Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago in United States. I'm so excited to have here with me today, a good friend and colleague, Dr. Silke Gillessen, who is a professor of oncology, as well as being the director of the Oncology Institute of Southern Switzerland and the head of medical oncology there.

Thank you so much for being here with me today. PEACE III is a really important study and part of its importance is actually the bone health analysis that you and the team performed to help us understand how the combination of enzalutamide and radium or enzalutamide alone might affect bone health and fracture rate within these patients with metastatic castration-resistant prostate cancer. Can you tell us a little bit about the analysis that you so expertly presented at ASCO 2021?

Silke Gillessen: So thank you very much, Dr. Morgans. I guess I have to give a lot, a lot, a lot of credit to Matthew Smith who actually presented and also published the ERA 223 trial. And they went very much into that, and you know the story. So the ERA 223 trial was a very similar trial, like PEACE III. They were also testing in first-line MCRPC abiraterone. So they used abiraterone plus radium versus abiraterone plus placebo. And as you well know, I think it was in November 2017 the IDMC decided to unblind the study because they saw in one arm more fractures and also more death. And then I guess all of us would have expected it would have been the control arm, but actually, it was in the combination arm.

And I think they did really a great job, also it's really nicely described in the publication. They went back, they did an independent review of the imaging they had, and not only were there much more fractures in that combination arm, but interestingly, in both arms, these fractures were in 75%, not at sites of metastasis. So I guess most of us would expect fractures in a patient with bone metastasis and you would think, oh, this is probably the bone metastasis. But in that study, it was really very different, and I think we learned for the first time that there were a lot of osteoporotic fractures there.

And then they looked also back and they did a subgroup analysis, but it was retrospective, a post-hoc analysis. And they saw that these patients who had a bone protecting agent in both of the arms did much better. And in reality for metastatic CRPC, as you well know, the use of bone protecting agent is actually recommended in almost all the guidelines, but obviously in the ERA 223 trial, there were 60% of the patients who didn't receive a bone protecting agent.

And then obviously that came out and we were thinking, oh my God, because we have a very similar study with enzalutamide. We need to check what happens in our study. And we did at that moment already, so very urgently, a safety letter and said, "All patients have now to receive bone protecting agents." Then the IDMC decided also, okay, you can go on, but everyone has to receive a bone protecting agent. And this year is now the safety analysis of what I presented of the fractures, like for all patients before the amendment and after the amendment. So before it made it really mandatory that everyone had a bone protecting agents at least six weeks before starting the radium.

So I guess it's really Matthew Smith and the team there from ERA 223 that made us understand that a lot of the fractures could probably be prevented by having a bone protecting agent. Yes. And then we looked in our data. So first of all, what we saw before, we did the safety letter, we saw the same thing, much more fractures in the combination arm than in the enzalutamide alone arm.

And so the safety analysis is now like that, that we have 160 patients included. And in both arms, we saw that the cumulative fracture, so for the patients before the amendment who didn't have a bone protecting agent, after one year, the fracture risk was 37% for the patients with the combination. So really high, but also 16% for the patients on the enzalutamide alone. What I think is a really relevant number. And then if you give the bone protecting agents, you can reduce that to below 3% in both arms. So I guess what we learned from this analysis is really that we should comply with the recommendations to use these bone protecting agents in patients with metastatic CRPC and bone metastases.

Alicia Morgans: I think it's so interesting that it really was both arms where we were seeing this. Now, obviously the combination had more than a third of patients having these fragility type fractures or osteoporosis-related type fractures, but even in patients who are on active therapy for first-line MCRPC. So in the enzalutamide arm, there was around a 15% risk of fracture, 15, 16%.

 And as you said, this is so striking because we are well aware that this has been a recommendation for actually many years, partly because of some of the earlier work that Matthew Smith has done with things like denosumab and then of course, studies of zoledronic acid. So how is it, do you think, that we can support the integration of bone health agents, obviously by presenting data like yours? Because this, I think is a very important prospective wake-up call of patients who, by the way, are healthy enough to get onto this trial. So this isn't a real world study. These are generally going to be healthier patients than some of the men we see in our clinic. How can we support that increased adoption do you think?

Silke Gillessen: So for me, it's two things. So first I have to say, our safety analysis at the moment is just the fracture rate. So we don't know how many of them are frailty, osteoporotic, traumatic, or really at sites of metastasis. But we're going to go also and look into that into detail. For me, it's really two things. I guess, one thing that is maybe a bit overlooked is when you start a man on ADT that would be a long-term ADT, you should think the first time about bone health. So here we know that ADT is a treatment that can induce bone loss. That is really well shown, and you can prevent that bone loss and fractures by giving bisphosphonates, or denosumab.

And that's important I think, in that very low dose, like denosumab only twice a year, as you know, zoledronic once a year. So this is 10 times lower dose than what we're using later for preventing SREs. So I think this is, I have the impression, something that is underestimated. Probably not many people think about the calcium, the vitamin D, and then maybe adding in also one of the bone protecting agents. And I don't know what you're using in the United States for making that risk calculation, there is a FRAX score. I'm mostly using the ESMO guidelines for bone health in that situation when I start ADT. That seemed to me very pragmatic and very easy to do, but you need a DEXA scan, at least in some of the patients.

