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Neeraj Agarwal: Hello, Dr. Hannah McManus, Assistant Professor of Medical Oncology at the Duke University Medical Center. And thank you for joining us today at UroToday to discuss your research and data you presented at the 2025 ASCO GU meeting.

Hannah McManus: Thanks so much for the invitation.

Neeraj Agarwal: So, Hannah, tell me about this practice-informing research and the data on patients with metastatic hormone-sensitive prostate cancer from the IRONMAN registry, where you looked at the PSA responses and the outcomes as far as survival outcomes are concerned in our patients with metastatic hormone-sensitive prostate cancer.

Hannah McManus: Thanks again for the chance to highlight this work. So we know the treatment landscape in metastatic hormone-sensitive prostate cancer has evolved with inclusion of treatment intensification strategies really building on top of ADT monotherapy. And then across trials, we've seen data suggesting that undetectable PSA nadirs at different time points, particularly six months, can be associated with better outcomes. And so we really wanted to look in a global, diverse setting in the real world at multiple treatment types to see what were rates of that undetectable PSA nadir at six months and what was that association with outcomes, so things like relapse and overall survival.

And so this study is in the IRONMAN registry, which is a prospective registry of patients with advanced prostate cancer around the world. And we looked in four countries that are sort of high-accruing sites with similar practice patterns—so the US, England, Canada, and Spain—and we looked at all of the patients with metastatic hormone-sensitive prostate cancer between 2017 and, I think, mid 2023 and looked at patients who had ADT monotherapy, ADT plus an ARPI, and ADT plus docetaxel.

We didn't have huge numbers of triplet therapy at this point, and the follow-up is pretty limited, so we excluded them from this analysis. But we were looking at what percentage of patients got an undetectable, which we defined as less than 0.2—similar to a lot of other studies—PSA nadir at six months and 12 months. And then, we also looked at what were rates of relapse, which we had to create a real-world definition of relapse in this prospective registry, based on whether patients had that PSA nadir at six months or not.

Neeraj Agarwal: I must congratulate you, Dan, and everybody involved in the IRONMAN registry for your leadership. This is, I think, for the first time we are getting real-world data in such a comprehensive fashion—patient-level data. There are multiple trials which have reported these kinds of analyses, but all of those trial-based results are pretty much wedded to one type of drug, and they are trial patients who are healthier in general.

So, first of all, I love this database and the research because this really is coming from the real-world patient population, if you will. So tell us about how many patients were there when you looked at it and what the findings were.

Hannah McManus: So we had a little over 1,300 patients in the study. And about half of those had ADT plus ARPI. And then the other half were a couple hundred each of the ADT monotherapy or ADT plus docetaxel.

Neeraj Agarwal: And so, what were the results?

Hannah McManus: So I think first, looking at that first piece of data—do you get an undetectable PSA nadir or not—and we looked in the overall population and then by treatment type. We found that you saw this—again, this is non-randomized data where patients are probably being selected for different therapies—but we saw the highest rates of undetectable PSA nadir in our ADT plus ARPI group, a little over 50% at six months. We saw lower rates in ADT monotherapy and docetaxel, probably a little over a quarter of patients with both of those.

And then I think an interesting part looking there was we also looked at 12 months, and we saw you got another probably 10 or so percent of patients that actually, in that 6-to-12-month period, still did get an undetectable PSA nadir. So it’s not necessarily you’re going to get it at six months or not. But we really look at that early time point as kind of a signal of efficacy.

And then, looking at those relapse rates: we looked at relapse at 12, 24, and 36 months. We defined that using PSA progression, which was the vast majority of the patients, or things like a switch to a neuroendocrine prostate cancer regimen, or a change in therapy with new metastasis because we don’t have robust radiographic progression-free survival in this setting. And the large finding there was that really having an undetectable PSA nadir, regardless of treatment type, was correlated with having lower rates of relapse even as far out as 36 months.

And I think, not comparing across groups, but we really saw similar rates even between therapies if you looked in those undetectable PSA nadirs.

Neeraj Agarwal: So 50% of patients—for our viewers—50% of patients are able to achieve undetectable PSA after six months, and if that happens, it looks like disease progression doesn’t happen. I’m just using relapse as disease progression. It doesn’t happen for up to 36 months. Pretty long PFS in those patients. So what happens to those patients who do not achieve a PSA of less than 0.2?

Hannah McManus: We see higher rates of relapse. Now I think, interestingly, it’s not a 100% thing. So even if you look in the patients that had detectable PSA at six months, there still are some patients who at 36 months are relapse free. But those rates are lower. And so it’d be great to understand what are those predictors we’re missing there. But in general, you see much higher rates of relapse in those patients.

