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Oliver Sartor: Hi. I'm Dr. Oliver Sartor with UroToday, and it's really a pleasure and honor for me to have Bertrand Tombal join us to be able to discuss the PEACE-3 data that was presented at ESMO 2024 in Barcelona. Bertrand is incredibly well-known to our listeners, former president of the EORTC and all-round leader in terms of prostate cancer research. Welcome, Bertrand.

Bertrand Tombal: My pleasure being with you. Thank you for inviting me. It's a pleasure to give you a quick summary of the PEACE-3 trial that was presented by my co-investigator, Silke Gillessen, at the last ESMO. Actually, PEACE-3 is a trial looking at the combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic CRPC, meaning patients who will progress on ADT only.

The background: you know that enzalutamide and abiraterone have been the standard of care for patients progressing on ADT only, that radium has been one of the drugs that was also tested in that setting that increased overall survival in the ALSYMPCA trial that was known for its good toxicity profile, was recognized as a very good agent, but then was moved to later stage. Because of the known interaction between hormone therapy and radiotherapy, synergy between these two treatments, two trials have investigated the combination of radium-223 and either abiraterone in the ERA-223 and in PEACE-3 in combination with enzalutamide.

It's a very, very simple, pragmatic trial where patients with metastatic CRPC and more than two bone metastases. We also later included patients who were supposed to progress on abiraterone, but we had very few patients. They were randomized between enzalutamide and enzalutamide plus six cycles of radium-223 at the standard dose of 55 kilobecquerel per kilogram every four weeks. The difference between the ERA-223 trial is that this trial was powered to detect the difference in radiographic progression-free survival. No study had ever really looked at that with radium before, and also safety, overall survival, and a few other endpoints I will show you quickly right away. After the ERA-223 trial showing an increased risk of skeletal fracture, we mandated to use bone-protecting agents in these patients, which makes sense because it's actually in line with the guidelines. As I said, it was tested to detect the benefit in radiographic progression-free survival, and we anticipated a hazard ratio of 0.68, and an interim analysis was foreseen at the time of that rPFS analysis, interim analysis for OS.

It's a typical population of patients progressing on ADT alone. A third had received docetaxel. They were in their 70s. 50/50 had more than 10 bone metastases or less than 10 bone metastases. As I said, very few patients progressed on abiraterone only. One of the first observations was that when you give radium at that stage of the disease, close to 90% can receive the six cycles, which is not usually the case in real-world evidence because radium is given later. It's very rare to see 90% of the patients receiving the radium, so it's already a success, I would say. This is the primary endpoint. We detected a major benefit in terms of PFS. I would like to highlight that the final hazard ratio is 0.69, so we were quite good in setting the scene and deciding on the endpoint with a p-value of 0.00009. It's interesting to see that the PFS rate at two years is 36% with enza versus 45% with enza plus radium.

We've done a quick subgroup analysis. We're going to do more in the near future, but we haven't really detected one group of patients that didn't benefit from the treatment. You see that the group of patients over 75 and those who received docetaxel, these are not very large groups. As mentioned, there was an interim analysis of the overall survival at roughly 80% of the events. You see that if you look at the log-rank, the hazard ratio for overall survival is also 0.69 with a very positive log-rank. However, we just want to be careful; if you see, there is a small initial crossing of the curve due to a few non-prostate cancer deaths, probably. There's still a lot of patients in that initial part, so we're going to keep monitoring these patients and come with final analysis. We anticipate between 18 months and two years to confirm the value of the hazard ratio and the p-value, but at this point in time it is super encouraging.

All other endpoints have been analyzed. The time to next systemic treatment, very important for patients considering that it's a simple six-cycle of radium, was increased by more than 20% at two years, and the hazard ratio is 0.57. There is no benefit in time to pain progression, SSE, but you see this is still very few events, and we believe that in these patients receiving enzalutamide, actually symptomatic skeletal events and pain, there's something that's happening much later, so it's not at all, to me at least, a surprise that we don't see a benefit in these endpoints. Further analysis will be done.

