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Oliver Sartor: Hi, I'm Dr. Oliver Sartor at ASCO 2025 with UroToday covering interesting topics in metastatic CRPC. And a special welcome to somebody who's traveled far to get here, Professor Louise Emmett from the St. Vincent's Hospital in Sydney, Australia. Welcome, Louise.

Louise Emmett: Oh, thanks so much for asking me.

Oliver Sartor: Yeah so, Louise, there's so many things we could talk about. And we could probably talk for a very long time. But on this particular segment, we're going to talk about a very provocative study that you're going to be delivering here at ASCO 2025.

And you're going to be talking about something that stretches the imagination a little bit. And that is how PSMA PET scans might be used to predict therapies and results beyond things like theranostics and lutetium 177. Is that right? Did I get it right?

Louise Emmett: Yeah it's so cool, isn't it? That we can see an expansion of the use of PSMA PET in metastatic castration resistant prostate cancer beyond assessing someone for suitability for lutetium PSMA. So that's exactly right.

Oliver Sartor: Well, this is a step out for the PET scans because everybody is stuck in the nuclear medicine department. They say, oh, let's just send them down to nuclear medicine. They'll tell us about nuclear medicine things.

But now, put someone in the nuclear medicine department, and you can tell us about things that are different, like enzalutamide, a rather important drug. So first of all, let's talk briefly about ENZA-p. We've already talked about that before. But just give a little bit of a landscape on ENZA-p. What does it mean? And then what did you do in this particular setting that enabled you to make a conclusion about enzalutamide?

Louise Emmett: Yeah, so ENZA-p is a randomized phase II trial. It's 162 patients. The patients in metastatic castration resistant prostate cancer, they received either enzalutamide or enzalutamide plus 2 or four doses of lutetium PSMA. Built into ENZA-p, or built onto the back of ENZA-p, was a large translational program, which is actually funded by the PCF Challenge Award, which we got in 2023.

And ENZA-p has serial PET scans in it and also serial ctDNA. So we can try and develop biomarkers to decide who should have enzalutamide, who should be on combination, who's going to benefit best from what. So this is one of the first things that we've done is to look at the screening PSMA PETs.

So the nice thing about the screening PSMA PETs in ENZA-p is we quantified them as we went. So we used total body quantification. We did it within 72 hours of them being enrolled in the study. It got uploaded, quantified, and the results were set then. So that's what we've analyzed in this study.

And there were two things that we want to look at, both volume of disease and intensity of disease. Because we know that intensity predicts response to lutetium PSMA 617. But we don't know whether intensity predicts enzalutamide. And we don't know what volume does with enzalutamide or, really, even with lutetium PSMA very much.

We did both those analyses. We looked at PSMA total tumor volume. And what we found is in those patients with enzalutamide alone, if you just split volume at the median, and in ENZA-p, the median was 234 mL, then the patients who had low volume, or below the median, had a 39 month overall survival. And patients who were above the median had a 20 month overall survival.

Oliver Sartor: That's almost double.

Louise Emmett: Almost double, a hazard ratio of 0.23. So very significant difference in survival in patients with high versus low volume disease on PSMA PET.

Oliver Sartor: Wow, 0.23 hazard ratio? Yeah, that's cool.

Louise Emmett: Yeah, and so then when we looked at enzalutamide plus lutetium PSMA 617, less of a difference. 28 versus 35, hazard ratio of 0.69. Not such a difference. So if we take patients who had high volume disease, 20 month survival if they were on enzalutamide alone. And then high volume disease, 28 months. So an eight month improvement in survival with the addition of lutetium PSMA, which is what we actually found in the whole study.

But then in low volume disease, 39 months survival in the enzalutamide alone, 35 months survival with the combination. So no improvement at all.

Oliver Sartor: Interesting.

Louise Emmett: Yeah, so the p test for interaction was 0.008, p-value of 0.008.

Oliver Sartor: There's the difference.

