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Tom Keane: Hello, everybody. This is Tom Keane from UroToday. Professor Bertrand Tombal needs no introduction, but I will introduce him anyway. He's the current Chairman of the Division of Urology and Professor of Urology at the University Catholique de Louvain in Brussels.

Professor Tombal is a member of the Royal Academy of Medicine of Belgium. He's also the current Chairman of the Clinical Trial Division of the European Organization for Research and Treatment of Cancer, and one of the leading European academic researchers in Europe.

His primary clinical interest is the treatment of advanced stages of prostate cancer and particularly hormonal treatment and development of new biological agents.

In addition, he has authored many published papers, books and book chapters, has presented at numerous national and international conferences, and been the recipient of numerous awards for his research in the field of urology, including the European Association of Urology Thesis Award, which he received in 2003.

He's a member of the Skeletal Care Academy and a member of the Scientific Office of the European Association of Urology. It is with a great pleasure that we welcome you here today. He gave an excellent presentation recently at ASCO, which he has very kindly agreed to re-present this because a lot of people need to hear this information. Professor Tombal, it's a pleasure to have you here.

He's going to present Decreased Fracture Rate by Mandating Bone Protecting Agents in the EORTC 1333/PEACE III Trial, combining Radium-223 with Enzalutamide versus Enzalutamide alone. These are early results. Thank you.

Bertrand Tombal: Thank you very much for inviting me tonight. It's indeed a pleasure sharing this data with you. You may ask yourself why we do something quite unconventional in that we submitted at ASCO the preliminary result of a trial which actually is a safety analysis. So usually when you do a trial, you run several interim analyses and the first ones are usually on safety and you're gonna understand very soon why the safety results of these trials are of importance for practicing physicians.

So, this is not my work, it's a collaborative work between EORTC in Europe, the Canadian Uro-Oncology Group in Canada, UNICANCER in France, and Cancer Trials Ireland in Ireland, as you may guess. So, you can find the disclosure of the different partners on the ASCO website. The study was funded by an educational grant from Bayer. And Enzalutamide is provided by Astellas in Europe.

So, as you know, we have several agents approved in the metastatic CRPC setting. They are now going all over the place, so we believe the observations we have made are also of equal importance from other stages of the disease. In Europe, we don't have sipuleucel-T approved, so the usual first line for treatment are either abiraterone or enzalutamide that are approved for asymptomatic or moderately symptomatic metastatic CRPC patients. And Radium-223 is approved in the first line, but usually in symptomatic patients.

So this work has been on the market for several years. We use them as an everyday basis and what we tend to forget is that they're not used alone. And that they're always combined with androgen deprivation therapy (ADT), and they really have extended the lifespan of the patient. And one of the consequences that they are extending the life of the patient who lives on ADT.

And one of the observations is that actually if you look in the recommendation for physicians to this drug, because the patient probably spent more time on ADT, there is a significant increase in the reporting of fracture.

There has been some confusion in the urological and medical oncology world about the difference between symptomatic skeletal events, you know, these are, I mean, pathological fracture that are happening quite late in the disease spectrum, usually caused by deterioration of the metastatic site. And the non-pathological fracture, osteoporotic fractures that are actually happening as a consequence of long-term ADT. And we tend to have underestimated this in the last few years.

So, that's because of this that bone protecting agent and mostly denosumab and zoledronic acid are recommended in these patients. They are basically recommended at two stages. They're usually recommended early on to prevent osteoporotic fracture, and in such case, you usually use either low dose of denosumab administered every six months, or low dose of zoledronic acid either once a year or three times a year. And that's to reduce the risk of osteoporosis. Strictly speaking, only denosumab has shown a decrease in the risk of fracture.

Later on, when the patient is progressing and has more metastases, denosumab and zoledronic acid are also suggested to reduce the risk of skeletal-related events or meaning, pathological fracture at a higher dose. One monthly for both agents, and there have been two randomized controlled trials showing a significant effect of zoledronic acid and denosumab. So, zoledronic and denosumab compare okay, I mean, denosumab a little bit better, but you see that the most important benefit is to give one of these two drugs.

So, that is a little bit the context we're using abi/enza. We tend to forget about fracture and I'm not sure we have not forgotten about these though.

Every time you speak about radiotherapy and hormone therapy in the treatment of prostate cancer, there is some synergistic effect. Radiotherapy and hormone therapy have been there forever so it looks natural to combine radium-223, which basically is radiotherapy to modern AR antagonists like enzalutamide or abiraterone.

And it looks, actually, a little obvious to use radium-223 earlier in combination with abi or enza to increase their efficacy.

So that basically, two trials have been initiated. The first was called ERA-223. It was a trial sponsored by Bayer, that investigated abiraterone acetate alone versus abiraterone acetate plus radium-223 in men that were asymptomatic early disease, early metastatic CRPC patients. Still asymptomatic or mildly symptomatic.

In parallel, EORTC is conducting a similar trial, which is using enzalutamide instead of abiraterone, so combining enzalutamide to radium versus enzalutamide alone. And the trial started with maybe one year delay, so ERA-223 started first. And we recruited office space in like one year after ERA-223. And you know it was very obvious that you combine two agents, that are increasing overall survival, so everybody was expecting a good outcome from this trial.

So, this was the ERA-223 radium plus abiraterone versus abiraterone alone. Please note something important is that these are patients selected with bone metastases, so these are patients that are indication for radium, so no visible metastases, still asymptomatic, no chemotherapy, so early patient. But patient with dominant bone metastatic disease and actually that's where it started actually to go wrong. In November 2017, the independent data monitoring committee, the IDMC of the trial, recommended unblinding after noting more fractures and deaths in the abiraterone acetate prednisone plus radium-223 arm. So it went like a big surprise, so everybody was a little bit surprised, and at that point in time and we were in the US, and in Europe people were layering radium on top of abi and enza so it created a lot of doubts about the combination.

