Daniel Heinrich: Yeah, thanks for having me. Really a pleasure, and as you said, it should have been an easy task to talk about this since both you and I have been involved in Radium and Radium development for such a long time, but it's still a challenge to select the right patients for this treatment.
Oliver Sartor: Well, when you presented at APCCC, you talked about how to select these patients. Now, I wonder if you'd give us an overview, and particularly in the context of today's environment where there are many more alternatives, including Lutetium-177, that are potentially feasible for patients to receive, so help us understand how you think about Radium-223 today.
Daniel Heinrich: Yeah, right. Thanks. So obviously, it has become much more difficult than back in the times when we were running the pivotal phase-III trial when it was more or less docetaxel or not, and if you were not feasible for docetaxel, then you could go into the trial. If you had received docetaxel, you could go into the trial, and if you had not received docetaxel, you could deny docetaxel and go into the trial with Radium. So today, it's different. Unfortunately, bottom line, we still lack any biomarkers for selecting patients for Radium, at least any validated biomarkers, and that's true for both molecular biomarkers, whether circulating or genomic, that's true for radiologic biomarkers, and that's even true for biomarkers from the nuclear medicine field. So unless you would include a bone disease not showing on a technetium bone scan being a negative selecting biomarker, you really don't have anything there. So we still need to select patients for Radium-223 by the clinical scenario that the patient is in, and of course, individual factors like patient preference.
So let me give you a couple of examples. Everyone is talking about the PEACE-3 results, and we've seen an overall survival advantage, which is pretty impressive with adding Radium to enzalutamide in the first-line mCRPC setting. And then everyone is telling me those patients, they don't exist anymore because everyone is receiving an ARPI before becoming castration-resistant.
I've actually looked into our patients from 2025, just at our own institution, covering 400,000 inhabitants in the middle of Norway, and those patients, they do still exist actually. Typically, having been diagnosed with metastatic or non-metastatic prostate cancer, only having seen an urologist, and by whatever reason, being treated with ADT only. And then when becoming metastatic castration-resistant, they are referred to an oncologist, and then that's their first-line treatment. So those patients who have never seen an ARPI and becoming mCRPC patients, they do exist.
On the global scale, and when we are looking at larger institutions, I guess there are only a few percent of those. So where do we fit Radium-223 into the treatment algorithm is maybe a better question than how do we select patients for Radium-223? I don't know if you have any ideas about that, Oliver.
Oliver Sartor: Well, one comment that I might make, there was a German study several years ago, and I'm sorry I forget the exact author, but what they showed is if you look by PSMA PET scan, and in fact, you're bone only or extremely bone-dominant, that the outcome is better than if you simply select on conventional imaging. So the idea that molecular imaging today can add value to conventional imaging when selecting patients for Radium did in fact make sense to me.
The other element, of course, is, as you pointed out, the conventional bone scan with the presence of osteoblastic metastases, and if you don't have those osteoblastic metastases, then you're not going to do well with Radium. That's a fact. But I appreciate you raising the issue on the PEACE-3 trial about the patients who have ADT monotherapy as their treatment when they become castrate-resistant, and yes, those patients do exist.
They are not part of the major academic centers because we almost always will be using a ADT-ARPI combination, but there are lots of patients who for whatever reason, perhaps cost, perhaps related to practice patterns in the community, are still receiving ADT where they become castrate-resistant metastatic, so I appreciate you raising that point.
Daniel Heinrich: And I guess the other more important results from the PEACE-3 study for me is a kind of insurance that this treatment is actually still today, even though we developed it 20 years ago, one that could contribute importantly to patient's treatment algorithm, to patient's quality of life and as a life-prolonging therapy, which some people might have doubted in the context of so many other therapies having been proven life-prolonging in the meantime and Radium for quite some time having had a niche indication or at least a niche existence with only some 10% of mCRPC patients receiving it. I guess there is a potential, and I do see that potential for more patients getting it, not only now, in the future, and the PEACE-3 results ensuring that it's really a treatment we should have in our tool box, right?
Oliver Sartor: Yeah. One of the interesting things about the PEACE-3 versus the ALSYMPCA phase-three trial, in the ALSYMPCA, there was no RPFS. There was no progression that was assessed, whereas in the PEACE-3, it was. So not only did you have the OS benefit showed in another large phase three, which I think was very important for Radium, but in addition, you had the RPFS, which was clearly positive, and I think that added value. One of the things I do want to emphasize, and this is just critically important in PEACE-3 and when giving Radium, I believe you do need to use bone health agents, and I wonder if you might expand upon that. And I think you're very aware about the utilization of bone health and how it affects the skeletal-symptomatic events and how it affects the fractures, and wonder if you might help our audience understand that better.
