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Oliver Sartor: Hi, I am Dr. Oliver Sartor. I'm with UroToday, and it's truly a pleasure to be able to welcome Øyvind Bruland. I'm going to give a short introduction to Øyvind and then ask him to augment that a little bit. Øyvind is a remarkable serial entrepreneur. Perhaps you have heard of a company called Algeta that developed radium-223. Perhaps you've heard of a company called ARTBIO—Øyvind was one of the co-founders—and perhaps you've heard of a company called Oncoinvent, which Øyvind also was a co-founder. Øyvind is an emeritus professor at the University of Oslo and a sarcoma specialist, and I'll simply say, welcome, Øyvind. Really a pleasure to have you here today.

Øyvind Bruland: Thank you so much. Thank you. It's a pleasure.

Oliver Sartor: Now, is there anything that you'd like to add to that brief introduction? Is that covered?

Øyvind Bruland: I think it's just two things. I think for the American audience, we have the clinical specialty called clinical oncology, and that embraces both medical oncology and radiation oncology. So I'm not a nuclear medicine physician; I'm a clinical oncologist. And this entrepreneurship has been made possible by the good friend and colleague Roy Larsen, who is the gifted nuclear chemist. So we have been a kind of yin-yang couple working with this for some decades.

Oliver Sartor: Yes, and thank you for mentioning Roy. He's a remarkable individual and a true brainiac. He's one of the smartest guys I think I've ever met.

Oliver Sartor: I'm going to start off with something very broad. Øyvind, you've been in this field for a long time, but why radiopharmaceuticals? Why did this radiopharmaceutical field capture your interest in the first place?

Øyvind Bruland: Well, of course, coming from chemotherapy, treating metastatic disease, coming from radiation oncology, giving localized external beam palliative treatment to a single or a few skeletal metastases, I wanted to dive into something that could have a systemic effect on the multiplicity of the widespread metastases—for instance, in the bone, which is the problem for most patients, including the castration-resistant prostate cancer patients. So something that could target many metastases following, for instance, an intravenous injection, not by a machine from outside in. We want something from inside out.

Oliver Sartor: Well, and the truth is you were thinking about things like alpha particles before people were even aware of what an alpha particle might be. I'd like to give a little bit of a shout-out because the very first alpha emitter approved in all of medicine was part of Øyvind and Roy putting together Algeta—that's radium-223. And really, I think that Øyvind is the father of radium-223, along with Roy Larsen, and was thinking about alpha particles many years ago.

Now, let's briefly talk about isotopes, and you are a true expert in this area. I'd like to hear a little bit about your thinking about what particular isotopes are intriguing to you and how you see this isotopic field evolving.

Øyvind Bruland: Well, as you yourself have experience with Quadramet, samarium-153, which is a very nice beta emitter, we were intrigued by the clinical challenge because most of our patients, they have chemotherapy-resistant disease. I come from osteogenic sarcoma, and the young patients will lose to metastatic disease. They have failed a super toxic combination chemotherapy. So we wanted something radiobiologically that could really kick and kill chemo-resistant disease, and that's how we went into alpha emitters.

The first one was astatine-211. We played around for a few years trying to couple that to monoclonal antibodies—a lot of challenges with cyclotron production, problems with specific activity, etc. So that brought us from antibodies into bone seekers, which we can discuss more. And Xofigo was the first and still is the only approved alpha radiopharmaceutical. We actually called it Alpharadin, not Xofigo—alpha particles from radium for injection. So what's in a name? I think that's a good name. But Bayer wanted another name, and they re-baptized it to Xofigo.

Oliver Sartor: Well, thank you. And you were thinking about alpha particles long before they were in vogue. Now, currently you're with a little company called Oncoinvent, and yes, you're involved with ARTBIO, but we're not going to really discuss ARTBIO today. But tell us a little bit about Oncoinvent and the use of alpha particles there.

