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Phillip Koo: Hi, my name is Phillip Koo, and welcome back to UroToday. Today we have with us Dr. Louise Emmett, who's the head of Theranostics and Nuclear Medicine for St. Vincent's Hospital, Sydney, and also professor at the University of New South Wales.

First off, Louise, just thank you so much for the amount of amazing work you've done in the diagnostic landscape and treatment landscape, especially when it comes to PSMA.

Louise Emmett: Well, thank you. It's actually been so fun to be part of this space and we've had so many questions and to be able to put that into trials and then watch the answers come out has been an absolute privilege.

Phillip Koo: So one of the trials that you presented at ESMO last year was about ENZA-p. And for those listeners who aren't familiar with ENZA-p, I encourage you to go to UroToday and check out the interview that you recorded with Alicia Morgans that really goes over the highlights of that trial design and some of the results. So now we have ENZA-p, we've had therapy, we obviously have, at least in the US, FDA approval for lutetium-177-PSMA-617. We have PSMAfore, and then we have all these other trials, ECLIPSE, it's just, SPLASH, a lot sort of being thrown at us, help us break this down into sort of digestible pieces on how physicians should be reacting to all this data.

Louise Emmett: Well, I think first of all, when you look at perhaps VISION and TheraP to start with, so we have approval post-chemotherapy in the mCRPC space based on the VISION data. VISION was standard of care versus standard of care plus lutetium. So that was actually a kind of a messy combination trial, but it showed improved overall survival post-chemotherapy therapy. Really it was a phase two trial, but it showed that it was equivalent to cabazitaxel chemotherapy. So second line chemotherapy, but not better. And overall, survival in VISION was, what, 11.3 months with standard of care, which excluded chemotherapy versus 15. So it was okay, but it's not fantastic. So the question is, if we move it earlier, can it be better and is it better for patients? We know it's a really well-tolerated treatment. It is effective in about two thirds of the patients who actually receive it, and is it better?

And I think that's the super interesting part where we're up to now with PSMAfore, with SPLASH and with ECLIPSE. So PSMAfore has read out. We know it definitely improves progression-free survival compared to a change in ARSI, but it hasn't actually shown that it improves overall survival at this stage. And that's because of the crossover, probably because of the crossover. And that's been shown it looks like with both SPLASH and with PSMAfore. So I guess the big question now is are we going to get lutetium PSMA on its own funded pre-chemotherapy in the mCRPC setting?

And then the other question that I have is we're also doing PSMAAddition, which is using lutetium PSMA in the hormone-sensitive space in conjunction with an ARSI. And if they struggled in mCRPC, are they going to struggle more with PSMAAddition with overall survival in terms of getting approval?

So I think it's raising lots of questions at the moment in terms of what's actually going to happen. And then when you put ENZA-p into that mix, ENZA-p is saying, let's use two active agents together. Let's use lutetium PSMA with an ARSI in the metastatic castrate-resistant setting pre-chemotherapy. And we did get very deep responses and very nice PSA progression-free survival, but we need to prove overall survival for that too, and we won't get that until July of this year is when we'll be looking at overall survival. So I actually think it's a really open space at the moment in terms of where we're going.

Phillip Koo: That's a great summary, and I agree, it's a real open space and it gets tricky as we look at these trials upfront. Really using overall survival as the goal is tricky, and crossover I think is great for patients. It's something that we actually need to do. But is it reasonable to expect an overall survival benefit given the confounding factors? What are your thoughts on that?

Louise Emmett: Look, I think one of the things that we do know is that it's much better tolerated than chemotherapy, but at the moment, a lot of the trials that have been done are second-line ARSI. So personally, I think we should be able to prove an overall survival benefit compared to second-line ARSI. I do think that it should be used for that. At the same time, in my patients, I really want to use it pre-chemotherapy. It's so well tolerated in that 2/3 of men, you actually get good responses. Some of the patients have really, really long responses and the patients feel really well.

There's something in Australia, it's quite weird. Men are obsessed with mowing their lawns, and you get these patients who come in pretty sick and they come in after the first or second dose, and they're excited because they have the energy to go out and mow their lawns again. You don't get that with chemo. You get that with lutetium PSMA-617. And I really like that. I think that's a treatment we should be trying to move earlier. But I do think overall survival is an important thing.

Phillip Koo: So one of the interesting pieces of ENZA-p is you had this adaptive dosing of lutetium-177 PSMA. And all these other trials tend to use sort of standard dosing, four, six doses. Where do you see the future moving with regards to dosing of lutetium?

Louise Emmett: I really hope that adaptive dosing is adopted more generally, both in trials and clinically. I think it's different to chemotherapy. Theranostics is something you can see. You can see the target and you can track the target based on the images that we get from the therapy itself, either using PET or SPECT. So it's a treatment that lends itself to adaptive dosing.

