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Alicia Morgans: Hi. I'm so excited to be here today with Professor Louise Emmett of St. Vincent's in Sydney, Australia. Thank you so much for being here with me today.

Louise Emmett: Oh, big pleasure. Thank you for asking.

Alicia Morgans: Well, it is my pleasure and such a pleasure to talk about ENZA-p. This was really an exciting study that was presented at ESMO 2023 and one that you presented again at the Prostate Cancer Foundation, so really exciting work using lutetium and enzalutamide. Can you tell me a little bit about this?

Louise Emmett: Yeah, yeah. So the whole concept of ENZA-p really came around with  TheraP. So when we did the TheraP trial, it was great, lutetium PSMA versus cabazitaxel, but like with the VISION trial, the responses are not as good as we would like them to be. It's not as durable as we would like them to be. So the question was, how can we make it better, and ways to make it better is using combinations, obviously, but combinations that are really effective in the cell together and perhaps not using it as the primary treatment, but as an adjunct or secondary treatment. So ENZA-p was about trying to do both of those things.

Alicia Morgans: Great. So tell me a little bit about which patients were involved and how you randomized those patients.

Louise Emmett: Yeah, so it's in the early metastatic castrate-resistant prostate cancer space so it's PREVAIL trial. It's patients who had on PREVAIL trial, had shown that they had quite limited responses with enzalutamide. So five-year survival, actually 24% to 5% so really short five-year survival. And so these patients, how do we randomize them, so we screen them with a PSMA PET and they needed to have minimal SUV max. We used an SUV max rather than liver cutoff, but not very strict criteria 'cause we knew we were using two agents. We did the PSMA PET and then patients had to have two risk factors for early treatment failure, and then they were randomized one-to-one to either enzalutamide or enzalutamide plus two or four doses of lutetium PSMA.

Alicia Morgans: So interesting, and you'll have to tell me why did you choose two doses or four doses? This is a really important part of the study.

Louise Emmett: Yeah, so we knew that they were going to be on a really active agent with enzalutamide, and the idea was to minimize toxicity. And what we did was we had an interim PSMA PET. So everyone got two doses and at the interim PSMA PET, we were really looking to see what was left. If there was no target left and the PSA was right down, then we didn't give the extra two doses. It's this idea of minimizing toxicity by only treating if the target is present, and then if they've got persistent target, we gave four doses.

Alicia Morgans: Wonderful. So tell me what was your primary endpoint here?

Louise Emmett: Primary endpoint was PSA progression-free survival, and then we had other progression-free survival endpoints, and then overall survival, health-related quality of life. We did a whole slew of secondary endpoints.

Alicia Morgans: And what have you reported so far?

Louise Emmett: So this is the interim analysis. We're at 75% of the primary endpoint events. 117 out of 162 patients reached the PSA PFS event, and it was a really strongly positive PSA PFS. So hazard ratio, 0.43, and 13 months for the combined arm versus 7.8 months for the enzalutamide-alone arm.

Alicia Morgans: I think I just want to really emphasize here, the enzalutamide in this setting is a standard of care. This is a highly active agent. So seeing that lutetium added on top of the enzalutamide is really, really important, particularly with that hazard ratio and especially when we're talking about a PSA PFS because enzalutamide, obviously, is acting to really stop the androgen receptor signaling and stopping the production of PSA. So this I think is really impressive and something that we should all be very, very cognizant of.

Louise Emmett: I totally agree, and that's one of the reasons why we chose PSA PFS. It was actually quite a hard endpoint for this group and it is strongly positive. Patients, there was low toxicity in the combination. It was really well tolerated. And what I think is quite interesting is when you look at the two or the four doses, the patients who had two doses really have done very well. The longevity of responses in the patients who got two doses at the moment is longer than the patients who have four doses. So I think it's a really nice proof of concept.

One of the things interesting is PREVAIL trial, obviously, most patients have moved first-line ASI into the hormone-sensitive space. And where does that leave ENZA-p? It leaves it as a very nice proof of concept in terms of combining these two agents together. They work really nicely in the cell together. There's very good rationale for using them together, and I think we should really be doing that.

Alicia Morgans: So let's talk a little bit about that rationale because I think this is one of the primary reasons that you wanted to do this work. And we do know that PSMA expression is altered by exposure to these AR signaling inhibitors. And so I wonder, could you speak a little bit to that? And then, let me know if you think that there might be clinical implications, as you said, to the combination and use of combinations in different clinical settings?

Louise Emmett: So the answer is I totally do. I think that we can extrapolate this to different clinical settings. And the idea is that you've got this androgen receptor and PSMA receptor. They're both growth receptors so PSMA working along the PI3K-Akt pathway, and we have seen that in PET studies and CTC studies, both that you get this upregulation, particularly in mCRPC, and if you get upregulation of the PSMA receptor when you're on an ASI, you actually don't do particularly well.

