide is limited to:

• Doublet therapy only: Enzalutamide was tested with ADT alone (without docetaxel) in the ARCHES and ENZAMET trials for metastatic hormone-sensitive disease, where it showed benefit as a doublet. 1

• Different disease state: The PREVAIL trial tested enzalutamide in castration-resistant prostate cancer (not hormone-sensitive disease), showing improved overall survival (HR 0.71; 95% CI 0.60–0.84) in that setting. 1

The Clinical Algorithm for Treatment Selection

For High-Volume Disease (Multiple Bone Metastases or Visceral Metastases)

Step 1: Assess fitness for chemotherapy (performance status, organ function, comorbidities). 2

Step 2: If fit for chemotherapy → Triplet therapy is mandatory:

• ADT + docetaxel + abiraterone (with prednisone), OR
• ADT + docetaxel + darolutamide 1, 2

Step 3: If unfit for chemotherapy → Doublet therapy with ADT + novel hormonal agent:

• ADT + abiraterone (with prednisone)
• ADT + apalutamide
• ADT + enzalutamide 2, 5

Critical point: Enzalutamide is only considered when triplet therapy is not feasible. 2, 5

Network Meta-Analysis Rankings

In high-volume metastatic hormone-sensitive prostate cancer, the treatment hierarchy based on overall survival is:

1. Darolutamide + docetaxel + ADT (P score 0.92)
2. Abiraterone + docetaxel + ADT (P score 0.85)
3. Novel hormonal agent + ADT doublets (including enzalutamide)

Notably, darolutamide + docetaxel + ADT demonstrated superior overall survival (HR 0.76,95% CI 0.59-0.97) versus pooled novel hormonal agent + ADT combinations. 4

The Magnitude of Benefit: Why This Matters

The absolute survival benefit with triplet therapy is clinically meaningful:

• Abiraterone triplet: 14% absolute improvement in 3-year survival and 28% absolute improvement in 3-year progression-free survival compared to ADT alone. 6

• Darolutamide triplet: 23-month median overall survival gain. 3

Using enzalutamide doublet instead of triplet therapy in fit patients with high-volume disease represents suboptimal care, as it forgoes this substantial survival advantage. 2

Safety Profile Considerations

Triplet therapies do not substantially increase toxicity compared to doublet therapy with ADT plus docetaxel. 1, 2 The PEACE-1 trial showed:

• Grade ≥3 adverse events: 63% with triplet versus 52% with doublet
• Similar rates of neutropenia, febrile neutropenia, fatigue, and neuropathy 1, 2

This favorable safety profile removes the rationale for avoiding triplet therapy in favor of enzalutamide doublet in appropriate candidates. 1

Common Pitfalls to Avoid

Pitfall #1: Using ADT monotherapy or ADT + docetaxel doublet in fit patients with high-volume disease. The NCCN explicitly advises against this practice given the proven survival benefits of triplet therapy. 2

Pitfall #2: Assuming all androgen receptor inhibitors are interchangeable in the triplet setting. Only abiraterone and darolutamide have level 1 evidence for triplet therapy; enzalutamide does not. 1, 2

Pitfall #3: Reserving triplet therapy for "sicker" patients. The evidence shows triplet therapy is most beneficial in fit patients who can tolerate the regimen, not as salvage therapy. 2

When Enzalutamide IS Appropriate

Enzalutamide remains a valid option as:

• Doublet therapy (ADT + enzalutamide) when chemotherapy is contraindicated or declined by the patient 2, 5
• Low-volume disease where triplet therapy benefit is less established 4
• Castration-resistant disease where it has proven efficacy 1, 3

The key distinction is that in high-volume hormone-sensitive disease where chemotherapy is feasible, the evidence hierarchy clearly favors triplet regimens containing abiraterone or darolutamide over any doublet therapy including enzalutamide. 1, 2, 4