Fabio Turco: So thank you very much for your kind invitation. Good afternoon everyone. I'm Fabio Turco and I'm really proud to describe the DE-ESCALATE trial. As you say, this is a pragmatic trial that evaluated a de-escalation strategy in patients with metastatic hormone-sensitive prostate cancer. So as you know, the standard of care in this setting is represented by combination therapy. So ADT plus androgen receptor pathway inhibitor plus or minus docetaxel. And in this scenario, the ADT plus ARPI is a continuous therapy. So patients are treated with these combinations until progression or until some unacceptable toxicity.
We want to evaluate if in a subset of these patients with metastatic hormone-sensitive prostate cancer, we can use intermittent therapy because we think that maybe not all patients with metastatic hormone-sensitive prostate cancer needs continuous therapy. So we are enrolling this study because it's already open. Patients with metastatic hormone-sensitive prostate cancer treated with an ADT plus ARPI-based therapy, that means or double therapy, ADT plus ARPI, or triplet therapy, ADT plus ARPI plus docetaxel, or also patients who receive the radiotherapy to the primary or also radiotherapy to the metastasis.
So if these patients will reach a PSA below 0.2 after six to 12 months from the start of this ADT plus ARPI-based therapy, this patient can be enrolled in this trial that will randomize these patients in two arm. The standard of care are the discontinues the ADT plus ARPI therapy or the intermittent arm that is stop both ADT and the ARPI and restarted this therapy all in case of progression. This trial had the two co-primary endpoints. So the percentage of patients who did not restart the therapy after one year from the stop of the therapy and overall survival.
Kristine Peregrino Lacuna: I think that's wonderful. And to get back to kind of the rationale and the kind of reasoning behind the trial, we know that patients who achieve a deep response of PSA of 0.2 have better prognostic outcomes. Can you talk a little bit more about that in terms of the setting? And also going back many, many years ago we actually saw a trial from Maha Hussain looking at intermittent hormonal therapy and sort of debunked, at least at that time in that setting of hormonal therapy, that we should really be giving continuous. So kind of fast-forward to the contemporary times, can you talk about how your study fits into that and that PSA response?
Fabio Turco: Okay. So regarding the point that why we choose patients with a PSA below 0.2, we choose this patient because, as you say, there are several trials that show that reach a PSA below 0.2 is prognostic. So patient who reached this value, the better prognosis that the patients didn't reach this PSA value. These are true for patient treated with ADT monotherapy in the era when ADT monotherapy was standard of care. But it is also true in patients treated with the contemporary standard of care treatment. So patient treated with ADT plus ARPI, there were data in the LATITUDE, in the TITAN, but also we have data in the [inaudible 00:03:48] where patient who reached this PSA below 0.2 had a better prognosis. So we know that these patients are patients who are a better prognosis. And so we think that these patients could benefit from intermittent therapy instead of continuous therapy.
Regarding other studies that in the past have evaluated this intermittent strategy, as you know, the most important trial was the trial in 2013 published by [inaudible 00:04:16] et al. In the trial we'll enroll the patient with metastatic hormone -sensitive prostate cancer treated with ADT alone because ADT alone was the standard of care at the time. And if these patients reached the PSA below four nanogram per milliliters, they could be randomized in continuous, arm continuous ADT or intermittent ADT.
So this is one of the difference in this trial comparing to the DE-ESCALATE, because this patient should reach a PSA below four while in our trial we decide deeper PSA response. So PSA below 0.2 because PSA below 0.2 is this prognostic... Adds this prognostic value. So this is one of the difference of this trial. And in reality, if you read carefully the trial by [inaudible 00:05:11] et al, the trial wasn't inconclusive by a statistical point of view. So we cannot rule out that there is a difference between intermittent and continuous therapy in this setting of patients.
Kristine Peregrino Lacuna: Yeah. No, and I think that that's a great point. And in clinical practice, you and I probably see patients who it's very hard for them to continue continuous hormonal therapy. There's a lot of side effects. There's cardiac bone disease. And so I think it's really important to revisit this strategy. And so take me through a little bit more about your clinical trial design, how you came up with the two arms. It's a randomized study, which I think is really important. We'll get to A-DREAM later, but I think that's a really important study. Just take me through the arms, the different arms, and then the criteria that you use for restarting hormonal therapy.
Fabio Turco: Okay. So this is a pragmatic trial and this is a phase-three randomized trial. And in this study, as I said, we want to evaluate two different arms. So first arm continuous treatment. So patient will continue ADT and ARPI, while they're intermittent in the intermittent and the patient stop at both ADT and above ARPI. Since this is a pragmatic trial, we added the fixed criteria to establish when patients needed to restart the treatment. But this is left to the description of the physician. But we clearly stated in our protocol that we encourage, we suggest to restart the treatment, of course, in case of clinical progression or radiographic progression, but also in case of PSA progression, especially we wrote in the protocol that we suggest to restart the treatment in case of the presence of a PSA above the 15% compared to the baseline level or more than five nanogram per milliliters. So these are some of the criteria that we suggest to the clinician when to restart the treatment.
