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Oliver Sartor: Hi, I'm Dr. Oliver Sartor, and I'm with UroToday here at ASCO 2025. And it's really my pleasure to be able to welcome Professor Michael Hofman. And he's head of many things at Peter Mac, down in Melbourne, Australia. But I think head of the theranostic trials group would be a great introduction. But many people already know him. So welcome, Michael.

Michael Hofman: Thank you, Oliver. Real pleasure to be here.

Oliver Sartor: What's a little bit interesting is we're going to talk about a topic that has not been talked about before at UroToday. And we cover a lot of things, but I don't think we've ever covered Terbium before. And you have a very provocative presentation on Terbium-161 in prostate cancer. What the hell is Terbium?

Michael Hofman: Well, we're lucky in nuclear medicine to have the whole periodic table to play with. And Terbium-161 it's a radio metal, which is similar to lutetium-177 that many in the audience will be familiar with, but it's got different emission properties. So like lutetium, it emits a beta. The beta travels around 1 millimeter, causes a lot of single-stranded DNA breaks.

It also emits a gamma, somewhat similar to lutetium that we can image. So we can produce post-therapy images, but additionally it emits a substance called an Auger electron. Now, which many may not be familiar with. Auger electrons sit somewhere between a beta and an alpha in terms of the energy and the path length. So the Auger's have an ultra-short path length. The highest-energy Auger is actually travel less than the diameter of a single cell, as opposed to lutetium traveling 1 millimeter, or alphas that's traveling the diameter of several hundred cells.

So conceptually, when you get down to that very last cell of lutetium-- or sorry, of prostate cancer, or there's a micrometastasis swimming around, when the lutetium travels 1 millimeter, it targets tissue outside that last cell, but it can't eradicate the last cell. But the Auger electrons traveling less than the width of a single cell is very effective at killing micrometastases.

So it's got all the benefits of lutetium plus this Auger electron, which accounts for about 30% of its emissions. So it's significant. And at least, there's a lot of preclinical data in either cellular models, dosimetry modeling, or small animal experiments suggesting that it's significantly superior to lutetium-177.

Oliver Sartor: That's very interesting because I think many of our listeners may not be aware of Terbium-161. You've explained very clearly, different emission profile from the lutetium, which is very familiar. Yes, we've got the betas, but now we have an Auger, something else to contend with.

And prostate cancer, of course, is a beautiful area to explore for radioligand therapy. Thank you for your many, many contributions to the field, including the first prospective trial with the lutetium-177 or PSMA-617. Huge ramifications from that trial.

Here we are bringing this Terbium into the setting of advanced prostate cancer. Tell me a little bit about the trial that you have designed, and we'll start with trial design, and we'll talk about some of the components. So who did you treat? How did you treat them? Did you escalate the dose? Did you have DLTs? Are you going to go higher? Are they given every six weeks, give me every two weeks? Tell us a little bit about the trial design.

Michael Hofman: Yeah. So this is a phase I/II trial. It had three levels of dose escalation starting at 4.4 gigabecquerels, then at 5.5 gigabecquerels, and then at 7.4 gigabecquerels. So similar dose to Pluvicto, lutetium-177.

So we had three patients at each dose level. And then we had an expansion cohort of 18 patients to round out the pshase II component. This was a population of men with metastatic castration-resistant disease who had progressed after an ARPI, an androgen receptor pathway inhibitor, and mostly after docetaxel. But we did not mandate it. If the medical oncologist said this patient was unsuitable for docetaxel, they were still eligible for the VIOLET study.

Around 2/3 of men had had a taxane prior, and we used PSA and FDG to select patients for treatment. And we used a similar criteria to what we had used in our therapy-randomized trial. So you needed to have an SUV max of 20 or more. So a fairly high PSMA expression and no discordant disease on the FDG-PET.

This is an investigator-initiated trial run out of PDX, funded by the Prostate Cancer Foundation through the Special Challenge Award, which funds our Center of Excellence , with an industry partner, Isotopia, that funded the provision of the Terbium-161.

OLIVER SARTOR: That's terrific. So this is a population that's some familiarity. We built with positive FDG, negative or no mismatch disease, and a little bit higher on the SUV than perhaps was used in the VISION trial. But obviously, this is a patient with a lot of unmet needs, and they're getting the treatment. How did you administer the treatment in terms of frequency? You mentioned some of the dosing, and you got up to 7.4. Was it given a weekly, three weekly, six weekly?

Michael Hofman: Every six weeks.

Oliver Sartor: OK.

