What is the recommended treatment approach for metastatic hormone-sensitive prostate cancer with high-volume disease, specifically the evidence for triplet therapy including androgen deprivation therapy (ADT), docetaxel, and abiraterone?

STAMPEDE Triplet Therapy for High-Volume Metastatic Hormone-Sensitive Prostate Cancer

For men with high-volume metastatic hormone-sensitive prostate cancer who are fit for chemotherapy, triplet therapy with ADT + docetaxel + abiraterone (or darolutamide) provides superior overall survival compared to doublet therapy and represents the current optimal treatment approach.

Evidence from STAMPEDE and Related Trials

Original STAMPEDE Doublet Data

The STAMPEDE trial initially established that adding docetaxel to ADT improved overall survival in metastatic patients (HR 0.78; 95% CI 0.66-0.93) 1. The trial also demonstrated that adding abiraterone to ADT significantly improved OS (HR 0.63; 95% CI 0.52-0.76) 1. However, these were separate comparisons against ADT alone, not direct comparisons of triplet versus doublet therapy.

Triplet Therapy Evidence

PEACE-1 Trial (Abiraterone-based triplet):

• Demonstrated that ADT + docetaxel + abiraterone improved overall survival compared to ADT + docetaxel in high-volume disease (HR 0.75; 95% CI 0.59-0.95) 2
• Specifically in high-volume patients: HR 0.72 (95% CI 0.55-0.95) 2
• All patients had de novo metastatic disease 2
• Low-volume data were immature at time of analysis 2

ARASENS Trial (Darolutamide-based triplet):

• Showed triplet therapy with ADT + docetaxel + darolutamide improved OS over ADT + docetaxel (HR 0.68; 95% CI 0.57-0.80) 2
• High-volume disease: HR 0.69 (95% CI 0.57-0.82) 2
• Low-volume disease: HR 0.72 (95% CI 0.41-1.13) - not statistically significant 2
• De novo disease: HR 0.71 (95% CI 0.59-0.85) 2

Meta-Analysis Confirmation

A 2023 network meta-analysis stratified by disease volume confirmed that for high-volume mHSPC, darolutamide + docetaxel + ADT ranked first (P score 0.92), followed by abiraterone + docetaxel + ADT (P score 0.85) 3. Only darolutamide triplet demonstrated statistically superior OS versus pooled ARAT + ADT (HR 0.76; 95% CI 0.59-0.97) 3.

Current Guideline Recommendations

ASCO 2021 Guidelines Position

The 2021 ASCO guidelines predate the triplet therapy data and therefore do not recommend using docetaxel and abiraterone in combination or series, stating "the use of both standards in combination or in series has not been assessed and therefore cannot be recommended" 1. This represents outdated guidance that has been superseded by newer evidence.

ASCO 2018 Guidelines on Doublet Therapy

For high-volume disease specifically:

• Strong recommendation for ADT + docetaxel in high-volume disease per CHAARTED criteria (≥4 bone metastases with ≥1 beyond spine/pelvis, or visceral metastases) 1
• Strong recommendation for ADT + abiraterone in high-risk disease per LATITUDE criteria (≥2 of: Gleason ≥8, ≥3 bone lesions, visceral metastases) 1
• Docetaxel regimen: 75 mg/m² every 3 weeks for 6 cycles with prednisolone 1
• Abiraterone regimen: 1,000 mg daily with prednisone/prednisolone 5 mg daily 1

ESMO 2020 Guidelines

ESMO guidelines acknowledge that addition of abiraterone, apalutamide, enzalutamide, or docetaxel to ADT improves OS in mHNPC 1. The benefit of docetaxel was most pronounced in high-volume disease (HR 0.63; 95% CI 0.50-0.79 in CHAARTED) 1.

Clinical Algorithm for High-Volume mHSPC

Patient Selection Criteria

High-volume disease definition (CHAARTED criteria):

• ≥4 bone metastases with ≥1 outside vertebral bodies and pelvis, OR
• Any visceral metastases 1

Fitness assessment for triplet therapy:

• ECOG performance status 0-1 4
• Adequate bone marrow function for docetaxel 4
• No contraindications to chemotherapy 1

Treatment Recommendation Hierarchy

First-line for fit patients with high-volume disease:

1. ADT + docetaxel + darolutamide (strongest evidence, HR 0.69 for high-volume) 2, 3
2. ADT + docetaxel + abiraterone (strong evidence, HR 0.72 for high-volume) 2, 3

Doublet therapy alternatives (if triplet not feasible):

• ADT + abiraterone (HR 0.62-0.63 vs ADT alone) 1
• ADT + enzalutamide (HR 0.67 in TITAN) 1
• ADT + apalutamide (HR 0.67 in TITAN) 1
• ADT + docetaxel alone should no longer be standard given triplet data 4, 3

Specific Regimens

Triplet therapy dosing:

• Docetaxel: 75 mg/m² IV every 21 days for 6 cycles 1
• Abiraterone: 1,000 mg PO daily continuously 1
• Darolutamide: 600 mg (two 300 mg tablets) PO twice daily continuously 2
• Prednisone/prednisolone: 5-10 mg daily (with abiraterone or docetaxel) 1
• ADT: Continuous LHRH agonist/antagonist to maintain castrate testosterone <50 ng/dL 5

Important Caveats and Pitfalls

Disease Volume Matters

Critical distinction: The survival benefit of triplet therapy is most compelling in high-volume disease 2, 3. For low-volume disease, triplet therapy showed only extended progression-free survival without clear OS benefit in ARASENS (HR 0.72; 95% CI 0.41-1.13) 2, 4. Low-volume patients may be adequately managed with doublet ARAT + ADT therapy 3.

De Novo vs. Recurrent Disease

The strongest evidence for triplet therapy exists in de novo metastatic disease 2, 6. Patients with recurrent metastatic disease after prior local therapy have less robust data, though ARASENS showed benefit (HR 0.61; 95% CI 0.35-1.05) 2.

Toxicity Considerations

Triplet therapy adverse events are "almost comparable" to doublet therapy, primarily reflecting:

• Chemotherapy-associated neutropenia from docetaxel 4
• ARAT-specific effects: hypertension, hypokalemia, hepatotoxicity with abiraterone 7
• Fatigue, diarrhea, hot flashes with ARPIs 1
• Overall grade 3+ adverse events occur in approximately 50-65% of patients 1, 4

Common Errors to Avoid

• Never discontinue ADT during disease progression or when adding subsequent therapies 7
• Do not use ADT alone in high-volume mHSPC - this is no longer acceptable standard of care 4, 3
• Do not use doublet docetaxel + ADT when triplet therapy is feasible in high-volume disease 4, 3
• Do not extrapolate triplet benefit to low-volume disease without discussing limited OS evidence 2, 3

Strength of Evidence Summary

Highest quality evidence (2022-2024):

• PEACE-1 and ARASENS trials provide Level 1 evidence for triplet therapy in high-volume mHSPC 2, 6
• Meta-analyses confirm OS benefit specifically in high-volume (HR 0.76; 95% CI 0.59-0.97) and de novo disease (HR 0.73; 95% CI 0.64-0.82) 6

Guideline lag: Current ASCO guidelines (2021) predate triplet data and therefore cannot recommend combination therapy 1. Clinical practice has evolved beyond these guidelines based on compelling Phase 3 RCT evidence 2, 3.