A Renewed Analysis of ERA 223 - Fred Saad

October 27, 2018

Charles Ryan and Fred Saad discuss the recent analysis of data points from ERA 223. 

(Length of Interview: 4 min)


Fred Saad, MD FRCS, Full Professor and Chief of Urologic Oncology, Medical Director of Interdisciplinary Urologic Oncology Group, Department of Surgery/Faculty of Medicine; Institut du cancer de Montréal/CRCHUM

Charles J. Ryan, MD
Read the Full Video Transcript

Dr. Charles Ryan: Hello, I'm joining you from ESMO 2018. This is Chuck Ryan, from the Masonic Cancer Center, at the University of Minnesota. 

I’m here with Fred Saad, from the University of Montréal, who is an investigator on, and an expert in the area of bone-targeted therapy, and radium for CRPC. 

The big news at ESMO this year is a renewed analysis of the ERA-223 study, a study that was enrolling patients treated with abiraterone, plus prednisone, who were randomized to receive either a placebo, or radium-223. 

The study was reviewed by the independent data monitoring committee, in November of 2017. At that time, it was recommended that the study be unblinded, because of an imbalance in fractures, and survival favoring the placebo arm. 

At that time, the hazard ratio for survival was 1.35, in favor of placebo, and that was associated with a P value of .02. With the subsequent analysis that was presented here, that has changed to a hazard ratio of 1.195, with a P value of 0.128. In other words, it was looking like the placebo patients were doing better, but in fact, that is not the case on this continued analysis.

That's what we want to discuss with you today.

Dr. Fred Saad: Right, so it's very reassuring that we've lost the significance, in terms of survival, and it was based on very few deaths. We have to remember, this was very early signal, that got the IDMC worried, more about the fractures, but in combination with maybe a signal, in terms of survival. 

Now, we're seeing as the data matures, the survival difference is disappearing, but the fracture issue remains an issue that needs to be looked at, analyzed, and in retrospect, when we used radium in this study, radium was introduced as first line therapy, in combination with abiraterone, and prednisone in patients that oftentimes didn't have any bone supportive therapy.

So, you cause a situation where you have an increased risk of osteoclastic activity, increased bone loss, while blocking the osteoblast, with a very effective therapy, that is intended to block the osteoblast with radium. So, this sever imbalance probably explains a large proportion of the patients that experienced fractures, because we don't really see a difference in fracture risks, when patients had a bone-targeted therapy.

Dr. Charles Ryan: So, let me review with you, the number of fractures. There were 134 fractures that were experienced by participants in the study, 102 of them were occurring in the combination arm, and 32 of them occurred in the placebo arm. So, there's a pretty big difference there.

However, when we look at the fractures in the combination arm, 80% of the fractures in the combination arm, occurred in patients not receiving bone health agents, denosumab, or zoledronic acid, and 20% occurred in those who were.

When we look over at the 32 patients, and the placebo arm who had the fractures, 75% of them, similar to the other arm, occurred, in patients without bone health agents, and only 25% of them occurred in those who were receiving bone health agents. So, that's really the crux of the issue, isn't it?

Dr. Fred Saad Absolutely. I think it just reminds us that, drugs that we were using 15 years ago, are still necessary in a disease entity where a bone is a driving factor, in terms of morbidity, and eventual mortality. We have the unfortunate habit of, when we get new drugs that are exciting, and they make a difference in terms of survival, that we sometimes forget supportive care drugs, that do make a difference.  You and I know that patients who have optimal supportive care, don't only live with a better quality of life, they actually live longer. There was a very nice paper, that showed when you do optimal palliative care, patients actually live longer.

Dr. Charles Ryan: Right, so in essence, what we've seen with this revision ... Not revision, but a review of the data is, that the survival differences are going away, so that's less of a worry, but greater attention faced to this issue of bone health agents, which I think is the take-home message of ESMO 2018, with regards to the ERA-223 study.