The study we’re presenting at ASTRO is a randomised clinical trial from NRG Oncology, so it’s NRG GU006, also known as the BALANCE trial. It’s a randomised trial of men that have undergone radical prostatectomy for prostate cancer and have had a PSA recurrence. In these men with recurrent prostate cancer the standard of care is to receive secondary radiation therapy, we used to call this salvage radiation therapy so it’s used interchangeably. It’s randomising men to either receive a placebo or to receive apalutamide, which is a next generation or novel form of hormone therapy that blocks the androgen receptor. Both of those were given for six months orally.
It’s a double-blind, placebo-controlled trial and the novel part of the trial, beyond simply using apalutamide as monotherapy, which has never been done before in a trial like this, was a very unique biomarker-stratified design. So the main hypothesis of the trial was that we could, for the first time in history, use a gene expression biomarker that we developed back in 2015, it’s called PAM50. It actually was derived originally from breast cancer and we modified it for the biology of prostate cancer. We predicted that patients with what’s called luminal B tumours, so it’s a subtype of prostate cancer, would derive greater benefit from apalutamide than non-luminal B patients.
The patients were stratified as they were enrolled onto this trial by whether they had luminal B or non-luminal B status and then randomised, as I said, to placebo or to apalutamide with secondary radiotherapy.
What were the results of this study?
The results of NRG GU006 are practice changing. The primary endpoint of the study was an endpoint called biochemical progression free survival, this is a composite endpoint of biochemical recurrence, local, regional or distant recurrence or failure, or death from any cause. In the luminal B patients receiving apalutamide there was a highly significant and great both absolute and relative reduction of recurrence, or biochemical progression, with the addition of apalutamide. But if you were to look at the non-luminal B patients the hazard ratio was effectively 1.0 with a non-significant p-value with no difference at five years. So this essentially was a positive result for our trial, given our hypothesis was that luminal B patients would be the ones who derived the benefit and not luminal B.
Furthermore, and very exciting, was our secondary endpoint which was metastasis free survival. This is often the primary endpoint of phase III trials, it's a surrogate endpoint for overall survival. In the luminal B patients there was also a very large improvement in metastasis free survival, the hazard ratio was 0.27. So a very substantial relative reduction in the risk of developing metastasis or death. But, again, in the non-luminal B patients the hazard ratio was again effectively 1.0 with no difference at five years.
So between both of these endpoints, as well as other ones that are not actually in the presentation, it is very clear that the luminal B patients were the ones that specifically derived benefit from hormone therapy.
What is the clinical significance of these results and what is next for this study?
These results are likely to be practice changing for many people, especially in the context that this study enrolled patients, which specifically is recurrent prostate cancer with patients with PSAs less than 1.0. So these are the patients that we sort of debate routinely – do we give them hormone therapy or not? So this provides the strongest evidence, it’s actually the first biomarker in history in non-metastatic prostate cancer to ever undergo prospective validation in a biomarker-driven trial. So once these results are presented and published I expect them likely to change practice but, again, that’s in this patient population.
Future work will be very critical to understand does this apply to men with other types of prostate cancer, specifically localised prostate cancer, that men have not undergone surgery. Can we use this to help guide the use of hormone therapy in that setting? We are in development of a very large phase III trial led by Dr Angela Jia, she is here also at my institution in University Hospitals Seidman Cancer Center, as well as Dr Robert Dess who is at the University of Michigan, who are leading that trial. So I think there’s a lot more to come to hopefully expand this work to help men across the world in different settings of prostate cancer.
