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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 can have
either newly diagnosed disease, or have been previously treated with radical radiotherapy or surgery but
now have signs of progression such as a rising prostate specific antigen (PSA) (for further details on
eligibility see here). The trial will assess the effects of adding different agents, both as single agents
and in combinations, to the 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. The results of these comparisons have
now been presented. The results have also been published and 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. A further research arm involving prostate radiotherapy for patients with newly-diagnosed
metastatic disease was added (Protocol version 9.0).

From Protocol version 15.0, (vi) metformin, an anti-diabetic medication will be evaluated (Arm K) and
recruitment to the "enzalutamide and abiraterone comparison" (Arm J) has now closed. Recruitment to
the "M1|RT comparison" (Arm H) was completed on 02-Sept-2016. The current arms open to recruitment
are Arm A and Arm K ("metformin comparison").

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 entering
STAMPEDE. Radiotherapy is also mandated for men with node negative non-metastatic disease. The current
trial design is shown in the figure below; previous trial designs can be viewed in Protocol version 13.0.

                 Protocol_15_Arm_K_trial_schema

Please note that Arm H is not shown here as it closed to recruitment on 02-Sept-2016.


For each comparison of research arm against control, the trial will be 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 will only
continue to recruitment in the next stage if they have been 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 Apr-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
arein 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
whenaround 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 will depend 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 Protocolversion 9.0. The trial stages remain similar to those at trial inception but will
be 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 envisage 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. Protocol
version 15.0 includes the addition of the metformin comparison as a new research arm, open to all
non-diabetic men and reflects the completion of accrual to the “enzalutamide+abiraterone comparison”.

Patients will be 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 will be asked at
randomisation to donate a saliva sample (previously a droplet of blood), which will be 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 will also be 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.