Actually, what is interesting is actually to look at what kind of fracture they were, and this is the table from the recently-published paper by Smith from the ERA-223. And actually if you look you see that the most increase was seen in osteoporotic and traumatic fractures. So, this is something different from an SRE. So as you may guess, all ethical committee across Europe, all independent committee, review the trial, and the enzalutamide trial was put on hold immediately to decide do we keep these trials to go or are we going to be confronted to a similar mechanism.

At that point in time we made three observations which I believe are very important. The first one is that this is something like an acute toxicity coming from the combination of radium to abiraterone, because 40 percent of these patients of this fracture, I'll just show you, occur in the first six month following the exposure. So something that is quite happening very rapidly.

The second one is that although we're speaking about bone-dominant metastatic CRPC patient, very few were receiving bone-protecting agents (BPA) zoledronic acid or denosumab during the trial. And in post hoc analysis, it was clear in that ERA-223 trial that BPA were reducing the rate of fractures. So, it was very difficult to see and to decide if there was just an interaction of the drug, that is clear, but was that interaction actually not made on the ground that was enhanced by the fact that we were not recommending these bone-protecting agents. And this I must say, in contrast to most published guidelines.

So based on this we had to decide what to do with our trial. So, this is our trial, it's actually absolutely similar to the radium trial, so its enzalutamide versus enzalutamide plus six cycles of radium in bone-dominant, more than two lesions, asymptomatic or mildly symptomatic patients, and no visible metastases. The difference is that all primary endpoint was radiographic PFS, the ERA-223 was symptomatic skeletal event.

So as you may guess, when the results came, I mean it was like a tsunami of regulatory and ethical burden. I mean most ethical committees say you can't do the trial anymore, so we had to take urgent measure, and in March 2018, so two-three months after the publication of the IDMC from the ERA-223 trial, we sent an urgent safety letter, where we have made use of bone-protecting agents mandatory. So meaning that to enter the trial you need to have received a minimum of six weeks of denosumab or zoledronic acid, meaning that if your patient is randomized in the enzalutamide arm, it can start enzalutamide but you should start bone-protecting agent; if he's randomized in the radium-223 plus enzalutamide, you can start enzalutamide but you have to give at least two doses of the bone-protecting agent before you can start the radium-223.

And we also escalated the skeletal event to really understand, was it a problem of pathological fracture or osteoporotic fracture. Also, we had to discuss which dose of the agent we would use. Would we use a low dose to prevent osteoporosis or the high SSE-preventing dose, and we choose the SSE-preventing dose, because these patients have usually more than two bone metastases.

So the first observation was that at this point in time we still had a lot of patients on the enzalutamide. Many of the patients were done with the radium, but we were still in the early phase of the trial, so where most likely we would see the fracture risk.

So as you can see here, one surprising observation is that although in Europe we have very good EAU guidelines that are saying that we should give bone-protecting agents to metastatic CRPC patients, we didn't do it because before the safety letter only 42 percent of the patients were receiving BPA, similar to the ERA-223 trial. And when we made the recommendation to absolutely use BPA, it rose to 86 percent, so that in total, keep in mind there are two phases in the trial, in total, from the results, from the safety analysis made by the IDMC, 55 percent of the patient had received zoledronic acid.

So this is an analysis that has been done on the 25 of May with roughly 40 percent of the patient having received BPA, and then you see the effect is dramatic, because you can make two observations, I would say three observations. Meaning that when you give enzalutamide alone, in green, you have roughly 10% fracture, something that is reported in SMPC, quite normal really. Unfortunately, when you combine enzalutamide to radium you have a dramatic increase in the risk of fracture, so enzalutamide's not different to abiraterone in this regard. But the most important observation is that when you combine enza alone or enza plus radium, two bone protecting agents, the black and the red, you see basically no fracture at all. Actually, there's no fracture. There was one fracture at week 27 that happened to be a true symptomatic skeletal event, so these drugs have a major effect.

Another way to look at this, and this was actually requested by the IDMC, was to look at the cumulative incidence of fracture. And you once again see that clear effect of an early combination of radium and enza, which after six to nine months dramatically increased the risk of fracture to 37%. And basically, that is what we call the zero effect. If these patients are pre-exposed to bone-protecting agent, and the bone-protecting agent is maintained, we haven't seen any fracture for the twelve first months, only one fracture I mentioned before happened at month 27.

So this is for the numbers. So clearly the zero effect, we haven't seen any, and that is because of the amplitude of the results that the management of EORTC and the IDMC authorized the release of the data, because we believe that although it is preliminary, many people are questioning the combination, layering of abiraterone and enzalutamide. And I think our message that if you do that you would have to do it by putting the patient under the protection of BPA.

So the conclusions were that actually pathological and non-pathological fracture are a well-recognized complication in advanced prostate cancer. So, we know that we see the same thing that the enza combination with radium-223 is detrimental for the bone, but these early results strongly suggest that the risk of fracture is very, very well controlled in both arms when patient receive BPA. The study still closely monitored. The IDMC meet on the regular basis, and the safety analysis, that's to me a strange study because it just says "please, follow the guidelines," but obviously it was of importance to be minded, since 60 percent of us don't comply to the guidelines, and this seems to indicate that they may be very detrimental for our patients.

So having said that, I would like to recognize and acknowledge all the patients and their family. Trust me in the post-ERA-223, when patients have a broad access to Internet, it was very, very, I mean, patients had to be really into clinical trial, to accept to go in that clinical trial, so we really have to thank them, as well as my collaborators and the IDMC. Thank you very much for your attention.