Neeraj Agarwal: Welcome to UroToday. Today, we have the honor and the pleasure of having Dr. Paul Nguyen, Professor of Radiation Oncology at Harvard Medical School and Executive Vice Chair of Radiation Oncology at Mass General Brigham Radiation Oncology. Welcome, Paul.

Paul Nguyen: Thank you so much for having me, Neeraj. I'm so excited to be here. I love watching UroToday and watching your videos, so I appreciate the opportunity to be here.

Neeraj Agarwal: So Paul, congratulations for presenting the phase III ENZARAD trial in patients with localized high-risk prostate cancer. The trial results were very well received at the ESMO 2024 meeting, and we'd like to discuss more about the trial today.

Paul Nguyen: Yeah, that sounds great. All right, so up here we've got the schema for ENZARAD, and ENZARAD was a phase III investigator-initiated randomized trial that was sponsored by ANZUP and also known as ANZUP 1303. And this trial was trying to ask the question, can we improve metastasis-free survival for patients with high-risk prostate cancer by adding two years of enzalutamide to a standard backbone of two years of LHRH agonist plus high-dose radiation?

And as you can see on the left, the eligibility is localized prostate cancer, our stratification factors are listed, and this is about an 800-patient trial. And as mentioned, MFS was the primary endpoint, and this is based on conventional imaging. We're talking about CT, MRI, or bone scan because this was what ICECAP found as a surrogate for overall survival. So PSMA PET lesions alone were not sufficient, and the event of course is metastasis or death from any cause before metastasis. We enrolled 800 patients across eight countries, mostly Australia and New Zealand, but also the UK, Ireland, and other countries in the EU as well as the United States. And the median follow-up was eight years. I do want to note that in the control arm where we did not use enzalutamide, we used six months of a conventional nonsteroidal antiandrogen.

I want to explain our radiation to everyone. We treated the prostate to modern high-dose radiation, either 78 Gy or 46 Gy plus a brachytherapy boost. We allowed some patients with clinically node-positive disease in the trial and it turned out to be 11% clinically node-positive. And for those patients we required pelvic lymph node radiation. But for those patients who were clinically node-negative, it was optional to radiate the pelvic lymph nodes and it was at the discretion of the investigator; they just had to declare it prior to randomization.

Let's go to the primary endpoint. Okay, so here was the primary endpoint of the study, which is metastasis-free survival by conventional imaging. As you can see, there was no significant difference between the enzalutamide and control arms with a hazard ratio of 0.88 and a p-value of 0.34. At eight years, the MFS in the enzalutamide arm was 74%, and in the nonsteroidal antiandrogen arm was 72%.

There was a benefit in PSA progression-free survival with a hazard ratio of 0.78, a p-value of 0.044. And at eight years, it was 67% versus 62%.

No difference in overall survival. Hazard ratio 0.87, p-value of 0.4, and no difference in prostate cancer-specific survival. But I do want to point out that it was very high in both arms. In the enzalutamide group, it was 97% at eight years, and in the nonsteroidal antiandrogen group it was 96% at eight years, and so this is a success I think for all patients with unselected high-risk prostate cancer in the modern era treated with modern-dose radiation and two years of standard ADT. These patients are all doing well.

I do want to point out that we prespecified five different subgroups, which we also prestratified by, and I want to focus on these three subgroups at the top—we're going to forget about age and region. If we zoom in, this is the forest plot for metastasis-free survival within the prespecified subgroups. And as you can see, for patients who are clinically node-positive by CT or MRI, there was a significant interaction such that the p-value was 0.04 for interaction. And the hazard ratio for the benefit of enzalutamide on metastasis-free survival was 0.43 with a confidence interval from 0.2 to 0.92, no apparent benefit for patients who are clinically node-negative.

Similarly, for patients who were selected for pelvic lymph node radiation, either these patients were node-positive or the investigator chose to radiate their pelvis. There's another significant interaction with a p-value of less than 0.01, and a hazard ratio of 0.47 for the benefit of enzalutamide on metastasis-free survival. No benefit if you did not receive pelvic lymph node radiation.