Øyvind Bruland: Yeah, it's kind of a partly shared history because, with Xofigo, we wanted to combat the disease in the big organ—the skeleton. In Oncoinvent, we wanted to combat disease in the peritoneal cavity because peritoneal carcinomatosis is a big problem in colorectal cancer, gastric cancer, some mesotheliomas in the abdomen, and other cancers as well. And the beauty here is that the standard treatment in selected patients is so-called CRS HIPEC—cytoreductive surgery, removing all visible disease during laparotomy and then adding on, at the operation theater, the hyperthermic circulating chemotherapy, usually mitomycin C or oxaliplatin. But still, patients fail in the abdominal cavity, and we think that is due to the fact that there are remaining free-floating cells and microclusters, things we cannot see.

Once again, like when I met you the first time, we came from the Metastron, Quadramet beta field in bone seekers, and here in the peritoneal carcinomatosis, there is decades of experience with phosphorus-32, which is a very highly energetic beta emitter. And that showed actually antitumor effect, but for the patients living long, the track length of the beta particle harmed the small intestine. So the longer-living patients faced serious fistulae, adhesions, gastrointestinal complications, and re-surgery. So it was abandoned.

So we thought that, once again, alpha particles. And this time it is radium-224, a slightly shorter half-life—not the 11.3-day 223, but it's a 3.6-day half-life—and it's coupled to biodegradable microparticles. So we inject it two days after successful CRS HIPEC and in a big volume so it floats around the entire abdominal cavity where there are no macroscopic tumor deposits left, but there are microscopic deposits. And we hope that that will fit with the radiobiology of alpha emitters.

Oliver Sartor: Now, you have some preliminary data. I don't know if you're able to discuss it today. I don't want to bring up any confidential information.

Øyvind Bruland: Because it's published. It's actually now starting a randomized Phase II, both in ovarian cancer and a little later in colorectal cancer. We have completed this classical 3+3 designed dose escalation. In colorectal, we have published the 30-day safety, which is the Radspherin—we call it Radspherin, radium spheres. That's Radspherin. The names are invented by Roy and myself without any consultancies paid. So it's just a name: Radspherin.

We have also now a manuscript which is accepted and will appear soon in the Journal of Surgical Oncology on the 18-month follow-up. That has been also published at ASCO, one-year follow-up, and there is a super strong signal of therapeutic efficacy at the recommended dose of seven megabecquerels. But the number of patients in that dose escalation with the expansion cohort is only 12 patients at the recommended dose, but with 18 months. And we haven't seen a single peritoneal recurrence at the recommended dose. But as you know, Oliver, colorectal cancer, they can also face later liver, lymph node, lung metastases. So the disease-free survival is not clean, but the peritoneal recurrence-free survival is too good to be true. And we have now more trials going on, having recruited 24 more patients in Uppsala and Oslo. But these patients are in follow-up.

Oliver Sartor: Quite interesting. I could actually see a huge utility within the ovarian cancer space because that is a disease where the peritoneal metastases are so common, so problematic, and often you do not have systemic spread with ovarian cancer. So really going to be looking forward to this. It's not quite in the prostate space where you and I have spent a lot of time in the past, but as usual for Øyvind, you're breaking new boundaries and blazing new paths.

Øyvind Bruland: The Phase I dose escalation is the same. It has been completed in ovarian cancer, but the data has not been published, but it's underway to be published.

Oliver Sartor: Terrific. Now, one of the things that's a little bit interesting is that combinations between the radiopharmaceuticals and various other systemic therapies are now becoming somewhat vogue. People have talked about chemotherapy combinations, immunotherapy combinations, even alpha-beta combinations, radiosensitizers. I wonder if you might have any comment about combination therapy with some of your current alpha-emitting particles that you're exploring in the clinic?

Øyvind Bruland: Yeah, well, maybe a step back to the Xofigo. I'm quite intrigued, and I'm really looking forward to the mature AlphaBet trial from Australia where they combine beta-emitting lutetium-177 PSMA with Xofigo—a scheduled treatment. Because I think the two of us, we agree that there is a target heterogeneity, not only for PSMA but also for the osteoblastic stroma where radium really targets. So that may, in too many patients, be too heterogeneous, or there will be cold pockets within the metastases that are not really getting high enough radiation dose from a bone seeker alone. So I'm really intrigued to see the results from this AlphaBet trial.

The other thing is this alpha-emitting radioligand therapy and immunotherapy. There is a lot of papers preclinically on making a cold tumor hot, maybe speeding up like an internal vaccination or an abscopal effect. The literature is vast, as you know, but to my knowledge, there is very sparse experience clinically so far, isn't that correct?

