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Alicia Morgans: Hi. I'm so excited to be here at GU ASCO 2024, where I have the opportunity to speak with Professor Arun Azad. We're talking about the LIBERTAS trial. Thank you so much for talking with me today.

Arun Azad: Thanks, Alicia. It's a real pleasure.

Alicia Morgans: It is always a pleasure to talk to you.

Arun Azad: Good.

Alicia Morgans: And particularly about this trial in progress. Tell me a little bit about the LIBERTAS trial.

Arun Azad: Yeah. The LIBERTAS trial is a study that just opened in the last few months. It's in metastatic hormone-sensitive prostate cancer, and it really was born out of the idea of how we manage patients who get really good outcomes in metastatic hormone-sensitive prostate cancer with the novel anti-androgens in addition to androgen deprivation therapy. So in this case, it's ADT plus apalutamide. And of course, we know that apalutamide and other novel hormonal agents, or probably we should call them now androgen receptor pathway inhibitors, they're not so novel anymore, have been in the clinic for a number of years, and they lead to much better outcomes for patients, including much longer survival and all sorts of other secondary outcomes. And we all know that data.

And we've actually reached a point where a substantial number of these patients, probably around two-thirds, actually achieve what we used to refer to as undetectable PSA. It's not quite accurate now with ultrasensitive PSA, but a PSA of less than 0.2 nanograms per milliliter. And the study is looking at what we can do with those patients. How can we best manage those patients? Because for many years, I think physicians have been just using their own clinical judgment and deciding to deescalate therapy in some of those patients, knowing that they're doing very well. And so, we really actually want to design, we've designed a prospective trial to actually answer the question of whether we can safely deescalate treatment without compromising clinical outcomes but also seeing if we can improve quality of life.

Alicia Morgans: So tell me a little bit more about that because it seems like this is a certain population of patients with metastatic hormone-sensitive prostate cancer. Does this include patients with high-volume de novo metastatic disease? Does it focus on different populations? And maybe it doesn't in the inclusion/exclusion, but do you foresee a certain population might be sort of preferentially enrolled?

Arun Azad: Yeah, it's a great question. I mean, the study actually does include all patients with metastatic hormone-sensitive prostate cancer, irrespective of disease volume, or if they've had prior local therapy, or they're a de novo or newly diagnosed metastatic disease. I think that in the study we're enrolling all those patients to be randomized, and I'll talk about the randomization in a minute. Patients have to achieve a PSA of less than 0.2 nanograms per milliliter after six months on ADT plus apalutamide. So we know from the TITAN study, which is, obviously, the original study of ADT plus apalutamide in metastatic hormone-sensitive prostate cancer, that around two-thirds of patients achieve that PSA at six months. We do think that it's likely that there'll be more patients with low-volume disease, or perhaps relapsed disease after prior local therapy, who've got a better prognosis who will achieve that. But we're certainly recruiting a broad group of patients who are going to be enrolled. We'll see who ends up being randomized, but we're certainly not just focusing on those low-volume or relapsed patients.

Alicia Morgans: I think that's so important because, to your point, you actually don't know what's going to happen with someone until you get to that six-month time point. And the biology will declare itself after that run-in period, and you'll be able to really report out what proportion of patients are getting there, and actually who those patients are.

Arun Azad: Yeah.

Alicia Morgans: So that will be really, really interesting and meaningful data. So let's talk about the randomization. Tell me about what happens at randomization and what are your endpoints?

Arun Azad: Yeah, thanks. So that's really important to discuss. The randomization is to look at continuing either ADT plus apalutamide versus dropping the ADT and continuing apalutamide alone. And so, the ADT is then what we call intermittent ADT, where it can then be restarted in patients, and there are criteria for that in that experimental arm where it's been dropped. So if patients develop cancer-related symptoms, their PSA is more than 10 nanograms per milliliter, or if it was less than 10 nanograms per milliliter at baseline, it goes back to their baseline reading. Or if their PSA doubling time is less than six months. So there are criteria around that. And then it's stopped again when PSA drops to less than four nanograms per milliliter. So that's a little technical, but that's actually, we've provided guidance to the treating investigators, so that they're aware of how to manage intermittent ADT.

