STAMPEDE Trial Update
One of the important and emerging questions in cancer metastasis is: how does the primary prostate tumor engage in cellular and molecular communication with potential locations for a metastasis, distant from the primary tumor, often in skeletal bone. This distant location requires preparation so that the arriving tumor cells can establish a new home as they spread, called the metastatic niche. Outstanding questions include how chemotherapy, androgen deprivation therapy and radiation therapy should be combined to reduce metastasis and prolong survival.
There is much patient-to-patient variation in metastasis, so the best way to determine rigorously whether a change to the standard of care makes a true difference is to enroll large numbers of men based on very specific criteria, randomize them into groups that test the beneficial effect of the innovation compared to the standard treatments, and then follow them long enough that differences are observed in clinically important outcomes, like survival. In the STAMPEDE trial, an acronym for “Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy”, the investigator team set out to determine whether there was a survival benefit for different treatment approaches for men with high risk prostate cancer. The study has been open since 2005, and has compared innovations in treatment against the evolving standard of care, using patient survival as a key measure of success. So far, about 10,000 patients have been enrolled, which gives the study significant statistical power to draw meaningful conclusions.
The trial has several components, and the men in each component are included based on their treatments. The following groups are still open for men to join:
- Group A have hormone therapy
- Group K have hormone therapy and metformin
- Group L have the transdermal estradiol patch
The following groups are closed and some have results:
- Group B had hormone therapy and zoledronic acid
- Group C had hormone therapy and docetaxel
- Group D had hormone therapy and celecoxib
- Group E had hormone therapy, zoledronic acid and docetaxel
- Group F had hormone therapy, zoledronic acid and celecoxib
- Group G had hormone therapy and abiraterone
- Group H had hormone therapy and radiotherapy to the prostate
- Group J had hormone therapy, abiraterone and enzalutamide
In October 2018, results became available for Group H, a study of 2061 men with newly diagnosed prostate cancer (Parker et al. 2018), testing whether radiation therapy directed at the prostate improves survival in metastatic cancer, compared to the standard of care, which includes androgen deprivation therapy, docetaxel chemotherapy, and non-steroidal anti-inflammatory drugs like aspirin, ibuprofen, celecoxib or naproxen. The main outcome was overall survival, but the study also measured secondary outcomes: failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival and symptomatic local event-free survival. The men, with a median age of 68 years, were divided equally into the two groups, only one of which also received radiation, and followed for three years. The study, published in The Lancet, found that radiotherapy improved failure-free survival (hazard ratio 0.76, 95% confidence interval 0.68–0.84; p<0.0001) but not overall survival (hazard ratio 0.92, 95% confidence interval 0.80–1.06; p=0.266).
Side effects were expected in the group of men who received radiation, and these included bladder and bowel complications. Some treatments improved overall survival for men with metastatic cancer, including docetaxel, abiraterone and radiation for men with low metastatic burden. Treatments that did not improve overall survival included celecoxib and zoledronic acid.
Additional commentary was reported at the annual meeting of the European Society for Medical Oncology (ESMO) held in Barcelona from Sept. 27- Oct. 1, 2019. One of the lead investigators, Dr. Nicholas James, reported that, although docetaxel in addition to androgen deprivation therapy improves short term outcomes such as failure-free survival for non-metastatic hormone-sensitive prostate cancer, this does not appear to translate into an improvement in metastatic progression-free survival or overall survival benefit. Interestingly, in patients who receive radiation therapy in this context, docetaxel appears to eliminate the additive benefit seen from radiotherapy. The reasons for this are unclear. Though the authors have previously published that improved failure-free survival translates into greater quality-adjusted life years in this context, it is not clear that docetaxel should be incorporated into care at this disease state given both the unclear impact on patients who have received radiotherapy as well as lack of survival benefit.
These results of the STAMPEDE trial continue to be important and have changed the standard of care. The most recent report (Clarke et al. 2019) continues to consider the balance between toxicity of the chemotherapy treatment and clinical benefits. As follow up continues, more results are expected in coming months.