In terms of side effects, it is very reassuring. Actually, there is no side effect which individually is increased by more than 5%. If you look at the grade three to five drug-related adverse events, it is increased by 9%, which we believe is not a lot, and we haven't had any drug-related deaths related to adverse events. As I mentioned, we have a lot of hypertension, but I would say that that's probably because when we started the trial, that was the initial report of PREVAIL and there was a lot of concern between HTA, hypertension, and AR pathway inhibitors, so we put a lot of pressure on the centers to report all hypertensive events. We have a huge collection of reports, but you see for the red there is not a single side effect which is increased by more than 5% when you compare radium to enzalutamide.

In conclusion, what we show is that at least in patients who progress on ADT alone, adding six cycles of radium on top of enzalutamide significantly increased PFS, and at this point in time the interim analysis shows a very interesting improvement in OS as well. But because there is non-proportional hazards, we're going to keep monitoring these patients and keep with final OS analysis in one and a half to two years. I think it's a new combination. We know it's going to be submitted to registration authorities. We do hope that they will allow us to use radium earlier in the setting, which many studies have been done, including by you, Oliver, on that. Actually, radium is a good drug if you use it early enough. Thank you for listening to this.

Oliver Sartor: Thank you very much, Bertrand. A couple of questions. One thing about the trial is it took a long time to accrue, and I wonder if you just might make a comment about the long time to accrue because the truth is that there have been landscape changes in prostate cancer that are different then and now. We'll come back to that, but let's talk about the accrual time and then we'll talk about the changing landscape here in a moment.

Bertrand Tombal: Yeah. The trial was indeed painful. If you remember, it was initiated in 2014. It was first stopped for almost nine months because of a production problem of radium, if you remember, so we had to stop an in-clinical trial. It took six months to restart in Canada and then it took almost one year to restart in Europe. Then the recruitment was picking up again and then we unfortunately had the ERA-223, which put a lot of concern around radium, around fracture, so it took another year to restart and we were kind of lucky in the end that we could convince enough investigators to trust us and say, "Okay, abi is not enza. We're not going to get the same thing, so it was worth investigating." Because after ERA-223, everybody was just questioning the combination, "Why would you use an AR pathway inhibitor and radium where a trial has shown there is absolutely no benefit, an increase in fracture and initially an increase of death?" We had to reassure a lot of people, and hopefully we did it.

Now in the meantime, as you say, many patients do receive abi or enza or one of the two other earlier, but actually if you look in Europe, the number one indication for enza and abi is still patients who are progressing on ADT only. There's still a lot of patients like this. If we take my country, for instance, we do anticipate it's going to take another three or five years before everybody has received an ARPI, and there's still many places it's not like that, so we believe the results are still relevant. No, I hear a lot of people saying, "Okay, would you use it after abiraterone?" I say we have to be careful now. We had only two patients in that scenario. There are other alternatives, so it's going to have to be discussed case by case. But we believe that yes, the landscape is changing but it has not changed yet totally, so there's still opportunity to use that treatment.

To me, it's more a plea that yes, you can use radium earlier in combination with enzalutamide. You may layer it like we've seen in REASSURE and all these real-world evidence. If you protect the bone, the treatment is super safe. I think that beyond just the result of the trial is just to show that no, radium, it's a true drug. My impression having worked with that drug is that more and more people were seeing a super bone-protecting agent. No, no, no. It's the second trial together with ALSYMPCA which indicate a benefit in overall survival, so radium should be part of our armamentarium. It is different from PSMA, lutetium, it's an alpha and a beta, and if you use it early you can gain benefit of it. To me, the result goes beyond a simple combination. It's much more a reawakening to the people that radium should not be forgotten. It's an agent at work and that may help some patients.

Oliver Sartor: Interesting comments. Now one of the things I'm a little curious about, and I need a European perspective, bone health agents were mandated for trial participation because basically if you didn't use the bone health agents in combination with radium in particular, there was a large increase in fracture rate. Is the bone health agent utilization high in Europe, low in Europe?

Bertrand Tombal: It was not. Not so—

Oliver Sartor: That's what I was thinking. It's fairly low. It's actually fairly low in the United States as well. I think one of the critical elements to emphasize is this trial depended on not just enzalutamide and radium, but also the bone health agents without which there could be a real problem, but I want to get your perspective on that a little more.