So I think this upregulation is an indication of androgen resistant clones or activation of alternative growth pathways. And the really nice thing of that when you combine an androgen signaling inhibitor with lutetium PSMA is that you upregulate those nastier clones and then with lutetium PSMA, in fact, knocks off the brighter cells. We know that. So if you can upregulate the nastier clones and then knock them off, you really get left with a clonal population that's more responsive, better behaved, responds to ASI for longer.

And if you put that into the hormone sensitive space, you'll have more androgen sensitive clones, but you'll still have a proportion of patient who will have androgen resistance. So it will work in the hormone sensitive space and it will work in the metastatic castrate-resistant space. It's just that in the hormone sensitive space, probably don't need as many doses of lutetium.

Alicia Morgans: I love the way that you described that. I almost imagine it as if the ARSI is sort of flushing out the clones that are hiding and causing them to really put that receptor up on the surface, so now they're visible, now they're something that can be attacked by the lutetium molecules that are coming in with that PSMA target. So really a wonderful way to think that through and certainly makes me excited to see where PSMAddition may go, particularly for those patients who have the androgen receptor antagonists as the partner there because, of course, that's going to be treating physician's choice. What's the partner for the lutetium in that situation? So really, really interesting.

Now just as we start to wrap up, just to talk about the two versus four and your thoughts on where that goes, how do we as a field take what you've found and demonstrated here among those patients who only needed two and seemed to have quite responsive disease? Where does that go in terms of trying to find the right number of cycles for patients and potentially considering, because we've limited the initial exposure, re-treatment in patients?

Louise Emmett: Totally. So I think it's ENZA-p for adaptive dosing is a proof of concept in the metastatic castrate-resistant space, but it really belongs probably in hormone sensitive space. And a PSMAddition is a really nice trial, but it's right up front, six doses. And then, these patients are going to survive quite a long time.

If you do adaptive dosing using imaging to help guide, imaging or biomarkers, so not just imaging, but PSA as well, you could give two doses in the hormone sensitive space, have complete metabolic response of your androgen resistant clones, and then wait until PSA rise before you treat again. Then you can give another two doses, then you could stop. Then you wait for PSA rise and then you can give another two doses.

So I think the potential to get really durable responses, even in those men who have risk factors for early treatment failure in the hormone sensitive space is very real, and I'd love us to try that. And that's where I think we should be doing it.

In the castrate-resistant space, I think that this adapted dosing is about intensification more than de-intensification. So if we give two doses and we find on that PSMA PET, actually, there's an increase in clonal population, there's more sites of disease, that gives us an opportunity to intensify. So I think we'll be using it many different ways. I think it's a nice concept and I think it really works with PSMA-targeted radionuclide therapy.

Alicia Morgans: I think this is really fascinating and every time I think we're solving a problem, we see additional problems, but so many exciting avenues to sort that out. And I love the idea of this dosing over time because that allows us to keep the disease control perhaps for longer and limit toxicity at the same time. And of course, the intensification strategy is so important in mCRPC. So just I guess before we end, I did promise you that we could talk about limitations, so would love to hear your thoughts there.

Louise Emmett: So obviously with the limitations, it's where it's set. It's a proof of concept. It's patients who are first-line ASI in the metastatic castrate-resistant space. And obviously, that's not a setting that we're using very much, which means that doing a phase III or expanding it the way it is at the moment is a little difficult.

Another limitation from the trial was the fact that it's overlaid. We've got a biomarker trial overlaid with a therapy trial, and it was super interesting when we were doing rPFS. So what we found was rPFS was definitely longer, but the difference wasn't as marked as it was with PSA PFS. And we had PSMA and FDG PET done at first progression in these patients. And I think that when you have a PSMA PET compared to a CT and bone scan, and you've got high volume disease progression, it's very clear to the treating clinicians. So they just took those patients straight off trial without confirming CT and bone scan disease progression. So that did impact our rPFS results, particularly in our standard of care arm.

That's a clear limitation of the trial, but I think it's also a harbinger of where we're all going. If we embed PSMA PET into prospective trials in the future, we have to be very clear about how it's used.

Alicia Morgans: Absolutely. And really, it can be very difficult because clinicians don't want to burden their patients even when we put it into the clinical trial protocol. And so hopefully, we can do better, but I am not surprised that this happened at all. And I could imagine that even if I were in that situation, there may be a patient and I will say, I will not burden this person with this additional scan. And so I understand, I think we all understand why that could happen, but hopefully, not in your future work.

So as we do wrap up now, what is your message to listeners about ENZA-p, which I think is just really such a thought-provoking trial on so many levels? What is your closing thought?

Louise Emmett: Two things. First of all, androgen-signaling inhibitors and lutetium PSMA work extremely well together, PSMA and AR, and we should use them. We should use them and we figure out how to use them and use them in clinical trials and then clinically, to the benefit of our patients. We'll get longer responses, I'm absolutely certain. And we should be very thoughtful about adaptive dosing and how we treat our patients, I think six doses, six weekly, sequential treatments, we don't need to work that way.

Alicia Morgans: Wonderful. Well, thank you so much for taking the time and really walking me through this today. And I always love to talk to you and learn from your expertise. I appreciate your time.

Louise Emmett: Thanks so much, thanks for talking.