So I guess it's really something that we sometimes overlook, I think, at that early stage already. And then it's the second stage that is really preventing the SREs, where Fred Saad trial has shown that zoledronic acid works and then [inaudible 00:08:51] has shown that denosumab works even better, but that's monthly dosing. And I think this is something, because it's the same substance, it's sometimes a bit complicated. But one is really to prevent that osteoporosis, and the other thing is really to prevent skeletal events by the metastasis. So I think these are two different things and it's sometimes difficult to kind of divide them. But yeah, we should be more attentive to follow the recommendations for both situations.

Alicia Morgans: I completely agree. And thank you for walking us through that, because I agree that it can be confusing. And certainly something that we as oncologists and urologists need to keep straight, the two separate indications, the two different dosing schedules. And thank you also, of course, for pointing out, if we start early, as we're supposed to in the metastatic hormone-sensitive setting for appropriate patients, following guidelines and considering things like the FRAX score, we can hopefully have even lower rates of these complications by the time we get to our SRE risk prevention in the metastatic CRPC setting. I know you didn't talk about it.

Silke Gillessen: May-

Alicia Morgans: Oh please.

Silke Gillessen: Sorry, can I maybe just ... And good thing is also because I heard a lot from clinicians from the states, but I'm interested what you're saying, that there is also a fear of osteonecrosis of the jaw. And that's very understandable because that's a very bothersome side effect for, obviously, for patients that we know from denosumab and from bisphosphonates. But that's cumulative. And so obviously with the much lower dose, you have a much lower incidence of osteonecrosis of the jaw. So I think this is something also to keep in mind, that at least for the osteoporosis prevention dose, that is a side effect, and you should look for dental health in your patients. It's very important, but it's much less frequent than in the dose that we're giving for metastatic CRPC.

Alicia Morgans: Yes, I definitely agree. And thank you for bringing that up. And actually, that's exactly where I was going to go with my next question, which is not about what you presented at ASCO 2021, but it's really a study that you and your team from Switzerland are doing to see if there might be ways to reduce that cumulative exposure. Can you tell us a little bit about your bone health study? I think it's in MCRPC patients and how you're investigating the dosing frequency to potentially reduce that cumulative risk.

Silke Gillessen: Yeah, so there's a lot of studies to try to test if maybe three monthly dosing in the MCRPC setting could be enough. So there is some hints from breast cancer patients that zoledronic acid, if you give it every three months, it's non-inferior to monthly and obviously has less side effects. And we started in Switzerland because we are using much more denosumab than zoledronic acid. A study, actually in breast cancer patients and in MCRPC patients to give a loading dose. So we give a monthly dose in the beginning, but then we continue as approved, or in the second arm, we change it to three months later versus the monthly that is approved.

Yeah. We are still ... So it was very difficult to fund this trial. As always, if you want a de-escalation, obviously the pharmaceutical industry is not very interested to fund such a study. So we had to involve the Swiss insurers that worked in the beginning, but now we have some troubles to find money to continue to study, but I think this would be very important for our patients if it's non-inferior for skeletal-related events. And it may very well have less toxicity, we will see that when we finish, then I think it would be a good in-between option for our patients.

Because this cost a lot [inaudible 00:13:17] when we amended the study, but obviously in the end, we had to go with what was approved. But the big question is really, would less be more in this population? Especially because our patients, and that's very fortunate, have now so many options and live much longer. So we would really like to reduce the burden of the treatment if possible, without losing the effect.

And if I may say maybe one other word. So I think that there's also a lot of confusion because in prostate cancer it's really complicated because in the hormone-sensitive setting, there have been two big studies, one again from Matthew Smith who really has done a lot of these studies. And the second one was STAMPEDE where we tested zoledronic acid. And we didn't see any, any benefit, not OS, not progression-free survival, but also not skeletal-related event-free survival. So in that castration-sensitive setting, obviously it doesn't look like the skeletal-related events were reduced by giving these drugs in that high dosage.

Alicia Morgans: Very interesting and so much for us to continue to learn. And I always enjoy talking with you about things, but actually, this conversation on bone health has been incredibly enlightening. So as we think about your study, your presentation at ASCO 2021, PEACE III bone health complications, what would your bottom line be? Or your summary for listeners as they try to take home a message from this presentation?

Silke Gillessen: So for me, it's really the most important message is that we have to think about bone health. Because we are concentrating so much on the disease, on the overall survival, on the progression-free survival, but bone health is very important because it's so important for our patients. You know that we have drugs that induce falls, fatigue. So the fractures actually happen pretty fast, and especially in frail, elderly men, we know also that fractures can then really be really troublesome. It's in everyone, but if you're already kind of frail, it can really get you back in the whole disease stage.

And so it's very important for the quality of life that our patients can stay mobile, that they can move. And fractures obviously is not what is helping. So I think we really have to start to think and focus more on bone health as well, especially because, as we said, fortunately, our patients live so much longer since starting the ADT. But that also means that the side effects, the chronic side effects, the long-term side effects of ADT we will see more and more of them. And that's not the only bone health, there is probably also sarcopenia. And I guess this is really something we should focus on as a community.

Alicia Morgans: I could not agree more. And thank you so much for going through this and for really emphasizing the importance of bone complications. And of course, other complications in our long living survivors, things like sarcopenia that certainly put them at risk for falls as they age. And we all know that fractures in men are a very important cause, not only of morbidity, but also increased risk of mortality and certainly can limit people's ability to be independent, drastically changing their quality of life. So thank you so much for taking the time to do this work and certainly for presenting it today. We appreciate your help.

Silke Gillessen: Thanks, Alicia.