MRC Clinical Trials Unit at UCL
90 High Holborn
STAMPEDE is a multi-centre, randomised controlled trial for patients with locally advanced or metastatic prostate cancer who are commencing long-term Androgen Deprivation Therapy (ADT). Participants when randomised could have had either a newly diagnosed disease, or could have been previously treated with radical radiotherapy or surgery but later showed to have signs of progression such as a rising prostate specific antigen (PSA). The STAMPEDE trial has now completed recruitment, the final day of patient randomisation being completed on 31st March 2023. Follow-up for the final patients will continue for a couple of years from this point. The trial will continue to assess the effects of adding different agents, both as single agents and in combinations, to the standard-of-care or substituting standard of care.
When the trial opened in 2005 there were five "original comparisons" which included the following investigational agents (i) a bisphosphonate, zoledronic acid, (ii) a cytotoxic chemotherapeutic agent, docetaxel and (iii) a cyclooxygenase (Cox-2) inhibitor, celecoxib, alone and/or in combination. The results of these comparisons have now been presented and published. A copy of the Open Access paper can be viewed here.
Since then, the trial has been amended to include additional research arms in order to evaluate (iv) abiraterone, a steroid synthesis inhibitor and (v) enzalutamide, an inhibitor of androgen receptor signalling, alone and/or in combination. A further research arm involving prostate (vi) radiotherapy for patients with newly-diagnosed metastatic disease was added (Protocol Version 9.0). These arms are all now closed to recruitment.
From the current protocol, (vii) metformin, an anti-diabetic medication will continue to be evaluated (Arm K) and (viii) Transdermal Oestradiol (Arm L) will also be evaluated.
The trial has multiple arms; the control arm of the trial receives standard therapy alone. When the trial started standard treatment was androgen deprivation therapy (ADT) only, achieved through the use of luteinising hormone releasing hormone (LHRH) analogues or antagonist or bilateral orchidectomy according to local practice. Since primary results from the trial "original comparisons" have emerged showing a benefit in overall survival for patients receiving docetaxel in addition to ADT, the standard treatment has changed accordingly. Standard treatment may now include docetaxel chemotherapy for all men who entered STAMPEDE. Radiotherapy is also mandated for men with node negative non-metastatic disease. The most recent trial design in use when the trial was still open for recruitment is shown in the figure below; previous trial designs can be viewed in previous protocols.
For each comparison of research arm against control, the trial has been conducted in a number of stages: a Pilot/Safety Phase, Activity Stages and a final Efficacy Stage. The primary outcome measure of the Pilot/Safety Phase is safety, with 30-50 patients recruited to each research arm. Research arms would only continue to recruitment in the next stage if they were shown to be both safe and feasible, although patient data from all patients and all stages will be included in the final analyses. In the Activity Stages the primary outcome measure is failure-free survival (FFS). Each Activity Stage is triggered when a pre-specified number of FFS events have been observed in the control arm of the relevant comparison. Recruitment to Arms D (ADT + celecoxib) and F (ADT + zoledronic acid + celecoxib) was stopped in April-2011 after the second planned activity analysis when the IDMC and TSC considered the lack-of-benefit guidelines.
Some evidence of activity will be required for a research arm to continue past each stage and guidelines are in place for this assessment of activity. The Efficacy Stage will take place when a pre-specified number of deaths are observed amongst the control arm patients for that relevant comparison. This was when around 403 deaths had been reported in the control arm for the “original comparisons” (involving docetaxel and zoledronic acid) and will be when around 267 deaths are reported in the control arm for the “abiraterone comparison”, the “M1|RT comparison” and the “enzalutamide + abiraterone comparison”. The exact number of patients randomised to, and duration of, the trial depended on the observed accrual rate, observed event rate and the number of other research arms open to recruitment.
In Protocol version 8.0 a new Arm G (ADT + abiraterone) was added. Arm H (ADT+ prostate radiotherapy) was added in Protocol Version 9.0. The trial stages remained similar to those at trial inception but were staggered in time compared to the stages for the original Arms A-F. Protocol version 10.0 was approved following the completion of recruitment to the remaining original trial arms (B, C and E) and was a "housekeeping" change to remove references to the completed arms from the information sheets. Protocol version 11.0 was approved following the extension of the recruitment target sample for the “abiraterone comparison” from 1,500 to around 1,800 patients. Protocol version 12.0 added a new combination therapy arm containing abiraterone with enzalutamide; for this comparison we envisaged only two pre-planned interim analyses. Protocol version 13.0 was approved following the extension of the recruitment target sample for the "M1|RT comparison", from 1,250 to around 1,800 patients, and the introduction of saliva sample collection for DNA analysis. In response to the results of the primary analysis of the "original comparisons" the standard-of-care was updated to permit docetaxel in Protocol version 14.0. Protocol version 15.0 included the addition of the metformin comparison as a new research arm, open to all non-diabetic men and reflected the completion of accrual to the “enzalutamide + abiraterone comparison”. Protocol version 16.0 added the transdermal oestradiol comparison (Arm L), allowing diabetic men to be recruited.
Patients are assessed 6 weekly for the first 24 weeks after randomisation and then every 12 weeks up to 2 years, 6-monthly until 5 years and annually, thereafter. Quality of Life (QL) and use of health care resources (Health Economics) data is being collected in all patients until first Failure Free Survival event is reached or trial treatment completed..
In addition, there are translational sub-studies. Patients willing to participate were asked at randomisation to donate a saliva sample (previously a droplet of blood), which has been stored for DNA and protein analysis to try to identify markers that are associated with response to therapy, side-effects or susceptibility to prostate cancer. Patients have also been asked for permission to use some of their stored material (e.g. tissue samples obtained at prostate biopsy or surgery) for further studies aiming to understand the causes and nature of prostate cancer and to identify biomarkers of treatment response. Further information on the stub studies can be found in the Information on Sub Studies Page
STAMPEDE: Docetaxel and Zoledronic Acid Summary for Health Workers
STAMPEDE: "Abiraterone Comparison" Summary for Health Workers
MRC Clinical Trials Unit at UCL
90 High Holborn
Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy
See the latest News in STAMPEDE through the link to the right.