What is the initial management of a patient with metastatic hormone-sensitive high-volume prostate cancer, specifically the recommended doublet or triplet regimen to start with?

Management of Metastatic Hormone-Sensitive High-Volume Prostate Cancer

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

Preferred First-Line Regimens (Category 1)

The two evidence-based triplet therapy options are:

• ADT + docetaxel + abiraterone acetate (with prednisone): This combination demonstrated superior overall survival compared to ADT plus docetaxel alone (HR 0.75; 95% CI 0.59-0.95) in the PEACE-1 trial, with median OS of 4.4 years versus 3.4 years—a gain of 1 year. 1

• ADT + docetaxel + darolutamide: The ARASENS trial showed improved OS over ADT plus docetaxel (HR 0.68; 95% CI 0.57-0.80), with consistent benefit across high-volume disease subgroups (HR 0.69; 95% CI 0.57-0.82). 1, 2

Both triplet regimens are NCCN Category 1, preferred recommendations specifically for patients with high-volume de novo metastatic disease who are fit enough to receive chemotherapy. 1

Why Triplet Over Doublet Therapy

The NCCN guidelines explicitly state that ADT plus docetaxel doublet therapy is no longer recommended as a standalone option because triplet therapies have demonstrated superior overall survival. 1 The key evidence:

• Patients with high-volume disease in CHAARTED showed benefit from ADT plus docetaxel (HR 0.63), but this has been superseded by triplet data. 1
• Low-volume disease patients did not benefit from ADT plus docetaxel in CHAARTED (HR 1.04) or GETUG-AFU 15 trials. 1
• Triplet therapy provides additional survival benefit beyond doublet therapy without substantially different rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared to ADT plus docetaxel alone. 1

Alternative Doublet Options (When Triplet Not Feasible)

If the patient cannot tolerate chemotherapy or triplet therapy, the following doublet regimens with ADT are acceptable alternatives:

• ADT + abiraterone acetate (with prednisone) 1
• ADT + apalutamide 1
• ADT + enzalutamide 1

All three novel hormone agent doublets are ASCO-endorsed standards of care and ESMO-recommended first-line treatments with ESMO-MCBS scores of 4. 1 However, these have not been directly compared to triplet therapy and represent a less intensive approach. 1

Critical Patient Selection Factors

High-volume disease definition: Multiple bone metastases (>3) or visceral metastases. 1 This is the population where treatment intensification shows the greatest benefit.

Fitness for chemotherapy assessment: Patients must have adequate performance status and organ function to tolerate docetaxel (75 mg/m² IV every 3 weeks for 6 cycles). 1 Grade ≥3 adverse events occurred in 63% with triplet versus 52% with doublet in PEACE-1. 1

Common Pitfalls to Avoid

• Do not use ADT monotherapy in fit patients with high-volume disease—this represents suboptimal care given the survival benefits of combination therapy. ADT alone should only be used in vulnerable patients who cannot tolerate treatment intensification. 1

• Do not use ADT plus docetaxel doublet as the initial regimen when triplet therapy is feasible, as this is no longer considered optimal treatment. 1

• Do not delay treatment intensification—combination therapy should be initiated upfront rather than sequentially, as the trials demonstrating benefit used concurrent administration. 1

• Do not assume all metastatic patients benefit equally—the survival advantage is most pronounced in high-volume disease, and treatment selection should account for disease burden. 1