Andrea Miyahira: Hi, I'm Andrea Miyahira at the Prostate Cancer Foundation. Joining me from ASCO 2025 today is Dr. Louise Emmett, a nuclear medicine physician at St Vincent's and University of New South Wales in Australia. Doctor Emmett, thanks for joining us.

Louise Emmett: Thank you. It's such a pleasure to be here.

Andrea Miyahira: So at ASCO here you presented data from ENZA-p where you looked at using PSMA PET as a biomarker to choose between lutetium alone or with the addition of enzalutamide. So can you tell us about that?

Louise Emmett: Yeah. Absolutely love to talk about the paper that we presented that's also coming out in press in Lancet Oncology. And it's really about the predictive and prognostic value of PSMA PET-- screening PSMA PET within the ENZA-p trial cohort.

So ENZA-p is a randomized phase 2 trial of enzalutamide and enzalutamide plus lutetium PSMA-617. And what we were interested in was PSMA PET can essentially be a one-stop shop in terms of looking at the volume of disease and also the phenotype or the characteristics of that disease.

And so for this study, what we did was we quantified all the screening PETs and all the patients who came into the 162 patients. And then we looked to see whether the quantitative total tumor volume and also the intensity on the scans, the SUV mean, had any prognostic or predictive value. And what we found was that PSMA PET total tumor volume is really highly predictive of survival outcome, particularly for the enzalutamide group.

So in the enzalutamide group, if you just take the median volume of disease in each patient, which was 234 mL, if you were above the median in volume, you had a 20 month overall survival, and if you were below the median, you had a 39 month survival. So almost double the survival with low volume versus high volume disease on PSMA PET. And then when we took that and looked at the enzalutamide plus lutetium PSMA group, it was much closer. So it was 28 versus 35 months for high versus low volume disease. So it looks like PSMA PET total tumor volume is very predictive. So it is very prognostic for overall survival, but it's also predictive for the benefit of adding lutetium to enzalutamide in overall survival.

Andrea Miyahira: OK. Thank you. And how would you compare using PSMA PET for enzalutamide plus lutetium versus enzalutamide versus lutetium alone?

Louise Emmett: So that's a super interesting question. There was another part of the analysis that we did, which is looking at SUV mean. So SUV mean is the mean how bright everything is in all the tumor deposits. And we know from previous data from the TheraP trial and from VISION trial, which is lutetium PSMA monotherapy, that SUV mean in the upper quartile, it's really predictive for outcome. Those patients do exceptionally well.

So we had some concerns before we did this analysis. And in our analysis plan, the hypothesis was that it would not be so significant with enzalutamide plus lutetium PSMA because we know that enzalutamide probably actually treats the lower PSMA expressing cells. And that's exactly what we found. While SUV mean is highly predictive for lutetium PSMA monotherapy, with lutetium plus enzalutamide is not predictive at all. So it's absolute lack of prediction was a surprise. I thought it would have some predictive capability, but it really didn't. It was absolutely joined.

And so what we then went on and did, we did a post hoc analysis to see what was going on with the responses in those patients who were treated with enzalutamide alone. And what we found was in those patients who were treated just with the hormone therapy with enzalutamide, the PSA 90% response rates if they had low SUV mean, were twice that of patients who had high SUV mean.

So it really corroborates this idea that enzalutamide responds-- or low PSMA expression cells are much more sensitive to hormones, high PSMA expressing cells are much more sensitive to PSMA targeted agents. And then if you put the two together, SUV mean is not significant. So in our study volume was very important. And intensity SUV mean, when you use enzalutamide and lutetium PSMA together, not important at all.

Andrea Miyahira: So going forward, how would you advise clinicians to use PSMA PET to select treatments?

Louise Emmett: I think this data is fantastic. When you look at the enzalutamide alone, 20 versus 39 months overall survival, that's a massive difference in survival for high volume versus low volume. This is really the first time that we've shown that PSMA total tumor volume has this power in a treatment that's not radionuclide therapy. So what I would say is we need to be looking very closely in the hormone-sensitive space and across ARPIs (Androgen Receptor Pathway Inhibitor) to see whether this very powerful prognostic capability of PSMA PET is there earlier and in other ARPIs. And if it isn't, it looks like a fantastic tool in terms of deciding whether someone needs intensification or doesn't need intensification.

I had a patient come and see me last week who had a PSMA PET scan, had failed in ARPI and was considering going on ARPI or whether they should have intensification. That patient had volume of disease above 200 mL, and it was a very intense disease. And based on this data, I would say you must or you should intensify with the addition of lutetium, going on enzalutamide alone, we know your survival will be half.

Andrea Miyahira: And tell us about PSMA PET quantitation and availability and how everyone can start to use this in the clinic.

Louise Emmett: Yeah, it's a really frustrating time because we've got all this data showing that SUV mean, which is quantitation is great at predicting response to lutetium PSMA monotherapy. We've shown that PSMA total tumor volume has really powerful prognostic capability and predictive capability for enzalutamide, but it's not available regularly. We don't have it in the clinic, and it takes a bit of work from the radiologist or the nuclear medicine physician to actually get a total tumor volume. What we really need is automated programs that can do it for the clinician, so they just have volume up on their screen, and they can incorporate that into their report.

We're getting closer. So there's an abstract at ASCO 2025 that shows that a fully automated version in which a human has not touched the analysis is highly predictive of progression-free and overall survival for lutetium therapy. And that spits out a total tumor volume and an SUV mean, that can be incorporated into reports. So I think we're really close. We just need people asking for it. We need companies providing it. It needs to be available for the clinicians.

Andrea Miyahira: OK. Well, that's a really important message to share and such wonderful data. Thank you for joining us today.

Louise Emmett: It was a pleasure. Thank you.