Bertrand Tombal: One very famous urologist told me once that debate is the art of turning shit into wedding cake, so this is what we're gonna do. So, basically we are gonna use the same data and point at some, subtle difference because actually what Dr. Parker did, he eluded the question. He just say, I agree you should give somebody to everybody, but we disagree on the dose. So, this debate is not about dose so they asked me to speak about SRE. So, when I say you should give them bone protecting agent to everybody, I don't elude the question by saying you should give a small dose. I say, no, I will be speaking about zoledronic acid or denosumab at the SRE prevention dose. Although we will all conclude that it's probably excessive, there is a good rationale to do so.

This is the current landscape, so you know that very well. We speak about bone metastatic CRPC patients, so quite advanced. What we've been doing, basically, we've been extending overall survival but mostly we have increased actually the red box because patients are treated more and more, they receive abi/enza at time off. PSA progression, that was consistent conclusion of this symposium four years and two years ago. We have created a very long space. What we are speaking now is about skeletal-related events, already we gonna say that one of the consequences of creating that box is that ten years ago when we had meeting with Matthew, Fred, there were two different speech, one of us deposes because it was eluding to M0 patient receiving ADT as in Matthew's trial, an in-patient with pre-existing skeletal-related event, so we were speaking about two different groups of patient. 

The problem though is that we shouldn't have such discrimination because the black box mixed together osteoporosis and skeletal-related event and that's the number one complication of this talk, that's the number one observation in ERA 223. But let's focus on SRE because this was the topic, so you know that very well they are very prevalent, so this is actually data we used to present ten years ago, looking at the prevalence of bone metastasis and if you take Fred's trial, we usually would say that 50% of the patient would actually experience skeletal-related event. And [inaudible 00:02:45] that's not such a prevalent effect today, but is it? 

So this is Fred's trial, you know that very well, this is Karim's trial that compares denosumab to zoledronic acid, denosumab was more easy to use, so it took over the market. They don't increase over own survival, yes, that was not properly tested. Actually, if you dig in the detail you take Fred's trial, there was a signal, but simply that was not powerful for this. There is no measurement in quality of life either, no, but that was not part of the trial either, if I remember right, I may be wrong. That's not an argument. 

This is a trial that was produced by Karim Fizazi, I guess it's probably ten years ago and actually you see the jump if you just look at the time to the first SRE trial, you can actually maybe say that both trials were roughly similar because if you look to the time for the first SRE in the two zoledronic arms there were 16.3 months versus 17.1 months. So the trials were almost similar in terms of patients but by using one of these agents, by using denosumab we doubled the time to the first SRE without actually increasing overall survival.

Basically the idea was not to have patients live longer and still have the SRE in the end. It was the idea that during the same amount of life, reduce the number of SRE they are actually experiencing because one of the problems of this trial was that first SRE was the first-end point. Forgetting something is that when your bone starts to collapse, usually it's collapsing again and again and again and again. If you take the denosumab trial, the most important observation was not that you delayed the time to the first SRE, it's that you delay, you reduce the total number of SRE in the trial. So that was important. 

So based on that, it was approved by almost all guidelines except the Esmo guidelines. Actually, if you take their even recent EAU, offer bone protecting agent to patients with metastatic CRPC and skeletal metastasis to prevent osteosis complication. I mean, in [inaudible 00:05:11], long time ago there was a pity, a woman making prediction like this because, in the end, it doesn't say the [inaudible 00:05:19] but when do you start and what dose.

The patients although were very, very different from the patients we are talking today. We must agree with Doctor Parker on this, if you take Fred's trial, the average number of bone metastasis was 4.2, 30% had already experienced a skeletal-related event, 24% in the denosumab trial. The time since the first bone metastasis was 23.8 months and the pain at baseline was 72%. So you can guess that actually the drug and the trial would be done today really, really at the end of the red box. The question is that's not metastatic CRPC today, when you telling us about metastatic CRPC you are speaking about the patient who was newly diagnosed with bone metastasis had a rise in PSA or a non-metastatic CRPC was just converting it's bone scan and has no bone metastasis. Should we give these patients that early zoledronic acid or denosumab at the SRE preventing dose, that's the problem. 

What are the argument to do that? The first one I take exactly, a trial I know quite well, which is the PREVAIL trial. Actually people have been looking at that trial, and they say, "Yes but you see they are much less SRE than before?". But then you forget the nice presentation by Matt Sydes about statistic and trial and early reading of trial. What you should remember is that by the time this graph is produced, only 28% of the patient are dead. So it's a lot of patients which actually are experiencing SRE and probably from recent data, observational data. We are not close to 50% of the patient still experiencing SRE. This is a very recent survey from SEER-Medicare database when they look at 2000 patients and actually if you look at radiation therapy 27%, fracture 11.9, not asymptomatic because they trigger a medical record. Spinal cord compression very low, total 40%. So we are close, so the number today in era we are abi/enza, is still 40%. If you used patient before and after the prescription of bone-targeted agent, you see a similar reduction.

So I still believe that Fred Saad's data, today, is still valid, patients still experience SRE and they are still benefiting from bone-targeted agent taken at the time they developing bone metastasis and are castration-resistant. And then you've got Fred's analysis of COU-AA-302. Unfortunately, once again I may be wrong, I don't recall that SRE was one of the endpoints in COU-AA-392 in contrast to PREVAIL, but Fred has produced that very nice paper looking actually at patient with prior or no prior bone-targeted agent used and actually it shows indeed no major difference in overall survival although there was a slight trend. But when you look to endpoints that are known to be impacted by the occurrence of skeletal-related events such as time to opiate use or time to ECOG performance status deterioration, there was a benefit.

Then we've got that huge confounding factor, as mentioned by Fred the patient lived so long that they developing fracture. Then we've got that famous ERA 223 trial, we would not be there if that trial would have been negative because we would still have not given this drug. Then this is what we decided at the time of the EORTC trial, when Silke and I, we were confronted to Ra223, we say no. In the EORTC trial, so-called high volume, high-quality center, only 40% complied to guidelines. We had to decide on a dose because it's a clinical trial. We couldn't say to ethical community you should give oral bisphosphonates because honestly, the data was not that important. So what we did was we decided to give denosumab, also zoledronic acid to any patient that was starting enzalutamide in a PREVAIL-like setting, meaning asymptomatic, minimal 4 bone metastasis but no multiple bone metastasis, slightly elevating alkaline phosphonates and we decided to give denosumab and totally remove the risk of fracture. 

I believe that still today all these patients deserve treatment, we don't know what is the optimal dose and the trend today is either we accept the low risk of fracture or we accept a little bit of over-treatment and we hope that fifteen years down the line we gonna do the trial that Chris was mentioning. Thank you.