Atish Choudhury: Thanks so much for this opportunity.
Zachary Klaassen: We've had such success with doublet and triplet therapy intensification. Just at a high level, how are we and why are we even considering these de-escalation trials now?
Atish Choudhury: Yeah. It turns out that a lot of patients actually do incredibly well on these doublet and triplet regimens. So this idea came from patients that I've seen in my own practice where we start them on ADT with an AR pathway inhibitor and we see these profound responses where the PSA gets to undetectable and it stays undetectable for a year, two years, three years. And then you ask a question, well, do you really need to stay on these treatments because the patients are having side effects. They're having fatigue and hot flashes. They're asking about potential recovery of sexual function. They're asking about long-term effects on bone health and heart health. And so we just wanted to ask a question, do we actually really need to keep these patients who are doing so well on these treatments on medication forever or is there an opportunity for some breaks along the way?
Zachary Klaassen: I mean, a lot of us are asking that exact question. So I love this data that we're starting to see some Phase II with A-DREAM. Just set up the trial design for our listeners.
Atish Choudhury: Yeah. This is actually a very simple trial. It's just to gather some initial data of what to expect here. So we plan to enroll 75 patients across national clinical trial network sites, patients who have been on ADT with an AR pathway inhibitor, abiraterone, enzalutamide, apalutamide or darolutamide for 18 to 24 months and their PSA is less than 0.2 and falling. And we just stop the treatment at that point in time and follow them very closely. The PSAs are being checked every three months, scans are being done every six months and we set some reinitiation triggers. If the PSA gets back above five, if we see some changes on scans, if there's some symptoms related to prostate cancer, then we resume. So the primary endpoint of the study is what percentage of patients that we stop treatment can make it out to 18 months from the end of treatment with testosterone recovery back above 150 nanograms per deciliter without having to resume treatment. That was the design.
Zachary Klaassen: Excellent. And like you said, very simple. They come in, they stop and then you're checking all these metrics as they're going forward. What were the high level results from this trial you presented at ASCO?
Atish Choudhury: Yeah. So the high level result was that we were trying to exclude the possibility that 30% of less of patients would achieve that primary endpoint, because if less than 30% of patients actually get out to 18 months with testosterone recovery, maybe this is less interesting and less interesting to follow up. But it turns out that 41% of patients actually met that primary endpoint, which we were pretty excited about and met statistical significance. And we followed these patients for more than two years after this interruption. So the median follow-up was 26.9 months, that's what we're presenting. And at that time point, 38.5% of the patients actually did not resume any form of cancer-directed treatment at the time of our last follow-up.
Zachary Klaassen: That's great. So I mean, if we think you take a hundred patients, 41 of those are going to recover testosterone at 18 months. Almost 40% won't start treatment again at 18 months of median follow-up over two years. How do we take this data? I'm going to ask you a sort of a two-part question now.
Atish Choudhury: Sure.
Zachary Klaassen: How does this inform future trials, maybe things that are already happening? How do we talk to our patients about this now?
Atish Choudhury: Yeah. So in terms of informing future trials, I think we have some kind of parameters that we can design around because we also found that patients who had high-volume metastatic disease were the ones who are more likely to have to resume treatment, which certainly makes sense. And patients who had radiation to sites of metastasis were actually less likely to have to resume treatment during this follow-up period. So it gives us just some benchmarks to compare against if we're going to do some adjustments in terms of larger trials that might incorporate things like PET imaging or cell-free DNA-based biomarkers or might be more selective around the population that enroll. That's not to say that high-volume patients can't get a treatment break. It's just that they're more likely to have to resume, which again is something to be expected. In terms of how we counsel our patients, I'll just a little bit cheat and say that even before this data, it was quite routine for me to actually give patient treatment breaks because of my own clinical experience with treatment interruption and seeing what we see in terms of likelihood of recurrence.
So in patients who actually have radiation or some focal treatment to all sites of disease and you treat them for a couple years and then you stop treatment, there's actually a large number of those patients who are many years out from the end of treatment and haven't need to have any resumption of treatment and patients who don't have local treatment to all sites of disease, they're more likely to have regrowth, but then you can treat them again. And so when you're counseling an individual patient, you have to say that we just don't have level-one evidence around treatment interruption versus continuous treatment in the era of ADT with androgen receptor pathway inhibitors because all the trials were designed for continuous treatment. If you think about the bladder cancer trials with pembrolizumab, the pembrolizumab was stopped at two years, but in these studies, they were actually given continuously without a comparator for a shorter period of time.
So if you think about things like patient preferences, patient side effects, comorbidities, like competing risks of death, you just counsel the patient, "This is what we see. This is what we expect, this is the kind of probability that you might need to go back on treatment over this period of time," and then the patient can make an informed decision because many patients actually decide, "You know what? I'm actually totally fine and comfortable with the continuous treatment. Just check my bone density every couple years. I'll make sure I'm eating healthy and getting regular exercise to decrease the cardiovascular risks." And they're very comfortable staying on continuous treatment, but many patients are very interested in a break.
Zachary Klaassen: Yeah. Great summary. I think this is great data. We know the cumulative toxic effects of ADT, as you mentioned some of them. Congratulations on the A-DREAM trial. Any final thoughts before we wrap up?
Atish Choudhury: I think that it's just important because a lot of people in the community really want this level-one evidence around interruption versus continuous treatment. That's probably not going to happen for years and years, but there are other studies along those lines. So there's a EORTC DE-ESCALATE trial that is a randomized comparison between continuous and intermittent treatment. So I think if you have a patient in front of you tomorrow, you have to gather the information that we have and then offer patients choices so that they can make informed decisions.
Zachary Klaassen: Wonderful. Great conversation, Atish. Thank you.
Atish Choudhury: Thank you for the opportunity again.