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Neeraj Agarwal: Welcome, Dr. Arun Azad, Professor and medical oncologist at University of Melbourne and Peter Mac Cancer Center in Melbourne, Australia. So here Dr. Azad will talk about his data he's presenting at the 2025 ASCO GU meeting on the LIBERTAS trial. So Arun, I'd like to, first of all, welcome.

Arun Azad: Thank you, Neeraj. It's always a pleasure. Always enjoy doing the UroToday interviews and a chance to talk to you is always an honor and a pleasure.

Neeraj Agarwal: So Arun, let's talk about the LIBERTAS trial first. So we'll talk about the LIBERTAS trial, what the trial is about, what is the patient population, what are the objectives? And then we'll talk about the findings you are presenting at the meeting today.

Arun Azad: Yeah, thank you, Neeraj. So LIBERTAS is a phase three study in metastatic hormone-sensitive prostate cancer. And this is a de-escalation study. So all the patients in this study receive six months of ADT plus apalutamide. And then at six months, the patients who have a PSA of less than 0.2 nanograms per mil, the so-called undetectable PSA, are randomized to continue either apalutamide alone with intermittent ADT or to continue ADT plus apalutamide. So a one-to-one randomization.

And the primary endpoint is looking at radiographic progression-free survival and hot flashes at 18 months. And what we're hoping to see is that by dropping ADT, we will not compromise efficacy in these patients but improve quality of life, for example, by reducing hot flashes. So this will be the first de-escalation study to read out in prostate cancer, and it's very exciting to be part of it.

Neeraj Agarwal: This is great. Thank you for talking about the design. And PSA of undetectable level after month six is emerging as a theme today. We discussed about the IRONMAN registry and Dr. Hannah McManus was here talking about how they are doing—they are doing really well, actually, over time. And we talked to another doctor from Germany who—they are performing radical prostatectomy and lymph node dissection in these patients and ablating the metastatic site.

So I think PSA undetectable after six months definitely has emerged as a biomarker, a response biomarker, which is really defining, at least in the clinical trials, a different course of action. Hopefully will translate into a better quality of life for our patients down the line. So kudos to you and the team for doing the trial. Tell us what you're presenting at the ASCO GU.

Arun Azad: Yeah, thanks, Neeraj. I just echo your points about undetectable PSA. I mean, there's evidence from the TITAN trial as well as other mHSPC studies showing that undetectable PSA at six months is a strong prognostic biomarker. These patients do much better. And that's why the whole question of whether we can de-escalate in these patients is actually effective and safe has come up.

In this presentation, or this abstract we presented at ASCO GU, we looked at the initial patients who were enrolled on the study to see what proportion of them were actually achieving undetectable PSA. Because of course, you see it in one trial—you want to see it validated in another. And we saw it in the TITAN trial. We wanted to see what happened in this study.

And what we saw in terms of the initial patients enrolled in the study is after the six-month period of ADT plus apalutamide, 71% actually had undetectable PSA, which I think is the highest proportion of undetectable PSA we've seen with any combination of treatment for metastatic hormone-sensitive prostate cancer. Seventy-nine percent of these patients had a PSA decline of more than 90%, and 96% had a PSA decline of more than 50%. So we're really seeing very powerful and deep early responses to the combination of ADT plus apalutamide.

And the fact that we were able to have 71% of patients achieve undetectable PSA means that we've been able to randomize quicker than expected. And so this study will read out quicker than we anticipated, which is also fantastic. But it's just so gratifying to see data from one trial translating and being confirmed in another, and to see so many patients achieving such good responses, because we know that, as I mentioned earlier, this PSA undetectable at six months is a strong prognostic biomarker.

So it's wonderful to be able to tell these patients you can be randomized now and continue on the study. But also, whatever happens, you're going to have a long survival from here, which is obviously something we want for all of our patients and obviously what they want as well.

Neeraj Agarwal: Absolutely. And I must tell you, it's so gratifying to hear that such a high proportion of patients are achieving undetectable PSA responses after six months. Because we just heard from another investigator—they are seeing 50% to maybe 55% undetectable PSA responses in the real world, where patients were treated with ADT plus docetaxel or ADT plus different types of ARPIs. I would say definitely ARPI, ADT plus docetaxel is associated with lesser PSA undetectable responses after six months. And ADT plus ARPI do better. But I don't think we have seen these kind of PSA responses from others, even in phase three trials of other ARPIs.

Arun Azad: Yeah, this is really the highest we've seen. And of course, we always have to be careful comparing one trial to another. But I think this is the highest level that we've seen reported. And that shows how potent the combination of ADT plus apalutamide is. And so I think this is fantastic for the trial and it's fantastic for the individual patients. But just to know that we're giving these patients a chance to participate in the randomized part of the trial is wonderful. But to know that they're going to do well, irrespective in terms of their overall survival, whatever treatment, whichever arm they're randomized to, is fantastic.

Of course, what we're then trying to see is, OK, if we know they're going to have very good survival, is there any difference by dropping the ADT or using it intermittently? Making sure we're not compromising their survival. So we're looking at radiographic progression-free survival. But we also then want to see whether that improves quality of life. And we know that with ADT, one of the most troubling side effects is hot flashes. And it can be very disabling for some patients and some men. And so we're hoping that at 18 months, if these patients have had a substantial period off ADT, we'll see less hot flashes.

Because we know that hot flashes is not just the fact that you're having them. It interferes with their sleep if they're having it during their sleep. It interferes with their ability to exercise and do normal activities. And these patients are going to be alive for a long time. We know that from the TITAN trial and other trials that the median survival of these patients, particularly with low-volume disease, is very, very long. So we want them to have good quality of life as much as possible. And that's what we're trying to achieve here.

Neeraj Agarwal: I agree with you. And I think this brings another point, which is many patients are already being de-escalated in the real world. So as we just heard from a retrospective study—the same study I was talking about in Germany—that in these patients who achieve a PSA, very low PSA, patients are taking the break, but we don't have prospective data for that to support that. So I think these data hopefully will reinforce the current practice, which is being pursued on an ad hoc basis, and will probably allow us to do it in a more evidence-based fashion.

Arun Azad: Exactly. Yeah, I agree, Neeraj. I mean, people are doing it a lot and talking about doing it a lot. And I must admit, outside of the clinical trial setting, I do de-escalate in some patients, mainly if they have toxicity and they want a treatment break. But if they don't have a treatment break, I say to them, look, we could do this, but we don't have evidence. We're gathering the evidence. But at the moment, I'm still wanting to be sure. I try to be evidence-based. We all try to be, I think, or many of us try to be.

And at the moment, I'm still not sure whether treatment breaks are the right thing to do or to de-escalate. We need the data from this trial. And there are obviously other de-escalation studies that are ongoing, but we need the data, because we need that to be sure. Because it comes down to is there going to be any compromise in efficacy by doing this? And some patients will be happy to compromise some efficacy for better quality of life, but other patients won't.

So we need to know to be able to say to them exactly, look, this is what will happen from an efficacy point of view if we de-escalate. And this is what will happen in terms of improved quality of life. And then we make a decision with the patients jointly from there. But we need the evidence. Yeah.

Neeraj Agarwal: So congratulations for conducting this study. And hopefully, you will be back here to discuss the primary outcomes results.

Arun Azad: Look forward to it, Neeraj. Thank you.

Neeraj Agarwal: And hopefully, this study will allow us to pursue de-escalation in a more evidence-based fashion down the line.

Arun Azad: Exactly. Thank you, Neeraj. Look forward to it.

Neeraj Agarwal: Thank you.

Arun Azad: Thank you. Bye bye.