Daniel Heinrich: Yeah. So the issue was basically there all the time, and in the starting phase of developing Radium, we thought about bone-targeting agent, especially zoledronic acid back then in the times as an add-on and helping agent to get Radium more to the right place. And then after the results of the ERA-223 study came out, obviously we understood that if you treat a patient with both one and two and three and four different drugs which target the bone and may affect it negatively, then you get an increased number of bone-related events, whether it's cancer related or not.
And of course, that led to the ERA-223 being negative. And as you all may recall, then the PEACE-3 protocol was amended to demand bone-targeting agents given concomitantly, and finally, the trial is a positive one.
I just a couple of weeks ago talked toØyvind Bruland about that, and he's still emphasizing that we should be using bone-targeting agents, not only to avoid negative effects of either the cancer or the treatment, but even to prepare the bone microenvironment for Radium. So even though I've always been doing that, but I've not been thinking about that as an active measure of preparing the body for Radium, but ¯yvind proposed to give at least two doses of zoledronic acid before the first dose of Radium. So that was an interesting new way to look at it for me.
Oliver Sartor: Interestingly, ¯yvind and I have been talking about this for a long time and published many years ago about stromal-targeted therapy and the ability to manipulate the stroma in order to enhance the binding of Radium. I think it's a very interesting concept. We don't have the randomized trial that would show the survival benefit, but we do have the ERA-223, which in essence did not use bone health agents and it was a negative trial with an excessive amount of fractures. And the initial phases of the PEACE-3 trial, when the DMC noted that the fracture rate was exceptionally high, the addition of bone health was mandated, bone health agents were mandated, and of course, we have a positive trial with PEACE-3.
It's an interesting concept and one that I think is good for the patient overall, particularly these bone-metastatic patients who have a heavy burden, are at risk for fractures, and certain fractures can be literally life-threatening, particularly hip fractures and others that are very debilitating to the patient.
Let's get back briefly to the selection of patients because we'll be wrapping up here in a little bit. So when you're thinking today, what type of imaging, what type of patient do you think about when selecting for Radium-223? Because I want to leave our audience with that as a important capsule of our conversation.
Daniel Heinrich: Most of our patients will, at some point of time nowadays, have had a PSMA PET, so you basically can't avoid that patients have had that kind of diagnostic tool, and that will lead to that you will be having patients which on conventional imaging, including bone scan, wouldn't have had any visceral METs and maybe not even any pathologic lymph nodes, which now will appear to have that. And keep in mind that for all those studies we have been talking about, now the selection of patients for Radium was not made by adding a PSMA PET to the diagnostic workup. So if you are seeing tiny, small lesions on PSMA PET outside of the bone, that wouldn't exclude for me any patients for Radium.
Obviously, it's important to have the bone scan included, and actually, I'm seeing in my clinical practice now that many patients do not have any bone scan on initial workup anymore, and that means we have to do that later on in the disease course when we are planning for Radium. So patients without any evidence of osteoblastic bone METS on bone scan, they obviously are deselected for Radium. Patients with growth visceral disease, deselected for Radium, but elsewise, any mCRPC patient would be basically a candidate for me.
I do not really very much select patients for Radium. I'm just trying to fit Radium in their treatment algorithm and in their individual treatment algorithm, and that could be earlier in the course .if they had docetaxel for castration-resistant disease, not really tolerating that well, and maybe the time since last docetaxel is not so long ago, and that could be later in the course if they're a more typical prostate cancer patient who goes through several lines of therapy, both before and after becoming metastatic, castration-resistant, and still, the disease keeping only in the bone.
So idea more like finding the right spot in the treatment algorithm for a single patient, for every individual patient, more than selecting or deselecting patients for or from Radium therapy based on a subpopulation.
Oliver Sartor: Thank you, Daniel. We're going to be wrapping up here in just a moment. I wonder if you might have any last words or concepts you'd like to share before we do wrap up?
Daniel Heinrich: Yeah, I really wonder if we ever will be coming to that point of our knowledge where we could have this conversation within a minute or two and say you just have to measure one, two, three biomarkers, and then you can select those patients for Radium. I'm not seeing that at the moment.
Oliver Sartor: Well, thank you for your insights. Thank you for your participation at APCCC in Lugano, and I look forward to our continued communication on Radium and many other issues as we go forward. Thanks again, Daniel.
Daniel Heinrich: Thank you so much. My pleasure.