So the randomization then is, we're not dropping all treatment, which I think has been a point of discussion. Should we be deescalating? We're calling this a deescalation study, so we're dropping the ADT in the experimental arm. I think that if you stop everything, it's actually a stopping or a suspension study, which is slightly different. There are other studies that are planned to open or just opened through cooperative groups and other groups who are actually looking at stopping treatment in these exceptional responders, patients who get a very low PSA. We've actually decided to drop the ADT, or at least make it intermittent, and continue the apalutamide.

So the primary endpoint we're looking at in this study is at 18 months. There are two endpoints. It's radiographic progression-free survival at 18 months. Obviously, that's our efficacy endpoint. But we also really thought it was very important in this study to look at quality of life and patient-reported outcomes.

I mean, in the end, we're dropping ADT because we want to see if patients have better quality of life. Because we know ADT has detrimental impacts on both short-term and long-term quality of life. And so, the readout that we use is actually hot flashes, which we know are very troublesome for patients on ADT. So we're looking at the 18-month hot flash score as well. So it's a dual primary endpoint, which I think is a really neat way of looking at whether this strategy is not just effective in terms of not compromising efficacy, but also improving a symptom that's really troublesome and bothersome for patients.

Alicia Morgans: So interesting too, because it's really a composite there, or a mix, of a disease control and quality of life endpoint. Which we actually don't see very commonly in our studies, but I think certainly, patient advocates have called for these kinds of considerations. And so, it's phenomenal that you're able to do that. Are you looking at any other aspects of quality of life?

Arun Azad: Yeah. We do have a lot of quality of life and patient-reported outcome measures that are being used in the study. I mean, obviously, we have other secondary efficacy endpoints and the usual ones there. But we really are focusing a lot on quality of life, including things like smartwatches that patients are wearing that provide real-time monitoring of their physical activity and sleep. And we're looking at a whole range of other quality of life, using a whole range of other quality of life instruments. So there are very detailed quality of life studies that are being done as part of this. It's really a major focus of it. Because in the end, we really want to see whether this approach of dropping the ADT, or using ADT in an intermittent fashion, actually improves quality of life. Because we know that these patients, particularly the ones who achieve a PSA less than 0.2 nanograms per milliliter, we know that's a very strong and favorable prognostic factor. And we know that they're going to do very well and have long survival, which is fantastic.

We also know that ADT in the long term can have these detrimental effects on so many aspects of their physical, emotional, and psychological well-being. And so, if we can actually use less of it without compromising their cancer care, then that's clearly going to be good for them. And we're trying to actually capture that with those different quality of life and patient-reported outcomes.

Alicia Morgans: Fantastic. So many of these effects that we see are related to testosterone suppression. When we use apalutamide as a single agent, we're expecting, actually, after we stop that backbone ADT, that we'll probably see T recovery and testosterone levels increase. So, are you doing all these assessments in the context of understanding also testosterone recovery? And then as a follow-up, do you expect that there might be complications related to testosterone levels increasing that you also need to be aware of?

Arun Azad: Yeah, it's a really good point. I mean, I think, yeah, you're right. So the patients who are randomized, and then who are randomized to the experimental arm, will have had six months of ADT on the study; they can have up to three months in the lead-in as well. So they might've had somewhere between six to nine months of ADT. So clearly, then, we think that the recovery of testosterone will happen, let's say somewhere around 12 to 18 months if we double that time period that they've been on ADT. So we are, obviously, monitoring their testosterone in that period, because we want to know what it is. And then we know that as testosterone recovers, that there will be, first of all, there'll be effects on PSA and the sort of disease status. And we have those criteria, as I mentioned earlier, for restarting testosterone.

But yeah, we need to really watch out, as the testosterone recovers, that the disease doesn't progress too quickly. And so, we're still going to clearly monitor those patients carefully. And knowing that they will need to restart ADT at some point, but hopefully, they'll have a decent period off ADT. And of course, once they restart it, and their PSA then drops to below four nanograms per milliliter, they can actually stop it again. So we're hoping that patients will actually be able to use intermittent ADT with apalutamide as a background for, hopefully, many years in the best outcomes.

