Most of the time, when we talk about clinical trials of drugs (or other treatments) for prostate cancer, we are talking about trials in which new treatment X is compared to standard (current) treatment Y or, if there is no standard, new treatment Z is compared to a placebo (a benign, “dummy” substitute).
Experienced patients and advocates often become aware that typical trials like these address only part of the problem, because they are designed to collect comparative data to test only one alternative or additional treatment a patient may be offered. Arguably, it might be wiser to try to test two, three, or more treatments a man may actually need to be taking (together or over time).
The STAMPEDE trial, which has been enrolling patients in the UK and Switzerland for much of the past 7 years, is rather different to typical trials. Instead of comparing a standard therapy in one treatment arm to one or two investigational therapies in other trial arms, it started out with six trial arms.
STAMPEDE stands for Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy. It is a randomized, controlled, multi-center, multi-stage, multi-arm trial that will enroll a total of about 5,000 patients taking one or more of several different therapeutic agents. What is more, it is a trial that has been able to accept addition of new trial arms over time.
The STAMPEDE trial was designed to compare outcomes of potential treatments for men with high-risk, non-metastatic (M0) or metastatic (M1) prostate cancer for whom some form of continuous androgen deprivation therapy (CAD) was now considered appropriate.
There are two basic approaches to CAD:
- Bilateral orchiectomy (surgical removal of the testes, also known as surgical castration)
- Medical suppression of testosterone to castrate levels using drugs like LHRH receptor agonists (e.g., leuprolide acetate or goserelin acetate), LHRH receptor antagonists, and anti-androgens
To date, about 98 percent of patients in STAMPEDE have been managed with a medical form of CAD.
More details about the STAMPEDE trial can, as usual, be found on the ClinicalTrials.gov web site. However, in what follows, we will try to offer a relatively simple overview of the trial and an explanation of why this trial is particularly important (and not just in the future management of prostate cancer).
The initial, primary goal (endpoint) of the study was to see whether any of the investigational treatments could increase overall survival for men with high-risk, non-metastatic (M0) or evidently metastatic (M1) prostate cancer compared to CAD. The secondary endpoints include things like biochemical progression-free survival (bPFS), presence of metastases, toxicities of the therapies (their side effects), the occurrence of fractures and other “skeletal-related events” (SREs), quality of life, and cost effectiveness.
Eligible patients could be enrolled and randomized to any one of the trial arms open to recruitment at a specific point in time. The trial arms are listed in the table below. (Just click on the table to see an “easy to read version.) All patients receive CAD; this is supplemented with standard radiotherapy for men with M0 prostate cancer. So all trial arms have a common therapeutic core and then “add on” therapeutic components are tested:
You will see that this trial assesses efficacy and safety of a number of interesting potential treatments at the same time. It has the potential to allow comparison of treatments that look like much more like “real world” therapeutic options, for example:
- CAD on its own (trial arm A) to CAD with zoledronic acid (trial arm B) and to CAD with zoledronic acid and chemotherapy (trial arm E)
- CAD on its own (trial arm A) to CAD with zoledronic acid and chemotherapy (trial arm E) to CAD with abiraterone acetate (trial arm G)
As of August 1, 2012, the trial has enrolled a total of 3,300 patients. No more patients are being enrolled to trial arms D or F (as discussed below) and recruitment to arm G was only initiated in November 2011. A further new research arm, radiotherapy to the prostate (arm H) for men with metastatic disease, will be initiated late in 2012; scientific approval has recently been granted for this.
The investigators hope to have the original research arms (B, C, and E) fully enrolled by early in 2013 and the trial should be able to provide detailed outcome data for these comparisons in 2015. Survival data for the abiraterone comparison should be known in 2017.
The trial is designed so that recruitment can be stopped early to research arms that are not looking sufficiently encouraging in terms of bPFS (because it is very unlikely that a benefit in overall survival would be seen at the end of the trial if there is no benefit earlier on for bPFS). Earlier this year, the STAMPEDE investigators published data on arms D and F [link to http://www.ncbi.nlm.nih.gov/pubmed/22452894 showing that the combination of CAD with celecoxib, dosed at 400 mg b.i.d., appeared to show no clinical benefit compared to CAD alone. The trial’s independent data monitoring committee therefore recommended no further accrual of patients to trials arm D nor any further accrual to arm F (celecoxib plus zoledronic acid); administration of celecoxib was terminated in all patients previously assigned to these two arms of the study. This result is commensurate with data from other trials investigating the clinical effectiveness of celecoxib in advanced forms of prostate cancer (a form of treatment once thought to look promising).
Trials like the STAMPEDE study are the likely “gold standard” for comparative effectiveness research because they ought to (a) provide quicker answers than a series of separate two-arms trials and (b) allow us to do more research with the funding available. These trials have also been constructed to fit “real world” forms of therapy along with investigational forms of therapy. We can expect to see (and should probably be insisting on) more trials of this type as the range of treatments available for the management of advanced forms of prostate cancer expands. Whether such trials will ever get conducted in America, where individual choice is a key factor in how people decide to get treatment, is open to greater question. We may be relying on data from Europe and elsewhere for trials like this for a while.
However, as an example of the possible, it would be highly informative to see data from another STAMPEDE-like trial in which men with metastatic, chemotherapy-naive, castration-resistant prostate cancer could be randomized to any one of the following seven therapeutic regimens:
- Trial arm 1: CAD + sipuleucel-T followed by enzalutamide followed by abiraterone acetate + prednisone (after failure of enzalutamide)
- Trial arm 2: CAD + sipuleucel-T followed by abiraterone acetate + prednisone followed by enzalutamide (after failure of abiraterone acetate + prednisone)
- Trial arm 3: CAD + enzalutamide followed by abiraterone acetate + prednisone (after failure of enzalutamide)
- Trial arm 4: CAD + abiraterone acetate + prednisone followed by enzalutamide (after failure of abiraterone acetate + prednisone)
- Trial arm 5: CAD + enzalutamide + abiraterone acetate + prednisone (all together)
- Trial arm 6: CAD + enzalutamide + radium-223 (all together)
- Trial arm 7: CAD + abiraterone acetate + prednisone + radium-223 (all together)
Following complete failure in any one of these trial arms, participants could then (perhaps) be further randomized to one of a couple of chemotherapy regimens.
The same general trial structure might also be appropriate for men with non-metastatic, castration-resistant, chemotherapy-naive prostate cancer.
It is only going to be through trials like this that we will ever have a chance to discover “the best” way to manage most men with CRPC. and mCRPC
Readers who are interested in understanding more about the theory behind trials like STAMPEDE might want to have a look at an article by Parmar et al. that was published in the Journal of the National Cancer Institute back in 2008.