Kristine Peregrino Lacuna: Gotcha.
Fabio Turco: And another important point of this study is that if the patient in the intermittent arm should restart the treatment because of PSA progression, clinical progression, radiography progression, these patients could re-suspend again the treatment if they reach again a PSA below 0.2 after the start of the treatment.
Kristine Peregrino Lacuna: So it's a cycle. Yes.
Fabio Turco: Exactly.
Kristine Peregrino Lacuna: No, and I think that's really great. I think this is a question not only for you, but for the entire community of prostate cancer. PSMA PET scan and evaluating disease, oligo progression. How are you factoring that in metastasis-directed therapy into your study? Is it still that they're on the off treatment when they're off and they can restart it afterwards? How does that fit in into your study?
Fabio Turco: Of course, since the PSMA PET is used a lot, of course, in this setting, especially in patients with a rising PSA. If the patients had a PSMA PET after rising PSA and the PSMA PET showed an oligo metastatic disease, it is allowed for the study to perform a metastasis-directed therapy without restart the hormonal treatment if the physician think that MDT will be an option for these patients without systemic treatment. So in this case, it is allowed to perform this treatment without restart the systemic treatment. This is led to the investigator to choose if for that patients with that PSMA PET, it is useful to perform an ADT instead of restart the hormonal treatment.
Kristine Peregrino Lacuna: No, and I think that's great and it mirrors clinical practice. I think that this is a very pragmatic approach. It's a large study and I think that's really great. And as a segue to that, we saw data from A-DREAM yesterday, which was a positive study, a single-arm study, cooperative group study, but showing that it's possible that intermittent therapy is something that we might be seeing in the future. Your study is a randomized study, which I think is really exciting. How does your study tie into that and talk about what your thoughts are surrounding A-DREAM?
Fabio Turco: Yeah, no, no. The results of A-DREAM that were presented yesterday were promising because as you said, it is possible to use this strategy in these patients. That was a single-arm Phase 2 trial. In that trial, patients received a longer time of ADT plus ARPI therapy, 18 or 24 month of this treatment. While our study is a larger study, it's a Phase 3 randomized trial, but the concept is the same. Also in A-DREAM trial, the patients suspended both ADT and ARPI if they reached the PSA below 0.2, like in our study. And the results were very promising. 41% of the patients were in a testosterone recovery, 18 months after the testosterone recovery, they didn't restart the treatment. So this is very promising also for the results of our trial. And I think that our trial that is a randomized Phase 3 trial will give us the final answer to the question, it is possible to use a de-escalation treatment in this setting.
Kristine Peregrino Lacuna: Yes. No, I think that that's great. And one of the things that they talked about in A-DREAM was looking at other biomarkers in the beginning. Are you doing any correlative studies looking at those patients who might have high-risk markers and those who are able to cycle on and off treatment throughout your study?
Fabio Turco: Yeah. Since it is a pragmatic trial, at this moment we aren't evaluated some, for example, molecular analysis, some NGS analysis, because as you know, it's not standard of care in every country to perform a large NGS panel. Maybe now with the results of TALAPRO and AMPLITUDE, maybe we started to perform at least BRCA or HRD alteration in metastatic hormone-sensitive prostate cancer. But this is not standard yet. And for sure it's not standard yet to perform a large NGS also to evaluate other biomarker that will be, I don't know, LB1, TP53, PTEN. This could be useful, but since ours is a pragmatic trial, we should keep it pragmatic. And since it's not yet standard of care and since it's not possible to perform this analysis in every country at this moment we haven't performed this type of analysis in our study.
Kristine Peregrino Lacuna: Gotcha, gotcha. No, that makes total sense, especially how large the study is. And take me through where you are now in terms of the study. How many patients have enrolled? Where are we? Because we're obviously very much eager to look forward to the data that's coming.
Fabio Turco: Yeah. So in total, we want to enroll 1,600 patients. I had a call with my team a few days ago and we are very close to enroll 300 patients. So the enrollment is going very well and we received very positive feedback also from the center that started to enroll patients and also from the patients that are very enthusiastic to participate in this trial.
Kristine Peregrino Lacuna:That's wonderful. Well, congratulations on your trial. We're eagerly waiting the data and it's something that we should be thinking as a field for our patients for quality of life. If we can really do something like de-escalate therapy, that's something that we should really be thinking about in the safest way possible. So thank you for joining us today.
Fabio Turco: Thank you very much. Thank you.