Neeraj Agarwal: So do you have the hazard ratio for overall survival yet?

Hannah McManus: We don’t know. The overall survival—we have follow-up of about 18 months, and so the survival data are immature.

Neeraj Agarwal: So if I want to summarize these findings for our viewers and our patients—a lot of patients are watching this—if you develop or if you’re able to achieve a PSA undetectable rate, in general, they have good prognoses. And in those patients, if they are having—and I’m just extrapolating for my practice—if they’re having side effects which are difficult to handle, do you think it may be easier for those patients to accept treatment holds or discontinuation for a fixed period before we can restart, so sort of an intermittent therapy, if you will?

Hannah McManus: Yeah, no, I think that’s a really interesting way to take this. And I think we don’t have data from this to say that you’re going to get equivalent outcomes, but I think this data, and then, as you said before, multiple trials showing the importance of this sort of six-month endpoint... I think those are patients where we can feel more comfortable that it is a reasonable option—obviously weighing the pros and cons and lack of data with them.

And then I think with that too, like us developing—and people are doing this, but continuing to develop—intensification and deintensification trials around these adaptive endpoints, I think could really be a way to operationalize that and get the data for patients.

Neeraj Agarwal: And, in fact, there are two trials. The reason I brought that point up is because there are at least two trials ongoing, which are randomizing patients to continuous therapy versus intermittent therapy after a six-month PSA is reached if they have undetectable PSA level. So patients are being randomized to intermittent versus continuous therapy. For those patients who are in the real world right now, until we have the results of those trials, at least this factor may help them in their decision-making if they want to take a break because of side effects.

Hannah McManus: Yeah, I completely agree with you and use that information in my own practice as one data point to suggest they’ve had a more favorable response and may continue to have benefit even with a deintensification.

Neeraj Agarwal: And so what happens to those patients—of course, we don’t have overall survival data yet from your findings—but what happens to those patients who do not achieve a PSA level of less than 0.2? And it looks like there are more than 40% of these patients. So what is your assessment? What is going to be the median PFS or relapse-free survival? Any estimate?

Hannah McManus: It’s a little early to say what that exact number is going to be. But I think an interesting question there is what should we think about doing for those patients. I mean, I think that’s another interesting trial strategy, and there’s at least one ongoing or recently opened trial trying to look at intensification for those patients. But thinking about are there ways, if we know that we’re going to have worse outcomes potentially with that endpoint, can we actually improve upon patients’ therapies?

Neeraj Agarwal: And I thank you for reminding me. I would like to give a shout-out to the SWOG Canadian cooperative group trial, which just opened, which is randomizing patients who do not achieve a PSA of 0.2 after six months to continuation of ADT plus ARPI versus ADT plus ARPI plus addition of docetaxel chemotherapy. So I think these data are already informing at least the design of that trial. And hopefully, these will inform our practice in the near future.

Imaging studies in these patients who do not achieve a PSA of less than 0.2 after six months... In my practice, I don’t do scans every three months for these patients who are doing well on ADT plus ARPI, newly diagnosed, unless I have—I do maybe obtain scans once a year. But if a patient is there in the clinic who does not achieve a PSA of less than 0.2, do you recommend, based on your experience, we should be doing imaging studies more often, because these patients are likely going to progress faster and may develop neuroendocrine differentiation where PSA may not be reliable?

Hannah McManus: Yeah, it’s a really important point. I mean, I think there’s a lot of variability in how we all image in these settings. I think similar to you, I’m not imaging a lot of patients with mHSPC on any very short interval. I think getting imaging at that PSA nadir is kind of my practice, to have a sense once I think we’ve reached our maximal response, to understand what our new baseline is.

And then I haven’t been necessarily following those patients, at least with imaging, more closely unless they have other features to make me concerned they’re at higher risk of developing differentiated disease. But I think that is something for us to think about: How do we, not just from a therapy standpoint, but how do we adapt our monitoring for these patients to account for that increased risk of progression, as you said?

Neeraj Agarwal: Again, thank you for sharing those data with us. Congratulations, again, and hopefully, we’ll get to hear about the overall survival data in these patients in the near future. And kudos to you and all your investigators for conducting these kinds of studies which really inform us about what is going on in the real world.

Hannah McManus: Yeah, thanks again for the opportunity. And yes, shout-out to the entire IRONMAN team and my mentors that really make this possible. It’s a global effort, so excited to get to share the data.

Neeraj Agarwal: Yes, congratulations.

Hannah McManus: Thanks.