Michael Hofman: Up to six cycles. So very similar to VISION or TheraP trial population. We did do post-therapy imaging, and I think, I don't have the numbers in front of me, but most patients actually got all six cycles of treatment.

Oliver Sartor: Nice. Now, one of the things that's a little bit of a question, and I need to ask this for my own information, is a gigabecquerels on the Terbium side, equivalent to a gigabecquerels on the lutetium side. Are these 7.4 the same as 7.4? Are there some differences because now you're talking about all these different types of particles that are coming out of the Terbium?

Michael Hofman: It's an excellent question, and one that we really need to understand in order to know if it's equivalent. And they're not equivalent for two reasons-- one, the beta energy that's emitted has a slightly higher energy than the lutetium. So if you don't convert, 1 gigabecquerel of lutetium or Terbium is equivalent to roughly, I think, 25%, 30% more lutetium.

So our 7.4 gigabecquerels of Terbium actually equivalent closer to maybe somewhere towards 10 gigabecquerels of lutetium. So it's not like for like, and our current dosimetry models, they don't take into account these Auger electrons either. So you're getting the Auger electron boost as well. However, most of the literature to date, in animal models and other models, have just taken like for like, gigabecquerel to gigabecquerel comparison, which is a form of simplicity, but it's a little bit more complicated than that.

Oliver Sartor: But the bottom line is the 7.4 on the Terbium is actually the moral equivalent of a little higher dose--

Michael Hofman: Correct.

Oliver Sartor: --on lutetium. Now, briefly, the ligand is-- this 617-- is at I&T. It's a PSMA-targeted. Which ligand did you use?

Michael Hofman: Yeah so the ligand we used was a PSMA-I&T.

Oliver Sartor: I&T.

Michael Hofman: This was delivered in a kit form from the commercial provider. So a little bit different than 617 or even traditional I&T in that the company has developed a kit so that the site can be delivered. The Terbium delivered the PSMA kit and then makes it up on site. Simply this provides potentially a slightly different distribution model than Pluvicto, where it's bonded centrally and then gets shipped to sites.

There may be some minor advantages of let's say, having a fresh product labeled and then given to the patient. So in part, this trial validates this commercial kit as well.

Oliver Sartor: Nice. All right. So we set up Terbium. We set up the trial design. We set up the patient selection. What did you find?

Michael Hofman: Yeah. So there were no dose-limiting toxicities. We had a very low rate of grade 3 or 4 toxicities. In fact, I think there were only two. One was a grade 3 lymphopenia, which is not really clinically significant. And one was an exacerbation of pain that was attributed to the Terbium. So really a very low incidence of G3, 4 toxicities at any dose level in the cohort, which was very pleasing.

And then all the usual toxicities that we see with lutetium. So some grade 1 thrombocytopenia, xerostomia, et cetera, but an extremely well tolerated.

Oliver Sartor: Well tolerated.

Michael Hofman: Yeah.

Oliver Sartor: And response?

Michael Hofman: And response rates, the 50% response rate was 70%.

Oliver Sartor: Nice.

Michael Hofman: And the 90% response rate was 40%. And that takes into account those six patients who had the lower-dose treatments to start with, as well the 4.4 and the 5.5. So that's for the entire cohort of 30 patients.

Oliver Sartor: I think that's really good.

Michael Hofman: Yeah.

Oliver Sartor: Are you pleased?

Michael Hofman: Oh, I'm very excited by these results because the results-- I mean, we can't really compare because this is a single-arm trial, but it's slightly better than our own therapy lutetium data with really low toxicity. And there are CTCAE toxicities, which we report. And then there's the feel you get from treating all these patients. And this really was a really well-tolerated treatment. There were just not many side effects at all.

Oliver Sartor: No DLTs. Do you intend to go to a higher administration dose?

Michael Hofman: So as a result of that 30 patient cohort, which has been reported out and accepted to Lancet Oncology. So we're going to publish the results to date. But we have commenced a 9.5 gigabecquerel cohort.

And we've treated six patients at that dose level to date. It's just fresh. We're waiting for the safety cohort for that. And then we're going to expand it out to 9 to 12 patients at this 9.5 gigabecquerel cohort, which is well over 12 or 13 gigabecquerels of lutetium equivalent. So we'll have more data to present.

But clearly, I think we all acknowledge we never quite got the dose of lutetium PSMA correct to date at 7.4 gigabecquerels. It's still probably on the low side. So we've gone a little bit higher.

Oliver Sartor: Listen, this is very provocative, very interesting. Thank you for being at UroToday here at ASCO 2025. And congratulations for doing yet another important study.

Michael Hofman: Thank you so much. Real pleasure.