Read the Full Video Transcript

Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday. I'm at ASCO GU 2025. And I believe we have the star of the show, Professor Louise Emmett from St. Vincent's Hospital, in beautiful Sydney, Australia joining us today.

Louise Emmett: Thank you very much for having me.

Oliver Sartor: Louise had an amazing presentation on a trial that she had previously reported called ENZA-p. But before we get to those results, Louise, let's talk about ENZA-p. Why did you conceive the trial in the first place? What was your rationale, before we get to what you found?

Louise Emmett: Yeah. So my rationale really was I'm a nuclear medicine physician and I read PSMA- PET scans. And I also treat patients. And, it's really fascinating watching this biology as you do scan, after scan, after scan in different states of the disease and what the expression does over time and what it does within ARPI. And we had done some previous work where we had done serial PETs on patients, and we saw that there was a really big difference between the hormone sensitive and the castrate resistant state in terms of what the PSMA receptor did, and it seemed to upregulate and get brighter in the castrate resistant state and starting in RP rather than in the hormone sensitive.

That really started this idea as to whether you could value add lutetium PSMA with an RP. And then of course, an RP it's very effective as well. So whether you get a one plus one equals four, with RP plus lutetium PSMA in the metastatic castration resistant space. That was the start of the driver, really.

Oliver Sartor: Got it. Looking at scans, looking to the biology, seeing the evolution of the disease and saying, hey, I can hit that target better.

Louise Emmett: We can do better.

Oliver Sartor: Cool. ENZA-p was a phase II.

Louise Emmett: Yes.

Oliver Sartor: Let's talk a little bit about the design of the trial, endpoints of the trial--

Louise Emmett: Yep.

Oliver Sartor: --before we get to the results.

Louise Emmett: Yep. So ENZA-p was a phase II. We placed it in the mCRPC space in patients who had not yet had first-line enzalutamide. Patients needed to have risk factors for early treatment failure on enzalutamide. They need two risk factors. And they need to have a positive PSMA PET scan.

Oliver Sartor: Let's talk about those risk factors. So PREVAIL--

Louise Emmett: Yeah.

Oliver Sartor: --did a really nice job--

Louise Emmett: They did.

Oliver Sartor: --and had like a 20 month RPFS, which was outstanding. But you didn't take the PREVAIL population. You moved it around a little bit. How did you move it around?

Louise Emmett: I did move it around. At the time that we were doing this, it was very much the idea that PREVAIL had had such a good outcome-- I didn't really want to value add to those patients who did well. I wanted to try and see if we could take the poor players and make them do as well as the good players. And it's about 40% of patients on PREVAIL who have either primary treatment resistance or early treatment failure.

And in fact, they published a fantastic five year outcome paper that delineated the risk factors that predicted who was going to do well or not. And they had a low, intermediate, and high risk group. So what we really did was we took the middle. We said you had to have two risk factors, and that those kind of risk factors were three years since diagnosis, metastatic disease at diagnosis, prior docetaxel for hormone sensitive disease, whether the LDH and the ALP was above normal, whether they were required opiates for pain.

All of these prognostic risk factors, which are obviously prognostic not just for enzalutamide, but for any treatment, and that's patient population we chose. Because we wanted to see really the premise of the trial. It's a phase II. And it was to see whether we could improve outcomes in patients who we knew weren't going to do particularly well.

Oliver Sartor: Primary endpoint in the trial.

Louise Emmett: Yeah. So it was PSA progression-free survival was the primary endpoint. That was deliberate. We wanted to look for an effect and not to change practice with this trial. it was a phase II We weren't planning to change practice.

And then we had a whole slew of secondary endpoints. But the PSA, PFS I chose-- actually, I'm a nuclear medicine physician, and like it seems all nuclear medicine physicians, we don't like bone scans. So the idea of basing an endpoint on a bone scan, which I know has so little sensitivity and specificity, to me, was anathema. So I did what probably was not conventional and chose PSA, PFS instead.

