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Neeraj Agarwal: So welcome to UroToday. Today we have David Fisher, Principal Research Fellow at the Medical Research Council and the Clinical Trials Unit at University College London, who presented his research at the oral presentation, in one of the oral sessions, at the ASCO GU 2025 Symposium.The topic was which patients with metastatic hormone-sensitive prostate cancer benefit from androgen receptor pathway inhibitors. And this was a large meta-analysis of the individual patient-level data from multiple large Phase III trials. So congratulations, David, first of all. So we would love for our audience to learn from you about the research, about the implications, and about the message for the community, including patients and providers across the world.

David Fisher: Thank you very much for the opportunity to talk about this important presentation. So as Neeraj says, the title is, “Which patients with metastatic hormone-sensitive prostate cancer benefit more from androgen receptor pathway inhibitors, or ARPIs?” And this is a meta-analysis of individual participant data from multiple trials. And the idea here is to put that data together in order to hopefully draw firm conclusions about which patients benefit most.

And so, as at the presentation itself, we start with telling you what the key takeaways are, and then we'll go back and go through how we got there. And the primary result that we want people to take away is that there is a clear benefit from the addition of ARPIs to standard care on both overall survival and on progression-free survival—in other words, the delay to disease progression—for nearly all patients with metastatic hormone-sensitive prostate cancer. And in particular, for younger patients, again, there is a clear benefit from all the agents that were in our data sample.

For older patients, we found that the data were a little bit more mixed. And so we invite clinicians to consider the benefits and risks of the different agents for each patient in their clinic. And again, it's important to note that this is the first meta-analysis which brings together individual data from the eligible trials rather than the published results.

So very briefly, the trials themselves have already provided evidence of the efficacy of ARPIs. But really, we wanted to put the data from the trials together in this analysis and just go further and answer slightly more subtle questions. So in order to do this, we designed an individual participant data meta-analysis with our primary outcome being overall survival for main effects and progression-free survival for subgroup analysis because progression events accrue sooner and therefore give us more statistical power.

In terms of the analysis, we used standard meta-analysis techniques, but the important thing is that the individual data allows us to analyze each trial in the same way across all of the trials, which is different from the way the trials were individually analyzed and published originally. And so, to the results—we identified 11 trials.

And of those, we had seven trials available across two different types of ARPI. And of one of those types, the androgen biosynthesis inhibitor, we have 100% of patients. But currently, we only have around half the total data available on the amide class of agent. But in total, we have nearly 8,000 patients, which is nearly 70% of the current total number of eligible patients.

In terms of the patient characteristics across the different trials, there was some variation. And that's shown in this slide here. And just to note that these characteristics are often seen as some of the most important when differentiating between patients with metastatic hormone-sensitive prostate cancer. So all of those different types of patients are represented across the different trials. And again, there is a range of follow-up and control arm survival, but we have a decent amount of data from all of these trials.

Moving on to the results, and this is the overall survival result, pooling data from across all of our available trials. And the important thing to note here is that there is a clear, large, and statistically significant benefit from the addition of ARPIs on both the overall survival and the progression-free survival outcome, with no clear difference by the two different classes of agent.

We then looked to see whether we could see any evidence that those large overall effects that we see differ by different patient or tumor characteristics. And we saw very little evidence for any differences. In particular, we saw no evidence of difference by volume of disease or timing of metastatic diagnosis.

However, when we looked at patients’ age at randomization—which we actually found not to be prognostic—we did see evidence of a difference using our PFS outcome. We saw that for each decade older you are, the efficacy of ARPIs decreases by around 15%. And a similar result was seen using the overall survival outcome. So clearly, there is evidence here that older patients may not receive the same benefits.

This is the same data but shown here within prespecified subgroups. And this is a clearer way of showing the difference in the age groups. We can see that the over-75 group, shown in green, has a notably smaller effect of adding ARPIs to standard care.

Now, there was some heterogeneity in these differences across different trials. And so to try to explain that, we wanted to look at the different classes of ARPI individually. And with the abiraterone data, of which we have 100% of data available to us, we see again this strong difference between the over-75s and the younger age groups, where the hazard ratio in the over-75s is 0.8, whereas it’s 0.5 in the other two groups.

And when we look at the other two outcomes, we see that there's very little evidence of an overall survival benefit at all. However, when we look at prostate cancer-specific survival, we see that there is still a fairly large effect even in the over 75s of 0.77. And this suggests that other causes of death may be having an impact here.

When we look at the amide class of agent, we only currently have 48% available data, and we don't yet have any darolutamide data. Nevertheless, it appears from this data that there is no notable difference between the over 75s and the younger age groups when we look here. And this table summarizes the absolute effects that we see as a result of those hazard ratios.