Finally, we didn't see an interaction with our very high-risk group, but I want to point out this is not NCCN or STAMPEDE very high-risk. This was a different definition for the trial defined based on the ICECAP criteria predicting for a 75% MFS at five years. We did find that the hazard ratios for MFS and overall survival were well correlated as predicted by the ICECAP surrogacy. For those two subgroups, those patients who were node-positive, the MFS hazard ratio was 0.43. The overall survival hazard ratio was 0.46, and if you got your lymph nodes radiated, your MFS hazard ratio is 0.47. Your overall survival hazard ratio was 0.53.

And so in conclusion, we really feel the implications for practice are that for most contemporary patients with clinically localized or locally advanced prostate cancer receiving high-dose radiation and two years of ADT, these patients do not need enzalutamide. But for that subgroup of patients with positive nodes on CT or MRI or other indications for pelvic radiation, enzalutamide does provide good evidence of a benefit.

Neeraj Agarwal: Thank you, Paul, for summarizing these results so clearly. It looks like there is clear benefit in node-positive patients or patients who required pelvic radiation which was deemed necessary by the treating oncologist, clear benefit from the perspective of progression-free survival, metastasis-free survival, and even overall survival. Is that correct?

Paul Nguyen: That's right, yes. I think that for these patients who are clinically node-positive by CT or MRI, there's a clear benefit to enzalutamide as well as for those patients who got selected for pelvic lymph node radiation as you say. And honestly, we don't know why those patients who were not clinically node-positive were selected for pelvic lymph node radiation. We can speculate only—maybe some of them had some finding on a PSMA PET that made the clinician want to do it. We don't have that information right now, so that's going to be something we need to look into further. Who exactly are these patients that got pelvic lymph node radiation if they weren't clinically node-positive?

Neeraj Agarwal: If you look at the all-comer patient population of this trial, adding enzalutamide doesn't help everyone. Is it because of the improved techniques in radiation therapy for these patients?

Paul Nguyen: Wow, that's a great question, Neeraj. I mean I'd love to take credit with radiation dose and radiation technique for the outcome. But I must admit, the benefit of radiation dose escalation on metastasis-free survival has been pretty modest and so I'm not sure that we can take all of the credit for it, but I think there is some. If you look at our friend Vedang Murthy's trial looking at pelvic lymph node radiation, that appeared to have some improvement in metastasis-free survival. There is evidence that increasing the radiation dose to the prostate can have a modest benefit in RTOG 0126 for metastasis-free survival, so that could have something to do with it. But I also think that these patients, for the most part, were reflective of a modern population where we're screening out some of the more really aggressive disease, and these patients overall are doing pretty well with standard therapy.

Neeraj Agarwal: Yeah, 97%, 96% of patients alive eight years after—this is fantastic news for our patients.

Paul Nguyen: I think it is. I think it's good news for everybody that we don't necessarily need to intensify for those patients, that the vast majority of our typical high-risk patients are going to do great with modern radiation and two years of ADT.

Neeraj Agarwal: So this obviously brings up the question of comparing these results with the STAMPEDE trial presented by Dr. Nick James and colleagues from the United Kingdom. Taking a step back, the results of the STAMPEDE trial showed that adding two years of abiraterone to radiation therapy plus androgen-deprivation therapy improved survival. What is causing the difference in the results between these two trials, STAMPEDE versus ENZARAD?

Paul Nguyen: That's such a great question, and actually Nick James gave an amazing discussion afterwards, and it's something that everyone wants to know—how do these results compare to STAMPEDE? And I actually think they're very complementary and actually very consistent with STAMPEDE because if we look at the ENZARAD benefit in clinical N1, it's completely consistent with STAMPEDE—we found the exact same result. And if you look at the rest of the patients, you have to see that ENZARAD enrolled a much more favorable risk population than STAMPEDE did. Let's look first—if you were clinically N1, the hazard ratio in STAMPEDE for abiraterone was 0.49 for MFS, and our hazard ratio for ENZARAD was 0.43, so basically exactly the same story.

