Scientists say they have validated a "surrogate endpoint" – a reliable statistical shortcut in a clinical trial – that could accelerate testing of new adjuvant therapies aimed at reducing deaths from prostate cancer in patients who were treated for localized disease, but are at risk of relapse.
Reporting in the August issue of the Journal of Clinical Oncology, an international team of researchers, led by Christopher Sweeney, MBBS, of Dana-Farber Cancer Institute, found that measuring metastasis-free survival (MFS) – the length of time before the cancer spread beyond the prostate gland – was a strong predictor of patients’ overall survival (OS), which is the yardstick commonly used in evaluating an adjuvant therapy. The analysis found that OS requires a longer follow-up period to measure than does MFS, and that using MFS as an endpoint could enable more clinical trials to be carried out in a shorter period of time.
Sweeney is the corresponding author representing the Intermediate Clinical Endpoints of Cancer of the Prostate (ICECaP) Working Group, which carried out the study. The ICECaP Working Group comprises more than 50 investigators including statisticians, medical oncologists, urologists, radiation oncologists, and health economists from several dozen institutions around the globe.
Adjuvant therapies are drugs given following initial treatment of prostate cancer with radiation or surgery. They are aimed at ridding the body of cancer cells that survived initial treatment, and may save lives from prostate cancer.
Prostate cancer is a slow growing disease; therefore, it typically takes 10 to 12 years to evaluate an experimental adjuvant therapy for localized prostate cancer in clinical trials that use OS as the endpoint. With a number of new adjuvant drugs undergoing evaluation for this patient group, Sweeney said researchers in the field are seeking ways to get answers quicker and make effective drugs available sooner.
The patients in question are men whose cancer was confined to the prostate gland and were treated with radiation or surgery, but are considered to be at medium or high risk of relapse because of the aggressiveness of other pathological features of their tumor. Adjuvant drugs currently being evaluated include alpharadin, enzalutamide, abiterone, docetaxel, cabazitaxel, and sipuleucel-T vaccine.
The researchers analyzed data from 28 clinical trials involving 28,905 patients.
The analysis found that MFS could serve as a strong and reliable surrogate endpoint in evaluating adjuvant therapies. Using statistical validation models, the researchers showed that the proportion of patients who were metastasis-free at five years closely tracked with the proportion of patients who were alive at eight years following treatment.
As an example of how this would work in practice, Sweeney said that if a drug in a clinical trial achieved a 30 percent reduction in risk of patients developing metastatic disease, that would predict a 25 percent decreased risk of death.
The authors wrote that given this strong correlation, "clinical trials can be designed using MFS as a primary endpoint instead of OS," resulting in "being able to complete trials in a more expeditious manner." The idea is to "get a readout of the clinical trial sooner and get drugs to patients sooner," said Sweeney.
"The discovery of this surrogate endpoint has enormous implications for patients with prostate cancer. Reducing the time needed to conduct clinical trials will accelerate the development of new treatments that can be administered at the earliest stage possible, when the cancer might still be curable," said Howard Soule, PhD, Chief Science Officer and Executive Vice President of the Prostate Cancer Foundation, which supported the establishment of the ICECaP Working Group and participated in the project. "This project was a huge effort that involved collecting and analyzing an enormous amount of clinical trial data, which required the cooperation of several major co-operative clinical trial groups and pharmaceutical companies. The Prostate Cancer Foundation is very proud of Dr. Sweeney’s leadership and the ICECaP team for conducting this very important project for patients as we continue to work toward defeating prostate cancer once and for all."
In addition to Sweeney, Dana-Farber investigators on the project included Meredith Regan, ScD, and Wanling Xie, both of the Department of Biostatistics and Computational Biology.
The research was supported by funding provided by a Prostate Cancer Foundation Challenge Award and grants from Astellas Pharma, Medivation, Janssen Pharmaceuticals,
Takeda, Sotio, and Sanofi.