Oliver Sartor: I mean, perfectly fine because you have the OS backup. So before we get to the OS, let's talk about your publication, which people may or may not be familiar with, in Lancet Oncology. They covered the initial aspect of the trial. So tell us what you initially published, and then tell us what you updated here.

Louise Emmett: Yeah. So we did an interim analysis at the first 115 events, which was published in Lancet Oncology, and that looked at PSA progression-free survival, the primary endpoint. And it also looked at depth of response, as well as radiographic progression free survival.

So PSA progression-free survival was clearly different in that interim analysis. It was a hazard ratio of 0.43 in favor of the combination, and it was 7.8 months versus 13 months difference in PSA progression-free survival. And then depth of response was-- I still think it's really quite startling. So 50% PSA response if you take it in a non intention to treat.
So if you just look at everyone who actually received treatment, PSA 50% response was 95% for the combination arm versus 68% for enzalutamide alone. And then 90% response rate was 80% for the combination versus 37% for enzalutamide alone. So really, really deep responses.

Oliver Sartor: I am raising my eyebrows because when I first saw those waterfall plots, it was like, this stuff is working. I mean, it was a really powerful signal. Because that sort of depth of the PSA response, to me, was actually a little startling. So when I first looked at that data, it was just like, wow, that's actually pretty cool.
Louise Emmett: And then we had the kicker, which was RPFS. So that was so interesting.

Oliver Sartor: Well, I had some mistrust of your RPFS.

Louise Emmett: Everyone did.

Oliver Sartor: Yeah--

Louise Emmett: It's not going to last.

Oliver Sartor: No, I mean, look, there's a little bit of Australian nuclear medicine in--

Louise Emmett: Oh no, actually--

No, no, no, no, no, no. So the thing about our RPFS was because we were too ambitious, right-- so what we did was we embedded PSMA PET. And one of the PSMA PETs that we embedded was a PSMA PET at first PSA rise or radiographic progression, where 95% of patients it was PSA rise, confirmed PSA rise.

So our investigators saw those PSMA PETS-- actually, I have to say, including myself-- were a bit horrified at the volume of disease that was persistent in the enzalutamide alone population. And we took a PSMA PET that wasn't on trial for anything but for translational purposes and we all used it clinically, and we took our patients off trial.

Oliver Sartor: Mhm.

Louise Emmett: And then, we put them onto other treatments. And obviously, they had--

Oliver Sartor: Couldn't crossover.

Louise Emmett: --clinical progression. You couldn't crossover. We didn't have crossover. Well, actually we did have crossover. I'll go to that in a minute.

So what happened was we ended up with a lot of patients in our RPFS who were censored. More than half the patients at that interim analysis on the enzalutamide alone arm had been censored because they hadn't had confirmation of progression on their CT and bone scan, and we had a hazard ratio of 0.67. What's super interesting is in the subsequent publication that dropped to 0.61 and the curves uncrossed because our radiographic progression free survival was exactly the same as yours, Oliver, in all your other trials, which is radiographic progression or death. So it took death in that radiographic progression--

Oliver Sartor: To drive the events.

Louise Emmett: --to drive the events.

That's what drove it down. It was death. So yes, our RPFS nothing to do with being a nuclear medicine physician, but definitely was because we added the PSMA PET.

Oliver Sartor: Let me create a hierarchy in my own mind about important endpoints.

Louise Emmett: Yeah.

Oliver Sartor: There's one at the top. It's called overall survival.

Louise Emmett: It is.

Oliver Sartor: And then, there's everything else, which is less important. And here, at ASCO GU, you get a beautiful oral. Tell us about that OS endpoint and what else you presented here at ASCO GU 2025.

Louise Emmett: Yeah, I think what we found with the OS was important. So the overall survival between the two arms was very different. We had a hazard ratio of 0.549 with a P value of 0.0053 for overall survival. And with the enzalutamide alone arm, 26 months compared to 34 months for enzalutamide plus lutetium PSMA.

