Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We're in Chicago for ASCO 2025. I'm really happy to have on UroToday Dr. Adrien Holzgreve, who is a nuclear medicine physician at UCLA. Adrien, thanks for coming on UroToday to discuss your trial.

Adrien Holzgreve: Thanks so much, a pleasure to be here.

Zachary Klaassen: So we're going to discuss FLEX-MRT, which I'm really excited to talk to you about because it's really looking at maybe personalizing delivery of Lutetium-617. So just before we get into the trial, maybe take us through how we got to the current fixed dosing of lutetium and where that data came from.

Adrien Holzgreve: Yeah, sure. So lutetium PSMA has been approved by the FDA initially in 2022 with a quite fixed dosing schedule. So it's one dose of 7.4 gigabecquerels of lutetium PSMA, administered once every six weeks for a maximum of up to six cycles. And this follows the VISION trial, the large trial that led to the approval of lutetium PSMA in the US. And this was mostly derived from prior clinical experience, from early access programs in Germany, but also derived from other clinical trials using different radioligands, so lutetium dotatate, which was more established at that time.

But we know now actually that it seems to be safe to apply much more dose to these patients. So again, from Germany, from Australia, from different countries, we have data now that show that it seems to be safe to go well beyond the current approved doses. And that's what we try to do with the FLEX-MRT trial, but currently, it's six cycles and once every six weeks.

Zachary Klaassen: That's great. So maybe talk to us about the trial design, maybe some of the eligibility criteria for this trial.

Adrien Holzgreve: So the enrollment criteria pretty much followed the initial Pluvicto label. So we enroll patients that have metastatic castration-resistant prostate cancer, that have had prior line of chemotherapy, that have had androgen receptor pathway inhibitor before. And the patients are selected by the VISION trial criteria. And then patients are randomized one by one to either an investigational arm, so the flexible dosing schedule, which we're going to talk about later, and the control arm, which is the standard of care, so six cycles once every six weeks. And we plan to enroll 90 patients in this trial.

Zachary Klaassen: So talk about the investigation. So it's flexible by definition. So what's the assessment? How do you decide if patients are going to get more lutetium?

Adrien Holzgreve: So that's a good question. So we said before that actually it seems to be safe to apply more cycles. And so what we're doing in the FLEX-MRT trial is actually to pursue two concepts. So the one is extending the number of cycles, so we go for 12 cycles instead of the currently approved six cycles. And the other concept's idea is flexibilisation. So we know from clinical routine there are some patients that actually show exceptional response to lutetium PSMA before completion of the six cycles. So after one or two cycles, there's minimal disease left, completely or almost complete response.

So the idea is to spare those patients who already have a complete response additional potential toxicity, further trials, but to put them on a treatment break, treatment holidays, and only treat them later when the disease becomes active again. So that's what we're doing in the FLEX-MRT trial.

Zachary Klaassen: Excellent.

Adrien Holzgreve: And we use SPECT/CT and PSA to do so. So at every cycle, the patients will get a response assessment. We look at the individual patient's response. And then we take the decision either to continue treatment, to stop treatment, or to put the patient on treatment holidays.

Zachary Klaassen: That's great. So I think when we look at precision medicine, this is really taking lutetium into that next realm with this trial. I'm going to put you on the spot a little bit we just got approval pre-chemo. So is there going to be potentially an add-on or maybe a totally different trial or have to look at the pre-chemo setting?

Adrien Holzgreve: That's an excellent question. I hope there will be future trials. But now it's too late to add this to FLEX-MRT. So that would complicate the analysis. That would hamper the analysis. So we have to stick to the initial Pluvicto label. But actually, I hope to see those trials in the future.

Zachary Klaassen: It'd be great. So just tell us a little bit about the status of the trial-- when it opened, how many patients are enrolled, maybe when you anticipate enrollment being complete.

Adrien Holzgreve: So the trial's going pretty well. Of course, there have been quite some logistics to implement such a trial as an investigator-initiated trial with all this individual response assessment. It opened mid of last year, end of August last year. And we have enrolled so far one third of the expected 90 patients. We have two more patients about to be randomized next week.

Zachary Klaassen: Wonderful. Anything else we haven't hit on about the FLEX-MRT trial, any concluding statements?

Adrien Holzgreve: I think the FLEX-MRT trial is just one sign or one example to show how exciting the field currently is, how dynamic it is, and how diverse it is. So we not only have the extension of treatment, the flexibilization, but we also see much more focus on combination therapies, much higher injected doses per single application, and earlier stages, as we talked before, with the PSMAfore data, so pre-chemo stage, different radioligands, actinium, for instance. So I think it's a great time actually to be around this field.

Zachary Klaassen: It's so exciting right now, but it feels like we're in the early stages of RLT. So the next several years are going to be really exciting. This is going to add some great information in terms of the dosing schedule. So we look forward to seeing the results. And thank you for joining us on UroToday.

Adrien Holzgreve: Thanks so much.