By Nicholas D. James, MBBS, PhD; Matthew R. Sydes, MSc; Silke Gillessen, MD; and Mahesh K. B. Parmar, PhD; on behalf of the STAMPEDE Trial Management Group
- STAMPEDE uses a multi-arm, multi-stage platform design to answer many questions in a single trial, which saves time and money and makes the trial more efficient and effective than standard trials.
- Over 15 years (from 2005 to 2020), STAMPEDE will have initiated and tested nine research questions in men with prostate cancer.
- Data generated by STAMPEDE have already contributed to a change in the standard of care for men with castration-naive metastatic prostate cancer who are fit for chemotherapy from ADT alone to ADT plus six cycles of docetaxel.
- STAMPEDE is changing the way that investigators, funders, and regulators think about clinical trials, and the authors expect to see this design change the way that clinical trials are designed and run.
The trial tests the addition of various therapies to the contemporaneous standard of care (SOC), and the primary endpoint is overall survival. Secondary endpoints include failure-free survival, which is mostly driven by an increase in prostate-specific antigen, and time to first symptomatic skeletal-related event. There are three key advantages to the MAMS platform design over conventional trials (Fig. 1).
Advantages of the MAMS Platform Design
The multi-arm design allows several new research treatments to be tested simultaneously, meaning multiple trials are effectively being conducted concurrently under the same protocol. This is an efficient use of patients allocated to the control arm because fewer patients are in the single control arm than if each additional therapy would be tested in a separate trial with a separate control arm. It also means that research arms that are better than the control arm can more easily be compared with each other.
The multi-stage aspect uses pre-planned interim analyses to stop recruitment early for research treatments that look insufficiently promising. This uses lack-of-benefit analyses, ideally focusing on an outcome measure that is earlier than the primary outcome measure but is on the causal pathway to it. In STAMPEDE, the primary outcome measure is overall survival, and the earlier outcome measure is failure-free survival. The use of lack-of-benefit analyses can focus trial resources away from insufficiently promising arms. Follow-up, and possibly treatment, should continue for patients allocated to those arms that stop accrual early.
Finally, the platform design allows new research treatments to be introduced later in the same trial. This allows inclusion of suitable new research arms by protocol amendment, saving many years and substantial funds compared with establishing new, separate, competing trials. The control arm is always recruiting simultaneously and, therefore, generates a contemporary control group, thus avoiding a new trial for each new question. This makes the trial much more efficient and effective, makes recruitment faster, and avoids unnecessary time lost on all of the administrative hurdles that occur with opening a new trial. The SOC in the trial needs to be considered carefully and should (and can) be updated when required.
Trial accrual began in October 2005 with a phase II element and six arms: one control arm and five research arms, which examined the addition of docetaxel, zoledronic acid, and celecoxib either alone or in two pairwise combinations. To date, eight research arms have been included in STAMPEDE; in addition to the original five arms, three more arms were introduced in November 2011 (SOC plus abiraterone), in January 2013 (SOC plus radiotherapy for M1 disease), and in July 2014 (SOC plus abiraterone and enzalutamide). A new research arm (SOC plus metformin) was included in spring 2016. Recruitment to the trial is excellent, and more than 7,500 men from more than 100 centers in the United Kingdom and Switzerland have joined the trial as of January 2016. Figure 2 shows accrual over time.
A wealth of information and data have already been generated. Practical and statistical aspects of the trial and the MAMS design have been published.1-3 More recently, descriptive data have emerged from the standard arm, separately, for 917 men with metastatic disease4 and 721 men with nonmetastatic disease.5 These data give valuable insights into the prognosis of men in this broad cohort, as well as powerful data arising from variations in the SOC, such as use of radiotherapy.
Most important, the prespecified primary analyses on survival for three of the original five comparisons were released recently. These analyses demonstrated a clear survival benefit of adding docetaxel to ADT in this population, either alone or in combination with zoledronic acid.6 These data are changing global practice because they support CHAARTED trial data, which were released early by the trial’s data monitoring committee.7 Data from these two trials were combined with data from GETUG-15 in a meta-analysis published alongside STAMPEDE data.8,9 The conclusion broadens the indication for chemohormonal therapy to all patients who have metastatic castration-naive disease and are suitable for chemotherapy. The survival data are less mature in the men with nonmetastatic castration-naive disease because these men have a much better prognosis, so there is less information available. Furthermore, deaths from competing causes are more frequent in this cohort and dilute the effect of treatment on overall survival.
The mature data on zoledronic acid from STAMPEDE also were consistent with the findings from CALGB 90202; the addition of zoledronic acid alone does not improve overall survival or time to first symptomatic skeletal-related event in this population.10 The CALGB 90202 trial stopped accrual early, with 645 of the targeted 680 patients, and treatment was terminated early in trial by the industry partner, so estimates are difficult to fully interpret. The mature data from STAMPEDE is consistent with the data from CALGB 90202 showing that zoledronic acid does not add useful activity to ADT.