The other thing about adaptive dosing is say in PSMAfore or in SPLASH it was six doses, six weekly, fairly early in mCRPC. A significant proportion of those patients would've got down to no target. And so maybe two doses were effective, but four doses later they would've excreted most of that drug out. Can we be more effective and improve overall survival with adaptive dosing by treating when we've got the target, waiting when we don't have the target and then retreating again? I really think we can. I think it's a great way to improve toxicity, and I think it's the answer to moving this earlier in the space. I think it doesn't just reduce toxicity; it will also prolong survival in my opinion. And I think we need to be testing that.

Phillip Koo: You know, I agree with you 1000%. It's really a lost opportunity for us to not take all that information post-therapy with the PSMA diagnostics and really be a little bit more elegant with our approach. And I agree. I think overall survival is definitely a possibility and allows us to save radiation exposure potentially for retreatments in the future as well.

Louise Emmett: Yeah, I agree.

Phillip Koo: So talking about retreatments and other types of radiopharmaceutical therapies. I know you're working on trials looking at actinium. So can you give us your perspective on these other radiopharmaceuticals and where we're headed as a field?

Louise Emmett: Yeah. I mean, it's massive at the moment, isn't it? I think we now have lead-212, there's copper-67 in the mix. We've got lutetium-177, and how do we use all of these things? I think the thing with actinium is it's shown to be effective. We had the Lancet oncology paper come out, but looking at that paper, it's not more effective, I don't think, than lutetium at this stage in an all-comers group. So how can we use it?

It's definitely been shown post-lutetium to allow extra response or longer time of response in patients. One of the problems I have with actinium, and in my use with actinium, is that it has significant toxicity compared to lutetium. I don't get patients coming in much with actinium saying, "I can mow the lawn again." There's a higher burden of fatigue, and there definitely is the issue at the moment with the toxicity from xerostomia, from the dry mouth.

So for me, if I was a patient and I had a choice between lutetium and actinium, for me, 100% of the time at this stage, I would choose lutetium, because of the toxicity profile. The fact that about a third of patients really have very, very good responses.
Then if I was maybe one of those a third who actually don't respond very well at all, I'd definitely be considering actinium. So to me, that seems to be the way it's looking at the moment. Of course, there's the holy grail. Are we going to get an alpha that doesn't have significant xerostomia? That's what we're all looking for at the moment, really, isn't it? But at the moment, I think it's sequencing. If you're not responding to lutetium, can you use actinium in that space?

Phillip Koo: That's interesting. The sequencing is always sort of a big challenge whether we're dealing with radiopharmaceuticals, ARSIs, all these different types of therapies. So it's exciting to know there's a lot of work being done in this space, and I agree, it gives a lot of hope to what the future might hold.

So it's interesting. Nuclear medicine, clearly, it's a much more patient-facing specialty than the way it was 5, 10 years ago. What recommendations do you have for the practicing medical oncologist or urologist out there on when to sort of consult a nuclear medicine physician or discuss a case with them as they journey and progress through the different phases of prostate cancer?

Louise Emmett: So I think, first of all, in our patients, we don't want it to be a last resort. We know that taking patients with very high volume disease who are entering marrow failure, trying to pull them back from the brink is much, much harder with lutetium or with any agent than it is if we send them earlier. So I found that when we were first starting, and we have a great relationship with our oncologists, we worked very, very closely with them as a team to manage these patients. But when we were first starting, we got patients very late, the volume was very high always, and it was harder for us to get a treatment response. Now, they're sending them earlier, much earlier, and I really appreciate that. I think that looking after patient interests, making sure that you're trying to get the best response for the patient rather than keeping them on a drug that you know is good.

The other thing that I think is, the more that oncologists interact with nuclear medicine physicians, we can figure out whether any marrow compromise that's happening in a patient is actually from the lutetium or whether it's from progressive disease. And this is a conversation I have a lot with oncologists: oh, we're worried about the toxicity from marrow. If we use theranostic practices like imaging the patients after they've had the lutetium, we can actually see disease progression, which may not actually be PSA producing. It might be a PSMA positive, PSA negative clone, but we get that double biomarker effect.

So I would say to oncologists, work really closely with your theranostic specialists. Send the patients early and use every biomarker you can to try and figure out what's happening with that patient. Because we don't see a lot of marrow failure from lutetium that's not due to progressive disease. We see grade one, grade two, maybe anemia, but the severe anemia is, in my opinion, most of the time due to progressive disease, it's not picked up on conventional imaging.

Phillip Koo: Okay. I think those are some great closing remarks. Engage with your theranostic specialist early, and I think in the end, the patients will benefit just because so much is here in this space and there are so many contributions that people like yourself can make to those management decisions.

So thank you so much for your time and your expertise. It's been a wonderful conversation and we look forward to hearing more of the great work that you're doing down there in Australia.

Louise Emmett: Thanks. Thanks so much for asking me.

Phillip Koo: Great.