Oliver Sartor: Correct. Interesting.

Øyvind Bruland: But I think it's a promising approach.

Oliver Sartor: So alpha-beta combos, immunotherapy combos, and of course more. We're not going to be talking about an intriguing trial that'll be presented at ESMO this year by Silke Gillessen. That's the PEACE-3 trial with the combination of enzalutamide and the radium-223. Now, I won't go to that spot because we're going to have a later discussion with Silke Gillessen, and she'll have a presidential presentation at ESMO on that combination therapy.

Øyvind Bruland: Just 10 days from now, isn't it? Quite soon—10 days, 15 days.

Oliver Sartor: Yeah, about 10 days. I forget exactly, but it'll be not this weekend, but the weekend after next. So coming up quite soon.

Øyvind Bruland: That will be exciting.

Oliver Sartor: Now, I'd like to ask you a difficult question, a relatively succinct response. The question is, looking into your crystal ball into the future over the next five years, what do you think we will have accomplished with the radiopharmaceuticals that we don't know about today? What are the future aspects of radiopharmaceuticals that will develop over the next five years that you see in your crystal ball?

Øyvind Bruland: Well, of course, back to combos. Nearly all successful oncological therapies, including chemo, have been combo treatments—different drugs, different modes of action. So I think the future lies in combos. You will never kill everything with just one drug, one radiopharmaceutical. Maybe I'm wrong, but I think that is the case.

I think that I've discussed this with Roy Larsen for hours and weeks and months because I think that with all these recent big pharma acquisitions in the radioligand therapy, it's a super hot area, and I think the alpha space is among the hottest, even if we have some supply challenges with actinium, and there are not that many effector moieties. The payload alpha is not that easy to produce and sending—it's related to half-life.

But I'm a little worried. I think that there is always a hype and hope dimension. I think that too many of these startups, they look into their crystal ball, which is the metabolic pathways of cancer, and they are embracing this fascinating thing called theranostics. But I think that usually they rely on a PET scan, which is usually obtained just a few hours after injection. When it comes to radionuclide therapy, it's the area under the curve, compatible with the physical half-life of the radionuclide, the biological on-off rate. It's much more complicated. So I think you can be blurred by thinking that the PET image shows the whole picture.

I think that to have a decent radiation dose deposition in a targeted metastasis, you need to have the complete picture of area under the curve, the timeline, three half-lives of decay at the tumor site. So I think that there will be some people that we know that from the neuroendocrine space where the shift from beta to alphas seemingly is super promising. But when it comes to all the other more common cancers, I'm not sure if the path forward is that easy. I think there will be some success, but there will definitely be some failures.

Oliver Sartor: Well, absolutely. Now, we're going to be wrapping up here in just a moment, Øyvind, but I wonder if there might be any final thoughts or comments that you would like to leave with our audience?

Øyvind Bruland: Well, back to this PEACE-3 stuff coming with this use of bone protector. That's a secret. It will be released in a week or two. But I think that Xofigo is definitely not doing the job as well as we wanted it to do. I mean, you get a strong alkaline phosphatase decline. In the randomized Phase II, you remember we had even PSA response, but patients were selected differently. So I think that a better understanding of the target—the stroma when it comes to bone seeker—and maybe to manipulate the stroma with a bisphosphonate or a denosumab or something, or a chemotherapy, even a hormonal therapy, which is your field, Oliver. I mean, you have this flare response. A responding tumor usually gets more osteoblastic. And in my ivory tower, I don't think that that has been fully studied and fully understood. So I think there is a potential to have a higher percentage of your injected Xofigo reaching and staying at the target. But that's just a speculation.

Oliver Sartor: No, it's a fascinating topic. Øyvind, you and I had published a paper about a decade ago on stromal manipulation, which I think is still relevant. Well, listen, a real pleasure today to have Øyvind Bruland join us as a guest on UroToday. Thank you for your insights, Øyvind, thank you for your commentary, and thank you for your many contributions to the field.

Øyvind Bruland: Thank you, Oliver, and thanks for the collaboration with you and the other clinicians.