And of course, we found different results for the rest of the patients, but look at the overall population. STAMPEDE had 39% clinically node-positive, we had 11% clinically node-positive. The median PSA in STAMPEDE was 30, in ENZARAD it was 14. The clinical T3/T4 in STAMPEDE was 92%, and in ENZARAD it was 47%. And so I think we're talking about a threshold effect where certainly the node-positive patients benefit from the ARPI and there are probably some patients at the very highest end of node-negative high-risk that benefit from ARPI. But there's a whole bunch of patients in the lower and middle sections of high-risk that really don't benefit at all.

We did an exploratory analysis on this, completely exploratory of course, but we tried to look at the ENZARAD population based on who would have qualified for STAMPEDE versus who would not have qualified for STAMPEDE. And there's a suggestion of an interaction—p-value here is 0.08. For clinically node-positive, as we said, there's a significant benefit with a hazard ratio of 0.42. But if you look at the clinically node-negative STAMPEDE-eligible patients who were on ENZARAD, the hazard ratio is just 0.85, weaker than what was shown in STAMPEDE, and this wasn't really much different from the overall population. And if you looked at the clinically node-negative patients on ENZARAD who were not STAMPEDE-eligible, there is really no hint of a benefit to enzalutamide.

And so what I think we're seeing here is that for node-positive patients, definite benefit. Obviously STAMPEDE showed that the kind of patients who went on STAMPEDE benefited from abiraterone. But this would suggest that it's not everybody who meets STAMPEDE criteria that necessarily needs intensification, that there's a difference I think between meeting the STAMPEDE criteria versus looking like the patients who went on STAMPEDE—remember those patients had a median PSA of 35. So I think if you look like that kind of patient, definitely you should intensify or think about intensifying. But if you're a patient who meets STAMPEDE criteria, but you look more like an ENZARAD patient with a median PSA of 14, I'm not so sure we should be intensifying. And I think ENZARAD suggests that most of those patients are going to do fine.

Neeraj Agarwal: This is such a great comparison between the STAMPEDE results and the ENZARAD trial, and it basically reinforces the message that ARPI, when added to the ADT-plus-radiation therapy backbone, does improve survival in those patients who are at the highest risk of recurrence, such as node-positive disease or patients who receive pelvic radiation. And frankly, Paul, in my practice, if I see a patient with high-risk localized prostate cancer at the highest risk of recurrence and they are not a candidate for abiraterone, historically, I have tried to switch them to enzalutamide to allow them to benefit, and I personally think the ENZARAD data will make it easier for us to do so. Would you agree?

Paul Nguyen: Yeah, I think so, and I'm glad for patients to have more options in this space.

Neeraj Agarwal: Yeah. Well, any final message for our audience today about the results of the ENZARAD trial?

Paul Nguyen: Well overall, I'm really grateful for the opportunity to present here and just think it is a good news story. Most patients are going to do fine with standard-of-care therapy, and I think future work needs to be done to tease out exactly which are those patients that we need to intensify. And of course, work is going to be ongoing looking at biomarkers—is it the Decipher platform or something AI-based like the Artera platform? And certainly that kind of work is going to be ongoing. But overall, I'd say good news for most patients. And I think it helps us to see most patients are doing fine, but obviously the patients who are node-positive and maybe at the very highest risk of high-risk disease still need intensification.

Neeraj Agarwal: So a lot more to come from this.

Paul Nguyen: A lot more to come.

Neeraj Agarwal: Well, thank you, Paul, for taking the time to talk to us about these data, and congratulations again for presenting these results.

Paul Nguyen: Thank you so much. It was a team effort for the whole ANZUP team, and I want to shout out to the investigators, co-chair Scott Williams. We also had Chris Sweeney, Martin Stockler, and Ian Davis who were there from day one for the last 13 years, and of course all the patients and co-investigators. And thank you, Neeraj, for this opportunity to present.

Neeraj Agarwal: Thank you.