So we can see that overall, there is around a 25% to 27% absolute difference at five years for PFS and around 16% to 18% for overall survival and 17% for prostate cancer-specific survival. However, these drop substantially when we look at the abiraterone data within the oldest age group. I must also note here that we do not currently have cause of death data for all of the non-abiraterone trials, and so it becomes difficult to compare on that particular outcome. So there's more research needed there.

So our next steps, as I say, is we need to be able to explain this finding. And so we need more and better data. There are more trials coming along the pipeline. We require additional data from some of those trials, including cause of death data, so we can investigate the prostate cancer-specific outcome. And so our goals now are to take this finding forward and to try to explain what it means for practical clinical care and for patient outcomes.

The main strength of this project was that it is an international and strongly collaborative effort. And we've managed to obtain individual participant data from the vast majority of trials and from the patients within those trials. And we have done that by bringing together early all the collaborators from all of these trials. And this enables us to perform more reliable and thorough analyses than previous meta-analyses, which have used results from trial publications.

Neeraj Agarwal: That was a wonderful presentation, and congratulations again, David, for this analysis. I think if I want to summarize for our viewers today, I got three messages clearly from your talk, from your work.

Number one, all these androgen receptor pathway inhibitors, whether they are abiraterone or “-lutamides” like enzalutamide, apalutamide, darolutamide, they all result in survival benefit, which is quite significant—clinically and statistically significant. Then you combine all these data, patient-level data from large Phase III trials, more than 7,000 patients, and you see persistence of this survival benefit, both in terms of progression-free survival and overall survival.

And then we look at the age groups. We look at the disease characteristics. So number one finding I thought was quite striking is that androgen receptor pathway inhibitors benefit patients with low-volume disease, high-volume disease, de novo disease, metachronous disease. So it doesn't really matter how the disease is presenting—everybody is benefiting.

And the fourth one, which I thought was quite novel, although we experience that all the time in our clinics, is that lutamides may have an edge over abiraterone as far as those patients who are more than 75 years old. I think lutamides seem to have an edge based on your presentation. Although, you will be working in that direction further, as you mentioned, and we will see more data down the line.

But it looks like in older patients, prostate cancer mortality is also competing with all-cause mortality or non-prostate cancer mortality. So they may not benefit as much from this intensification or combination therapy, but still, lutamides seem to have an edge over abiraterone. So I think this is my message. What do you think, David? Am I correct? Anything I missed for our viewers today?

David Fisher: I think the only thing to add is that I think we can't be quite sure about the source of the finding on age because age is a tricky thing to pin down. It's not a biomarker. It's nothing that is intrinsic to the disease. And of course, patients differ substantially in terms of other characteristics, even within the over-75 age group.

So yeah, we will need to do a lot of work to see whether it's driven by fitness—patient fitness—or drug-drug interactions, or other comorbidities. And also maybe how the delivery mechanism of the two classes of agent differs. Abiraterone is given along with prednisone, I think. And so that may be having an impact.

So there are various things we wish to explore. And so I think, personally, I wouldn't want to be quite so strong of saying that this is a suggestion of the lutamides being superior in that age group. I think overall, the data is mixed within that age group, and we need to untangle it.

Neeraj Agarwal: Thank you. Thank you for clarifying. So I think one thing is very clear—that combination of androgen deprivation therapy with androgen receptor pathway inhibitors, whether it is enzalutamide, apalutamide, darolutamide, or abiraterone, all drugs seem to really improve survival.

David Fisher: Yeah.

Neeraj Agarwal: Both progression-free survival and overall survival. And it doesn't really matter what the disease characteristic is, meaning it's high-volume disease, low-volume disease, de novo disease, metachronous disease, younger patients, older patients—everybody seems to benefit. And hence, there is no reason for us to not offer these therapies to our patients with metastatic hormone-sensitive prostate cancer, unless there is a clear contraindication to use one of these agents.

So for our audience who are listening today regarding this fantastic presentation and analysis by David Fisher, I think it's quite obvious that androgen receptor pathway inhibitors improve overall survival and progression-free survival in our patients with metastatic hormone-sensitive prostate cancer. And the benefits seem to be present regardless of disease characteristics—volume status, high volume, low volume, and other characteristics—and age group. Most patients seem to benefit.

And I think, given these data and many other data presented in the past, there is no reason for us as clinicians not to offer androgen receptor pathway inhibitor-based treatments to our patients with newly diagnosed metastatic hormone-sensitive prostate cancer. With that, I'd like to thank David Fisher for the wonderful work and the entire STOPCAP team. And thank you for being with us today.

David Fisher: Thank you very much for having me.