Bertrand Tombal: That's very interesting because having spent most of my academic life on bone metastasis, it was curious first of all how people reacted to zoledronic acid and denosumab. Even after the trial, people were not absolutely convinced. You remember that in Fred Saad's trial on zoledronate, many of the people had already experienced skeletal-related events, so in the mind of patients this was something you would use later. Then even you remember COUGAR-301 and 302, PREVAIL, and AFFIRM, each of these trials showed that SRE happened later and that actually displaced by enzalutamide. But looking at that, we may have missed the most important observation, which is patients are living longer and they are exposed to another kind of fracture, which is not only skeletal-related events but are also frailty fractures, osteoporotic fractures. That appeared clear. I'm not sure it's an effect of abi or enza, maybe [inaudible 00:15:05] maybe, but in the end patients have more fractures.

Here we were kind of in a gap because we had very few agents and we have only one drug, which is denosumab low dose, to reduce the risk of fracture. At the same time these patients were metastatic and castration-resistant, so according to guidelines we should have given a bone-targeted agent at the SRE dose. Because we were in a clinical trial, we had to say, "Listen, the only way to clarify is that, no, according to guidelines they should receive a bone-targeted agent at the skeletal-related event. Do it. We're going to see if at least we diminish the risk of fracture, which interestingly we did." We are now reviewing all these fractures. The imaging group is looking whether they are osteoporotic or not, opening of fracture site or not, so we're going to get this data. But once again, I said many times that to me even if PEACE-3 was negative in terms of combination, at least it has contributed since 2021 reminding people that the skeleton is an important target that should be protected.

Oliver Sartor: Excellent. Thank you. One of the things that is absent from the trial, and I want to ask you as one of the organizers and designers of the trial, PSA. No mention of PSA and not included in the endpoints. I just wonder if you might have a remark on that issue.

Bertrand Tombal: Yeah. That to me... I will reassure you. We have collected PSA, so we're hopefully going to be able to show the result, but keep in mind that this is one of this mistake we had around the drug is that after ALSYMPCA and the initial trial and even paper published people like yourself, we take it for granted that radium has no or minimal impact on PSA. When we plan the additional research, we have collected bone markers and all of this, and then we say, "Well, but, my God, no, we've got such a benefit on PFS." Hopefully we're going to be able to come with that data because we had to monitor PSA for the rPFS component, but it is clear that to me we did a list of priority of the publication we should come with and to me, two are extremely important, is what are the response rates on PSA and alkaline phosphatase and repeat what has been done in other radium trials to see if there is really a synergistic effect between enzalutamide and radium, which maybe we're going to see on alkaline phosphatase or on PSA, but we're going to come with that but it's going to take more time.

Oliver Sartor: Got it. One of the other interesting things about potential synergy, it's not about the interaction between the potential for inducing osteoblastic lesions with healing bone after enzalutamide, but also a similar finding after use of bone health agents in which you change the stroma to a little more blastic as opposed to a little more lytic. I'm just curious if you think that there could be actually an interaction related to radium and the stromal interactions from the bone health agents that extend beyond just protection of fracture.

Bertrand Tombal: One of the very good things of using rPFS is that we have close to 2,000 bone scans and CT scans which are going to be analyzed by the imaging group, which is trying to see whether, or how could they image at the level of the bone this synergistic effect. The imaging PI is Frederic Lecouvet, who you know is a world specialist in skeletal imaging, so they're already very excited trying to see if we could see a difference in the flare phenomenon, in the remodeling, in the bone infrastructure because you can do a lot on a simple CT scan. All the data have been centrally stored, so everything is available for additional research, so anybody who would have a great idea about how to measure that, we would be pleased to welcome the idea.

Oliver Sartor: Terrific. We're going to be wrapping up here in just a moment, Bertrand, but I wonder if you might have any final comments for our audience, any final thoughts?

Bertrand Tombal: No, I think that clearly we... First, I really believe that these patients still do exist. I really believe that that's another... To me, that's another indication that really radioligand or targeted or non-targeted radionuclear drugs are going to get a huge increasing role in prostate cancer, and that clearly... To me, when I see the result of PEACE-1 and at the same time PSMAfore although when I say that... For most patients, no, the question will be how do we sequence lutetium and radium? But clearly these drugs can be given to, I don't know, a lot of patients who are not candidates to get it and it really reawakened radium and we're going to have to see how we combine or sequence these drugs in the future.

Oliver Sartor: Well, listen, thank you so much, Bertrand. Congratulations for helping to lead what I think could be a practice-changing trial. Thank you for your leadership and thank you for being here today.

Bertrand Tombal: Thank you.