When we come to crossover, what's interesting is-- in fact, what we had at first progression-- we did the PSMA PET. A lot of investigators got quite horrified. And then people who had lutetium PSMA available for their patients took their patients off trial and crossed them over. So we had 38% of patients went on to receive lutetium PSMA subsequently on coming off trial with the ENZA-p trial.

So we did have some crossover. Wasn't built into the trial, but definitely happened. And what's interesting is that we had an eight month overall survival benefit, despite the fact that 38% of patients actually received that treatment off trial.

Oliver Sartor: I'm just going to remember 0.549 and give you a little pause because it's amazing. That's the best ever reported for mCRPC, best in history. Congratulations.

Louise Emmett: Thank you. And I really hope that we can take learnings from this, find out why it's 0.549, why the overall survival benefit is so significant. And then expand that to other spaces in prostate cancer.

Oliver Sartor: Absolutely. You not only reported on the OS, you also had some quality of life parameters that were really intriguing.

Louise Emmett: Yeah.

Oliver Sartor: Let's cover those briefly as well.

Louise Emmett: Yeah. So we looked at two things. We looked at deterioration-free survival, which is a composite score of physical activity and also overall health and quality of life compared to other progression parameters. That was in a Kaplan-Meier curve, and we looked at a quality of life, standard quality of life, using repeated measures using the QRC30 patient information questionnaire.

And there were no quality of life parameters that were better with the enzalutamide alone arm than they were with enzalutamide plus lutetium PSMA. But the overall health quality of life and physical activity really significantly in favor of the combination.

Oliver Sartor: So this is pretty cool. We intensify the therapy and improve quality of life too--

Louise Emmett: Exactly.

Oliver Sartor: --as well as prolong survival.

Louise Emmett: That was so cool. More than that, you take a side effect that is common to both. So fatigue is common with enzalutamide. We had enzalutamide on both arms. And we added lutetium, which also causes fatigue. And then we got a reduction at every single time point in the trial in fatigue in the patients on the combination treatment compared to monotherapy.

Oliver Sartor: Patients whose cancers were getting better.

Louise Emmett: Exactly. So if you have no cancer, you feel cool. You feel good, right? I think that's really it.

Oliver Sartor: Very, very nice. Now, there must be some sort of adverse events. Let's talk about adverse events. Let's be conscious that there could be downsides.

Louise Emmett: Definitely adverse events. So we had more adverse events.

Oliver Sartor: Let's hear about them.

Louise Emmett: So we had 46% adverse events compared to 44% adverse events with enzalutamide alone. And I will caveat that because we didn't do treatment emergent adverse events on this trial. So this is a phase II investigator-initiated trial. So it was all adverse events. And patients who were on enzalutamide alone, they were on trial measuring adverse events for 7.8 months, compared to the combination, who were measuring adverse events for 13 months.

But we also had adverse events of interest. So they were the adverse events that felt that would be relatable to treatments on the trial. And when we look at those, the grade 3 adverse events between the two arms was 10% and 4%.

Oliver Sartor: I'm sorry, which one was 10%?

Louise Emmett: 10% for the lutetium PSMA plus enzalutamide and 4% for the enzalutamide alone. So we did have more hematologic adverse events grade 3 with the lutetium plus enzalutamide than we did enzalutamide alone. There was a 4% grade 3 anemia with no grade 4 or 5. And there was 1% grade 3 thrombocytopenia with no grade 4 or 5.
So that is half of the extra events that we got. I think we got one patient with arthritis, one patient with muscle pain. So very, very few grade 3 events and no grade 4 or 5 events that were attributing the adverse events of interest felt to be related to treatment at all.

Oliver Sartor: This is actually remarkable. I mean, it is. It is amazingly good results. And first of all, hats off to you. But I want to ask you something else before we-- where do you take it? Where do you go from here? What's your next trial? How are you going to make a difference next?

Louise Emmett: Well, first of all, I want to talk about why I think our adverse events were less. Why did we get less?

