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Alicia Morgan: Hi, I am so pleased to be here at GU ASCO 2024, where I am speaking with Dr. Guillaume Grisay, who is joining me from Belgium. Thank you so much for being here.

Guillaume Grisay: Nice to meet you. Thank you for the invitation.

Alicia Morgan: Well, it is nice to meet you too. And I am so excited to talk with you about the De-Escalate trial. This is a Trials in Progress presented this year. Can you tell me a little bit about it and why it was so important to think about doing a study like this?

Guillaume Grisay: Well, I think it's really important for the patients because all the trials currently ongoing are more of escalation trials than de-escalation. And we know that for some patients, patients who have a good PSA response after an induction treatment, maybe we over-treated them, or at least we're giving them treatment for a long period of time. By treatment, I mean ADT and AR pathway inhibitors, and this comes with chronic toxicities and financial burdens for the patient and society.

So, the whole idea is to reintroduce the concept of intermittent treatments that we used to do back in the day when ADT alone was the standard of care, and to see if intermittent treatment can be applied with the standard of care that we use today, which is ADT and AR pathway inhibitors. So the whole idea is to see if we can preserve the overall survival for the patient, while improving the quality of life when they're stopping the treatment or at least pausing the treatment.

Alicia Morgan: Wonderful. So tell me, who exactly are you enrolling in this trial and what are you doing and how is that randomization happening through the study?

Guillaume Grisay: The study population is patients with metastatic hormone-naïve prostate cancer who have achieved a deep PSA response, which we define as a PSA equal to or below 0.2 nanograms per milliliter after six to 12 months of induction treatments. And then there are some particularities of the study, mainly two. First, it's a pragmatic trial, which means that we are only going to collect data that are meaningful, such as the time without their treatment, their PSA level, and so on. The goal of the study is to be as close as possible to real-life clinical practice, so the patient will be randomized between intermittent and continuous treatment.

The other specificity of the trial is that we will use a two-stage consent developed by Andrew Vickers, which means that patients who achieve a deep PSA response will first sign the first informed consent, agreeing on data collection. And then, if they're randomly selected for the intermittent arm, they can either choose to participate in the intermittent arm and then sign the second ICF, or they can refuse and stay on the control arm, which is the continuous administration of ADT and AR pathway inhibitors.

Alicia Morgan: Wonderful. I love that design because I do think that it will help to improve feasibility because you're able to maintain that control arm. It definitely disrupts randomization, and so there could be some patients who might be enriched in one arm versus another. But I think that in an era where we have so many trials going on and are always trying to make things more patient-friendly and patient-centric, this is really thoughtful and responsive to patients who may have anxiety, not necessarily at the beginning when they start treatment, but at that time of randomization, and want to still participate and contribute to research but don't feel comfortable.

Guillaume Grisay: Absolutely.

Alicia Morgan: So I really commend you for that creative approach and a very patient-centric approach.

Now, what are the outcomes that you're looking for, and how are you doing the intermittent therapy? How are you standardizing that to make sure that it is similar across the intermittent arm? Or perhaps you're not standardizing it; maybe you're allowing it to reflect routine practice.

Guillaume Grisay: Yeah, absolutely. As we aim to be as pragmatic as possible, the whole idea is that the investigator will choose when to start or stop the treatment. So the point at which the patient will start the treatment again will be discussed with their physician. And I think it's really important because for some patients, they are more anxious when their PSA rises to one nanogram or so than others who can tolerate up to four or five, I don't know. So the whole idea is to be as close to real-life, once again, clinical practice.

This is really important too because I think it's vital to have patients on board with this kind of trial. We also asked the patient organization, Europa Uomo, to help us design the trial and to be as patient-centered as possible.

Regarding the outcomes, there are two co-primary endpoints. The first one is the number of patients that did not restart their treatment after one year. We're looking for at least 70% of patients who did not restart. This is for statistical reasons because if it's less than 70%, we won't be able to compare arm A to arm B. And the other one, obviously, is that it's a non-inferior trial, so we want the overall survival of the intermittent arm at three years to be non-inferior to the continuous arm, while improving quality of life.

Regarding quality of life, we also developed a new health questionnaire, [inaudible 00:06:00] questionnaire, with the patient organization, because the classical health questionnaires that we use, like PR25, don't really capture the way that patients feel when they stop their ADT. Such as sexual questions that don't really represent how patients feel when they stop the ADT, so we developed a new questionnaire to better capture what patients feel when they stop the treatments.

Alicia Morgan: I think that's so important, because as we've seen in multiple quality of life analyses that were designed five, seven, 10 years ago, unless we have precision on the part of quality of life that we really want to investigate and drill down on those symptoms that we expect to be different between the treatment arms, we will find in study after study that quality of life is similar between arms. When we know in clinical practice that there are very clear differences, we just haven't focused in on them as we wish we could.

So wonderful, and I'm glad it sounds like you've had a patient advocacy organization participate in that. Now, this study is being run through the EORTC, and as a non-inferiority trial, it may require a lot of patients. Can you speak a little bit about how many patients you expect to have in the study and how many countries you expect to participate in the work?

Guillaume Grisay: Well, we expect to enroll up to 1,600 patients all across Europe. So there are multiple countries involved in the trial, such as France, Spain, Germany, Ireland, and Belgium, obviously. So we really think that as an EORTC trial, we try to involve lots of different countries, also because it represents different clinical practices. So yeah, we hope that it will enroll as quickly as possible.

Alicia Morgan: Wonderful. And it is a big endeavor, and again, I commend you and the team for being bold and doing this kind of work because this is not easy stuff.

If you could just comment on the way that you, as a team, were so focused on being patient-centric. Do you have any thoughts to share about how important that was, and the ways in which you really engaged with the patient advocacy organization to make sure that the patient's voice was heard throughout this protocol?

Guillaume Grisay: Well, we involved them as early as the design of the trial, so they were with us all along the way through different phases of the development. And yeah, the whole idea is because, as you mentioned earlier, there's a clear difference between what we see in the study and what we experience in clinical practice.

So the whole idea was to involve patients as early as possible in the study development, sorry. And to really build a trial that represents as best what a patient can feel during the treatment to recapture these kinds of events that, as you mentioned, are not as often really captured in other trials.

Alicia Morgan: Wonderful. Well, I really appreciate that you've taken the time to talk to me about all of this. And I certainly commend the efforts that you and all of Europe are going to be going through to make sure that this trial is a success.

Do you have any final words or recommendations, thoughts, for the listeners on this trial as they consider De-Escalate?

Guillaume Grisay: Well, I think it's really important because there are other trials that are ongoing or will open soon that will labelize as a De-Escalate trial. But really important, I really want to stress out that this is a real de-escalate trial because the patient will stop both treatments, both ADT and their androgen receptor pathway inhibitors, whereas some other trials stop either of the two.

I think it's important to really prove that we can stop both treatments and really improve their quality of life. Because if you stop, for instance, only the ADT and the patient continues on their AR pathway inhibitor, they still get side effects such as fatigue or gynecomastia or something. So it's really important to improve the quality of life by stopping both treatments.

Alicia Morgan: And it's really important for us to do the studies to understand-

Guillaume Grisay: Absolutely.

Alicia Morgan: ... what the differences might be, and also to demonstrate safety in the era of these intensified therapies that we know are getting better outcomes for our patients.

So I truly thank you for your time. I commend you. I thank the patients who are going to be involved. And I really do look forward to hearing the results of this study, hopefully within a few short years. Thank you so much for your time.

Guillaume Grisay: Thank you.