Louise Emmett: Yep, so it's predictive. So it's prognostic for overall survival with enzalutamide, a bit less with the combination. But it's also predictive for improvement in overall survival. If you have a patient with high volume disease on enzalutamide, then they will do much better if you had lutetium PSMA, so for intensification.

Oliver Sartor: I think this is very cool. And nobody's ever made this observation before. This is a totally original observation.

Louise Emmett: Totally original. No one has looked at PSMA parameters with enzalutamide. And admittedly this is enzalutamide and mCRPC. And we need to see now what it does in mHSPC. So how does it perform in mHSPC? How does it perform, say, in patients in your trial in PSMAddition. It would be super cool to look at the data screening PSMA PET in other settings now.

Oliver Sartor: However, there's more to the story because you only talked about volume so far. Now, when you talk about intensity, what did you find when you looked at the intensity, the PSMA uptake on the PET scan?

Louise Emmett: Yeah, so once again, that was a pre-specified analysis. We know that if you are in the upper quartile of SUV mean, so if you have very bright disease, you get improved overall survival with lutetium PSMA alone. But we were a little bit worried because when we designed ENZA-p, it was this idea that we would use the two treatments to treat disparate clonal populations.

And in my head, that meant that we were using the enzalutamide for low PSMA expression and the lutetium PSMA for high PSMA expression, but no evidence for that. So when we did the curves, we split quartile 1 versus-- sorry, quartile 4, so the upper quartile, compared to the lowest three quartiles because that's really what's shown evidence before.

And we found absolutely no difference in survival, no difference in survival, p value almost 0.96 between enzalutamide or enzalutamide plus lutetium PSMA. So when you add lutetium PSMA with enzalutamide, rather than having lutetium PSMA 617 on its own, SUV mean is not predictive or prognostic at all for PSA progression free survival or overall survival. So I was looking at these curves going, wow, no prediction? Nothing? Curves completely joined.

Oliver Sartor: Did that surprise you?

Louise Emmett: I thought that there would be an effect. But I thought maybe it would make it less significant, not-not significant at all. And so we went on then and did a post hoc analysis, just in the enzalutamide group, actually in the combination as well, and we said, OK, so if we look at the median SUV mean, how does it actually affect response rates?

So we looked at 90% PSA response rates. And what we found is in the enzalutamide group, if you had an SUV mean below the median, your PSA response rates or 90% response rates were about double. So it went from 27% up to 47%. So if you have bright disease, you have low PSA 90% response rates with enzalutamide. And if you have less bright disease, you have higher PSA 90% response rate.

Oliver Sartor: Well, this is a little bit cool now because now you've got a treatment for those with a high uptake and a treatment, perhaps, for the low uptake.

Louise Emmett: Yeah, so if you're looking at a patient in the clinic, and obviously, there's not a lot of patients who fit into the ENZA-p group, because this is first line enzalutamide in mCRPC. But if you have one, and they have low volume disease with low PSMA expression, they're probably going to do pretty well with enza, enzalutamide alone. If you have someone with very bright disease who have high volume disease, then I think that we know the overall survival is not going to be so good if you don't add lutetium PSMA 617.

Oliver Sartor: But I think the element here that's a bit surprising is PET now informs the use of enzalutamide, particularly in those with a lower SUV mean. That's very cool.

Louise Emmett: It is, isn't it? It's cool. It's saying, we have been underestimating the value of PSMA PET in metastatic prostate cancer. And we need to look harder. We need to look harder. And we need to look wider.

And then what about the other systemic therapies? We had a little bit of information from therapy from cabazitaxel. But what about all the other systemic therapies we're using? How does it interact with that too?

Oliver Sartor: And you haven't even mentioned the circulating tumor DNA. We'll leave that for another day. But the bottom line is now you have the ability for PSMA PET scans to serve as a biomarker for therapies beyond the lutetium and extended into the hormonal realm. And I think that is very nice. And I'd like to congratulate you on a marvelously innovative finding and a marvelously innovative study.

Louise Emmett: Thank you.