Oliver Sartor: OK.

Louise Emmett: And it relates to that.

Oliver Sartor: OK.

Louise Emmett: Why did we get less anemia? Why did we get less thrombocytopenia? So we did two things. A, we gave two or four doses. We didn't give six doses, six weekly without stopping and not looking for a target. We actually had adaptive dosing on the trial. So patients got two doses if they had no disease left. They got four doses if they had persistent disease.

And the other thing that we did was, we did an induction and a maintenance. So we did six and six weeks. And then we did eight and eight weeks. So we had an increased distance for the last two. I do think that improves hematologic toxicity when you're giving lutetium. And also, because we didn't have progressive disease, we had less hematologic events. So I think, first of all, adaptive dosing has shown that it can be less toxic.

Oliver Sartor: 20%? What percentage of the patients had adaptive dosing?

Louise Emmett: So all of the patients had the interim PETs to look at what they were doing.

Oliver Sartor: Right.

Louise Emmett: All of the patients only had four doses.

Oliver Sartor: Right.

Louise Emmett: But 11% of patients only got the two. So it's not a massive--

Oliver Sartor: 11%.

Louise Emmett: It's not a massive thing. So I think it's the total doses that you get, plus the adaptive dosing, and the lack of progressive disease that we got on the trial because of the composite. That probably caused the lack of hematologic. But I think adaptive dosing is a really interesting concept that's built into the trial that we need to take into other spaces.

Oliver Sartor: OK.

Louise Emmett: I particularly think if we're thinking of taking it earlier-- so in mHSPC, you're doing PSMAddition, a great trial, where we're combining exactly the same drugs but in the metastatic hormone-sensitive space. Can we use adaptive dosing? Can we treat the target when it's there, but not treat it when it's not there? And does that improve outcomes in our patients, both duration and toxicity?

And then in the metastatic castrate-resistant space, obviously where ENZA-p is at the moment is no longer a space that exists. We're not using first-line enzalutamide in the mCRPC space. But how does it interact with second-line RP? And perhaps, I'd like to ask you a question about something that you presented yesterday as well, which is the second-line RP and the VISION data.

Oliver Sartor: Interesting data. And just to remind the viewers, in the VISION trial, we were post ADT, post ARPI, and post a taxane. So it's a little bit different--

Louise Emmett: A bit different.

Oliver Sartor: --than yours, where really it's just post ADT.

Louise Emmett: 60% post docetaxel in hormone-sensitive space.

Oliver Sartor: Thank you. 100% of ours for post taxane, so different populations, VISION population. But what we found is that the addition of ARPI, which was an option within the standard of care-- the design was standard of care plus or minus lutetium-- that the patients actually lived longer. And so this interaction potentially between the ARPIs, such as abiraterone and enzalutamide, contributed potentially to the survival advantage that we saw in VISION, so very provocative.

And then-- I'm sorry. I'll take just for a brief moment the next stage. So there's another trial coming, PSMA and ARPI. And this is not going to be in the first line of metastatic-CRPC space, but the second line. So this will be taking patients that have already progressed on an ADT and ARPI. Docetaxel could have been given. Now the randomization is to the six doses, 7.4 gigabecquerel that is typical in PSMAfore and now adding in the ARPI.

Louise Emmett: So let me give you your applause because I think that's exactly what should happen. That's what we should be exploring.

Oliver Sartor: Well, let's give Novartis the chance to applaud because they're the ones that are really sponsoring it.

Louise Emmett: Yeah. Great. Great.

Oliver Sartor: Louise, we're going to have to move on, regrettably, because I think you and I could talk a lot longer.

We have, in fact, talked a lot longer. I just got back from visiting Louise in beautiful Sydney, Australia, for almost two weeks. And it was a wonderful time.

Louise Emmett: Yes.

Oliver Sartor: Louise, thank you for being here. Thank you for doing the beautiful work that you do.

Louise Emmett: Thank you so much for having me.