What are the details of each arm in the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial for men with high-risk or metastatic prostate cancer?

STAMPEDE Trial Arms: Detailed Overview

The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial is a multiarm, multistage, platform randomized controlled trial that has evaluated multiple treatment strategies for men with high-risk, locally advanced, metastatic, or recurrent prostate cancer starting first-line long-term androgen deprivation therapy (ADT) 1.

Core Trial Design and Patient Population

The trial enrolled men with the following characteristics:

• High-risk locally advanced disease (node-positive OR node-negative with ≥2 of: T3-T4 stage, Gleason 8-10, PSA ≥40 ng/mL) 2
• Metastatic disease (M1) 1
• Rapidly relapsing disease with high-risk features 3
• WHO performance status 0-2 2
• Starting first-line long-term hormone therapy 1

Median patient characteristics across arms: age 65-70 years, PSA 53-112 ng/mL, with 52-61% having metastatic disease at enrollment 3, 4.

Treatment Arms Evaluated

Control Arm (Standard of Care)

ADT alone for ≥2 years, consisting of:

• LHRH agonists or antagonists, or bilateral orchiectomy 1
• Mandatory radiotherapy (74 Gy in 37 fractions or hypofractionated equivalent) for node-negative M0 disease 2
• Encouraged radiotherapy for node-positive M0 disease 1
• Optional radiotherapy for metastatic disease 1

Outcomes in control arm (M1 patients): median overall survival 42 months, 2-year overall survival 72%, median failure-free survival 11 months 4.

ADT + Zoledronic Acid Arm

Treatment regimen:

• Standard ADT plus zoledronic acid 4 mg IV 1
• Given every 3 weeks for 6 cycles, then every 4 weeks until 2 years 1
• Concurrent use of spironolactone not allowed 5

Results: No survival benefit demonstrated (HR 0.94,95% CI 0.79-1.11, p=0.450) 1. Grade 3-5 adverse events occurred in 32% of patients, similar to control 1.

ADT + Docetaxel Arm

Treatment regimen:

• Standard ADT plus docetaxel 75 mg/m² IV every 3 weeks for 6 cycles 1
• Prednisolone 10 mg daily during docetaxel treatment 1
• ADT continued for ≥2 years 1

Results in M1 patients: Median overall survival 5.4 years (65 months) versus 3.6 years (43 months) with ADT alone, representing a 1.8-year survival improvement (HR 0.78,95% CI 0.66-0.93, p=0.006) 6. Grade 3-5 adverse events occurred in 52% versus 32% in control 1.

ADT + Zoledronic Acid + Docetaxel Arm

Treatment regimen:

• Standard ADT plus both zoledronic acid (as above) and docetaxel (as above) 1
• Zoledronic acid: 4 mg IV every 3 weeks × 6, then every 4 weeks until 2 years 1
• Docetaxel: 75 mg/m² IV every 3 weeks × 6 cycles with prednisolone 10 mg daily 1

Results: Median overall survival 76 months (HR 0.82,95% CI 0.69-0.97, p=0.022) 1. Grade 3-5 adverse events occurred in 52% of patients 1. No additional benefit over docetaxel alone was demonstrated.

ADT + Celecoxib Arm (Discontinued)

Treatment regimen:

• Standard ADT plus celecoxib 400 mg orally twice daily 7
• Given until 1 year or disease progression 7

Results: Accrual stopped due to lack of benefit (HR 0.94,95% CI 0.74-1.20) 7. 2-year failure-free survival was 51% in both celecoxib and control arms 7. Grade 3-5 adverse events occurred in 25% versus 23% in control 7.

ADT + Abiraterone Acetate + Prednisolone Arm

Treatment regimen:

• Standard ADT plus abiraterone acetate 1000 mg orally once daily 3
• Prednisolone 5 mg orally once daily 3
• Treatment duration: 2 years for patients receiving radiotherapy, or until progression if radiotherapy omitted 3
• Mandatory radiotherapy for node-negative M0 disease 2

Results in M1 patients: Median overall survival not reached versus 3.6 years with ADT alone (HR 0.61 for metastatic disease) 3. In high-risk M0 patients: 6-year metastasis-free survival 82% versus 69% (HR 0.53,95% CI 0.44-0.64, p<0.0001) 2. Grade 3-5 adverse events occurred in 37% versus 29% in control for the M0 population 2.

Most common grade 3-4 toxicities: hypertension (5-14%), alanine transaminitis (6-13%), with 7 grade 5 events across both abiraterone-containing arms 2.

ADT + Abiraterone Acetate + Prednisolone + Enzalutamide Arm

Treatment regimen:

• Standard ADT plus abiraterone acetate 1000 mg orally once daily 2
• Prednisolone 5 mg orally once daily 2
• Enzalutamide 160 mg orally once daily 2
• Treatment duration: 2 years (or until progression if radiotherapy omitted) 2

Results in high-risk M0 patients: 6-year metastasis-free survival 82% (HR 0.53 versus control, p<0.0001) 2. No evidence of additional benefit over abiraterone alone (interaction HR 1.02,95% CI 0.70-1.50, p=0.91) 2. Grade 3-5 adverse events occurred in 58% versus 32% in control 2.

Most common grade 3-4 toxicities: hypertension (14%), alanine transaminitis (13%), with 4 grade 5 events (2 septic shock, 2 sudden death) 2.

Key Clinical Implications

For metastatic (M1) disease: Docetaxel added to ADT provides a clinically meaningful 1.8-year survival benefit and should be standard of care for fit patients (HR 0.78, p=0.006) 6. Abiraterone plus prednisolone added to ADT provides even greater benefit with median OS not reached versus 3.6 years (HR 0.61) 3.

For high-risk non-metastatic (M0) disease: Abiraterone plus prednisolone added to ADT and radiotherapy dramatically improves outcomes with 6-year metastasis-free survival of 82% versus 69% (HR 0.53, p<0.0001) and overall survival HR 0.60 (p<0.0001) 2.

Zoledronic acid showed no survival benefit and should not be used in this setting (HR 0.94, p=0.450) 1. Celecoxib showed no activity and was discontinued (HR 0.94) 7. Adding enzalutamide to abiraterone provided no additional benefit over abiraterone alone (interaction p=0.91) 2.