Accrual to the other two of the five original research arms of STAMPEDE was stopped early in 2011 for lack of sufficient benefit, as determined by failure-free survival. Both of the arms that contained celecoxib (SOC plus celecoxib and SOC plus celecoxib and zoledronic acid) stopped accrual at their second intermediate analyses; failure-free survival data from the celecoxib-only comparison were released at the time.11 Follow-up continued in both arms, and mature data were revealed during the 2016 Genitourinary Cancers Symposium. These data showed no evidence of a benefit for the addition of celecoxib alone but showed an interesting effect of the combination of this drug with zoledronic acid, which seemed to be larger than the modest effects seen from the addition of either drug alone. This was particularly pronounced in the metastatic setting, in which the estimate of the treatment effect for adding the combination of celecoxib and zoledronic acid was very similar to that of adding docetaxel. Additional analysis and follow-up will be needed to delineate the relevance of these findings.
After the SOC changed to mandate radiotherapy in patients with newly diagnosed N0M0 disease, STAMPEDE was amended, and a randomization was added to test the role of radiotherapy to the prostate in men with metastatic disease. For men with N+M0 disease, radiotherapy has always been optional, and its planned use is a stratification factor at random assignment. Therefore, the control arm can be used to give an indication of the effect of radiotherapy in that group by comparing results of those who received it with those who did not. Recent results demonstrated a large benefit in failure-free survival with radiotherapy in node-positive disease, an area in which no randomized trials are completed, in progress, or, to our knowledge, planned.5 Another paper that uses all of the data from the six original arms is planned and aims to assess the effect of nodal radiotherapy on survival.
Future Planning in STAMPEDE
In spring 2016, STAMPEDE opened accrual to its ninth research arm, adding metformin to SOC. There are several reasons for selecting metformin as a combination partner with SOC, particularly because SOC contains ADT. ADT causes a constellation of symptoms associated with metabolic dysfunction (i.e., the metabolic syndrome), including insulin resistance, hyperglycemia, and obesity, which increases the risk of cardiovascular disease. This well-recognized problem is a cause of substantial morbidity. Metformin has been associated with a decreased risk of myocardial infarction and prolonged survival in type 2 diabetes in a randomized, controlled trial.12
Metformin may counteract some of the unwanted adverse effects of castration, potentially leading to improvements in morbidity and mortality. In addition, metformin is postulated to have antineoplastic properties and has been associated with a lower risk of death as a result of cancer in observational studies in patients with type 2 diabetes. The antineoplastic effect may be because of the integral link between cancer progression and modulators of metabolism.13 By modification of this process, metformin seems to have an important effect on cancer progression and survival and reduces the risk of all-cause and prostate cancer–related mortality.14,15
Therefore, this new STAMPEDE arm will evaluate if this generally well-tolerated, inexpensive, and repurposed drug can both mitigate the deleterious adverse effects of castration and have direct anticancer effects in men with prostate cancer.
What else is in the trial’s future? The beauty of STAMPEDE’s platform design is that new research arms can be added as soon as emerging data suggest the potential for benefit from a treatment for this group of patients. The intention of the Trial Management Group is to incorporate stratified medicine questions, pairing treatments and genetically appropriate candidates. Treatments currently under discussion are immunotherapy, a PARP inhibitor for patients with defects in DNA repair genes, and local treatment to the primary and all metastases for patients with oligometastatic disease. Because setup for a new question and the accrual in this trial is so rapid, treatments targeted for subgroups of patients, such as the patients with genetic defects or oligometastatic disease, can be evaluated in STAMPEDE in a reasonable timeframe. Because of its unique design, a plethora of data will emerge from this trial. We recommend imitating the MAMS platform approach in trials of other cancer types to save time and money.
Results from STAMPEDE have driven a change in the SOC for men with castration-naive metastatic prostate cancer who are fit for chemotherapy from ADT alone to ADT plus six cycles of docetaxel. Thus, the control arm has been amended, and the backbone SOC has been updated to allow patients to have docetaxel, if appropriate, in any arm of the trial. Survival data from the current, active comparisons will continue to emerge over the next 5 years. Random assignment is stratified by intended docetaxel use, and the trial continues to test treatments that may drive additional changes to practice in the future. Perhaps the most exciting thing about STAMPEDE is that the trial is changing the way that investigators, funders, and regulators think about clinical trials. We expect to see this design change the way that clinical trials are designed and run.
The STAMPEDE Trial Management Group members are as follows: Nick James, Gerhardt Attard, Noel Clarke, Bill Cross, David Dearnaley, Silke Gillessen, Clare Gilson, Rob Jones, Malcolm Mason, Chris Parker, Alastair Ritchie, Martin Russell, and George Thalmann (clinical members); Mahesh Parmar, Melissa Spears, and Matthew Sydes (statistical members); Robin Millman and David Matheson (patient members); and Claire Amos, Nargis Begum, Clare Gilson, Claire Murphy, Orla Prendiville, Francesca Schiavone, Melissa Spears, Matthew Sydes, Carly Au, Peter Vaughan, Zohrah Khan, and Estelle Cassoly (trial and data management members).