STAMPEDE Trial: Comprehensive Overview
Trial Design and Structure
STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) is a groundbreaking multi-arm, multi-stage (MAMS) platform trial that revolutionized prostate cancer treatment by demonstrating that adding abiraterone acetate plus prednisolone to androgen deprivation therapy (ADT) significantly improves survival across multiple disease states. 1, 2
Core Design Features
- Platform structure: The trial uses an innovative adaptive design allowing multiple treatment arms to be tested simultaneously against a shared control group, with the ability to stop ineffective arms and add new ones mid-trial 3
- Patient population: Men with locally advanced or metastatic prostate cancer starting long-term hormone therapy, with no age restrictions and WHO performance status 0-2 4, 2
- Heterogeneous cohorts: Unlike LATITUDE which enrolled only high-risk metastatic patients, STAMPEDE included three distinct populations: metastatic disease (M1, n=941), node-positive disease (N1, n=369), and high-risk node-negative disease (N0 M0, n=509) 1
Abiraterone Arm: Primary Results
Metastatic Disease Outcomes
In the metastatic cohort, abiraterone plus prednisolone added to ADT reduced the risk of death by 38% compared to ADT alone, with median overall survival of 76.6 months versus 45.7 months (HR 0.62; 95% CI 0.53-0.73; P<0.001). 5, 2
- Radiographic progression-free survival: Dramatically improved with HR 0.31 (P<0.0001) in M1 patients 1
- PSA progression: Delayed from median 7.4 months to 33.2 months 1
- Long-term durability: Survival benefits maintained beyond 7 years of follow-up (median 96 months) 5
Non-Metastatic Disease Outcomes
For high-risk non-metastatic disease, abiraterone demonstrated a 40% reduction in mortality risk (HR 0.60; 95% CI 0.48-0.73; P<0.0001) and a remarkable 79% improvement in failure-free survival (HR 0.21; 95% CI 0.15-0.31). 6, 4
- Metastasis-free survival: 82% at 6 years with combination therapy versus 69% with ADT alone (HR 0.53; 95% CI 0.44-0.64; P<0.0001) 4
- Treatment protocol: Abiraterone 1000 mg daily plus prednisolone 5 mg daily for 2 years when combined with radiotherapy; continued until progression if radiotherapy omitted 1, 4
- Radiotherapy mandate: Required for node-negative disease and strongly encouraged for node-positive disease, delivered at 6-9 months post-randomization 6, 4
Critical Age-Related Findings
A crucial and often overlooked finding is the substantial heterogeneity by age: men under 70 years experienced dramatically greater survival benefit (HR 0.51) compared to men 70 years or older (HR 0.94), with older patients experiencing significantly higher toxicities. 1, 7, 6
- Toxicity differential: Grade 3-5 adverse events occurred in 47% of older patients versus 33% in younger patients 1, 7
- Treatment-related deaths: Nine deaths in the abiraterone group versus three in the control group, predominantly in older patients 1, 2
- Clinical implication: This age heterogeneity should strongly influence treatment decisions, particularly in men ≥70 years with significant comorbidities 7, 6
Safety Profile and Monitoring Requirements
Common Adverse Events
Grade 3 or higher adverse events occurred in 37-47% of patients receiving abiraterone plus prednisolone alone, and 58% when combined with enzalutamide, compared to 29-33% with ADT alone. 4, 5
- Mineralocorticoid excess effects: Hypertension (5-14% grade 3+), hypokalemia, and edema are the most common serious adverse events 1, 4
- Hepatotoxicity: Grade 3-5 liver toxicity occurs in approximately 7% of patients, with alanine transaminitis being the most frequent manifestation 7, 4
- Cardiac events: Severe hypertension or cardiac disorders occur in approximately 10% of patients, with cardiac causes being the most common cause of treatment-related death 7, 4, 5
- Overall discontinuation rate: Approximately 12% due to adverse events 1, 7
Mandatory Monitoring Protocol