Alicia Morgans: Well, I think certainly, patients are interested in this too. And this might be interesting for all kinds of patients, and not necessarily just the fittest patients who end up making it into many of our clinical trials, and certainly could be appealing to, again, just all ages, all races. Diversity, I think, is something that we're trying to enhance in clinical trials, and there would be interest from so many. So it sounds like in the LIBERTAS protocol, in the program, there's actually a real interest in ensuring that there is diversity of patients included. Can you tell me a little more about that? And what did you do to really put a stake in the ground as an innovative trial in this way?

Arun Azad: Yeah. I mean, that's a great question, Alicia. I mean, we had a lot of discussions with Janssen when the protocol was being developed. And from the very beginning, we really wanted to see that this study was very inclusive, and had a diverse population of patients that really reflects what we're seeing in the real world. That sometimes isn't captured, like you said, in clinical trials, just because of the nature of where sometimes the centers where clinical trials are conducted and the countries. And so, we really made that a big focus. So we really have focused, and there are ongoing strategies to help recruitment in some underrepresented populations. Some examples are Black and African American patients who are underrepresented in trials.

We've also focused on, it's a gender-neutral protocol. I think the very first, certainly in prostate cancer, maybe even in cancer in general, gender-neutral protocol. So we're actually looking to include, and we've got strategies to include transgender patients. We are looking to include patients with disabilities, and allowing them to have an ECOG performance status of two, rather than just ECOG performance status of zero to one, to allow patients who've got physical disabilities that may otherwise not be able to enroll in clinical trials.

So those are just three examples of patient populations who are underrepresented in prostate cancer, and probably not just prostate cancer, but other cancer clinical trials that we're hoping to actually at least recruit well in those populations. And we have strategies to actually, we're working with Janssen to actually reach out to some of these groups and communities to try and actually encourage enrollment in the study. So we really hope that this will happen. I think it's certainly setting a framework for what clinical trials going forward need to do. And I've learned a lot as the co-chair of the study about strategies, not just the importance of diversity, but the strategies that are actually in place to actually reach out to some of these underrepresented populations. It's been fascinating. I think it's a very important aspect of the protocol that I think will hopefully be a template for future studies, not just in prostate cancer.

Alicia Morgans: I certainly think it will. And I really applaud you and the team for being innovative, not just in the cool devices and tech that are incorporated into this trial, and certainly in the focus on quality of life, but also in the focus on inclusion, which is so important. And as you said, I think that this will serve as a roadmap, and maybe as something to which other studies can aspire and emulate, as they continue to try to make all of what we do more inclusive.

Arun Azad: Yeah.

Alicia Morgans: So congratulations on that. So, if you had to give a message to folks who are interested in potentially referring patients, opening the study, or patients who are interested in this, what would that be? And tell us too, it sounds like things are moving along and enrollment is happening. How is that going?

Arun Azad: Yeah, it's been open for four months and recruitment's going very well. So we're very happy with recruitment. It's running in nine different countries, and many of the sites are already open. So the study team's doing a great job getting it open.

I think in terms of the study, there's been a lot of interest. I can speak at our site, and talking to other investigators, there's been a lot of interest, both from the investigators but also from patients. I mean, I think we all recognize that ADT plus the not-so-novel hormonal agents, the formerly novel hormonal agents like apalutamide, are improving outcomes and doing great things for patients. But we've actually got to the point where we now need to talk about how we can actually safely deescalate and improve quality of life. And I think for patients, that really resonates because what do patients want from their cancer treatment? They want to live for as long as possible, but they want to live as well as possible as well. And living for a long time, but with poor quality of life, is not great.

And so, I think that's why there's been so much interest from not just investigators but particularly patients. When I've spoken to patients about this, and I can speak for other investigators who've told me the same thing, there's a lot of interest. I think the message to investigators and patients is, please consider it. I think it's a really important study. It's a very patient-centric study. And it's a study that could actually help to shape how we use these drugs in the future. So I think that's reflected in how well the recruitment is going, and we want that to continue, and look forward to further success.

Alicia Morgans: I agree. And just living is really not the goal anymore, is it? It's living well.

Arun Azad: It's living well.

Alicia Morgans: It's living well.

Arun Azad: Living well. Absolutely. Yeah.

Alicia Morgans: And I do commend you and the team for really ushering in a new era that's not just precise in terms of its targets but is actually precise in finding the right treatment to fit that patient. So congratulations, and I really look forward to hearing more about the LIBERTAS study as time goes on.

Arun Azad: Thanks so much, Alicia.