Baseline assessment must include blood pressure, serum potassium, comprehensive liver function tests, and cardiac evaluation, with ongoing monitoring throughout treatment. 7, 6
- Regular surveillance: Monitor for mineralocorticoid excess (hypertension, hypokalemia), hepatotoxicity, and cardiac disorders at each visit 7
- Dose modifications: Required for grade 3+ hepatotoxicity or uncontrolled hypertension despite medical management 1
Abiraterone Plus Enzalutamide Combination: Negative Results
The STAMPEDE trial definitively demonstrated that combining enzalutamide with abiraterone and ADT does NOT improve survival compared to abiraterone and ADT alone (interaction HR 1.05; 95% CI 0.83-1.32; P=0.71), while substantially increasing toxicity. 4, 5
- Survival outcomes: Median overall survival was 73.1 months with triple therapy versus 76.6 months with abiraterone alone, showing no benefit 5
- Toxicity burden: Grade 3-5 adverse events increased to 68% with triple therapy versus 54% with abiraterone alone 4, 5
- Clinical recommendation: Enzalutamide and abiraterone should NOT be combined for patients starting long-term ADT 5
Guideline Integration and Clinical Recommendations
NCCN Guidelines
The NCCN designates abiraterone acetate 1000 mg daily plus prednisone 5 mg daily as a Category 1 recommendation (highest level of evidence and consensus) for both metastatic castration-naïve and high-risk non-metastatic prostate cancer. 1, 7
ASCO Guidelines
ASCO strongly recommends (evidence quality: high; strength: strong) abiraterone 1000 mg with prednisone 5 mg daily for men with newly diagnosed metastatic prostate cancer, particularly those meeting high-risk criteria. 1
- High-risk definition: At least two of the following: Gleason score ≥8, ≥3 bone lesions, or visceral metastases (per LATITUDE criteria) 1
- Treatment duration: Until progression for metastatic disease; 2 years for non-metastatic disease receiving radiotherapy 1
ESMO Guidelines
ESMO recommends abiraterone as a Level I, Grade A evidence option for metastatic hormone-naïve prostate cancer, with particular emphasis on high-volume disease. 1
Key Distinctions from LATITUDE Trial
While LATITUDE and STAMPEDE are mutually supportive for high-risk metastatic disease, STAMPEDE uniquely provides evidence for lower-risk and non-metastatic populations that LATITUDE did not address. 1
- LATITUDE eligibility: Only de novo metastatic disease with high-risk features (≥2 of: Gleason ≥8, ≥3 bone metastases, visceral disease) 1, 8
- STAMPEDE eligibility: Included high-risk N0 M0, N1 M0, and M1 disease, with 95% newly diagnosed and 5% relapsing disease 1, 2
- Crossover rates: LATITUDE had only 27% crossover to life-prolonging therapy versus 58% in STAMPEDE, potentially affecting survival estimates 1
Quality of Life Outcomes
Patient-reported outcomes were significantly improved with abiraterone, including reductions in pain intensity progression, fatigue, functional decline, and prostate cancer-related symptoms, with overall enhancement of health-related quality of life. 1, 6
Clinical Decision Algorithm
For Metastatic Disease (M1)
Age <70 years with good performance status: Strongly recommend abiraterone 1000 mg daily plus prednisone 5 mg daily added to ADT, continued until progression (HR 0.61 for survival) 1, 5, 2
Age ≥70 years: Carefully weigh the reduced survival benefit (HR 0.94) against substantially increased toxicity risk; consider patient comorbidities, baseline cardiac function, and liver function before proceeding 1, 7
For High-Risk Non-Metastatic Disease (N0 or N1)
Node-negative with ≥2 high-risk factors (T3/4, PSA >40, Gleason 8-10): Recommend abiraterone 1000 mg daily plus prednisone 5 mg daily for 2 years, combined with ADT for 3 years and mandatory radiotherapy (HR 0.60 for survival) 6, 4
Node-positive disease: Same regimen with radiotherapy strongly encouraged; treatment duration 2 years with radiotherapy or until progression without radiotherapy 6, 4