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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Atish Choudhury. He's a senior physician at Dana-Farber Cancer Institute. Thank you so much for being here with me today.

Atish Choudhury: Thank you so much for the invitation.

Alicia Morgans: Well, wonderful. You know, Atish, I have really admired a lot of the work that you've done some of the work we're talking about today is a study that you're running through the Alliance Cooperative Group. And it's a study called A-DREAM really focused on how we can find the right balance of treatment duration for patients with metastatic prostate cancer. Can you tell me a little bit about why this is even an issue? Why, why don't we just treat patients with metastatic disease in perpetuity like we have been, for many years with their androgen deprivation therapy?

Atish Choudhury: Yeah, it's a great question because androgen deprivation therapy works very well for metastatic prostate cancer in, uh, many patients. And especially when you add some of these newer drugs that are used to block hormonal signals even more intensely, you get really profound responses. People's PSA levels can go to zero and their disease basically disappears on scans. And so we keep them on these treatments often for years and years and years. And what you see over time is that people start to develop more symptoms related to these medications, generally weight gain, muscle loss, bone loss over time. And there are some concerns that long-term treatment with these medications can lead to increased risks of other sorts of complications too, like cardiovascular complications, you know, slowing down of memory, mood changes. And so obviously if you're going to be on these medicines ongoing in forever, these are impactful and they accumulate over time. And so if you can incorporate some planned breaks in the treatment trajectory we do think that that might benefit patients along these different kind of avenues where they might have some side effects. In addition to that, there are costs of these medications, and so it might also help limit the cost of these medicines to give people breaks.

Alicia Morgans: Well, and I think one of the most important points too is that metastatic prostate cancer is a heterogeneous disease. And really there are some patients who, like you said, have a profound response with PSAs that are undetectable and, and lesions that are not visualized on their scans. That doesn't happen for every patient. Sure. And so this really allows you to have not just a one size fits all approach, but one that is really tailored to the, to the patient, tailored to the cancer and also, as you said, really is trying to limit the complications that may be worse from the treatment than they are from the disease. So, so tell me a little bit about, you know, the study, how does it work, who's eligible and what are you doing?

Atish Choudhury: Sure. So the A-DREAM stands for ADT interruption in patients responding exceptionally to AR pathway inhibitors, meaning the potent hormonal drugs in metastatic hormone sensitive prostate cancer. So it really is for the set of patients who've responded exceptionally to these treatments. And we define that with a PSA of less than 0.2.  It has to be downtrending because if it's starting to creep up, then it's starting to tell us that maybe the cancer is becoming a bit resistant to the hormonal medications. And the idea is that when people have completed about 18 to 24 months of treatment, and we wanna give a good long time on treatment to try to shrink the cancer as much as possible before that break, then you stop, you stop both the testosterone lowering injections, and you stop the more potent hormonal pills. And then you're just monitored very closely.

We check PSAs and testosterones every three months. We do imaging every six months, and then we've set some parameters to then resume the treatment. And those parameters are, if the PSA gets back above five or you see some changes on standard imaging CT scans or bone scans, or if the patient has some symptom related to prostate cancer, obviously we would resume the treatment. And part of the reason we feel comfortable with this is because the patients who respond exceptionally to those potent hormonal treatments to start with, we do expect to respond very well once we resume. So if we allow a bit of a break to recover some testosterone to allow the men to have maybe some recovery of sexual function or libido if they can, but also to have some recovery of muscle strength and bone strength, if they're eating well, exercising all of those things during that break, then by the time they might need treatment again, then their body would be more fit to undergo that next cycle of treatment.

Alicia Morgans: Great. Now, how is this different from the SWOG study published many years ago where we looked at intermittent therapy, in a metastatic population and had similar parameters around starting and stopping, but it was, you know, temporarily based to stop and then I think PSA over four to restart or you know, in that setting it seemed almost to many, well, the question is, is answered and, and there's potentially increased mortality. Now, how is this study different?

Atish Choudhury: Right. So that study was done at a time where people thought intermittent treatment was actually going to be better. That actually giving the cancer back some testosterone during these breaks would actually prolong men's survival because it keeps the cancer dependent on hormonal signaling. But that turned out not to be true. And so when they designed the study, they designed it in a very sort of liberal way around, very minimal treatment with the hormonal drugs. So actually patients were treated for only seven months and only with testosterone lowering alone, because this was before the era of these more potent hormonal pills. And as long as the PSA was anything for or less, then they could stop. And, you know, four is still a fairly, you know, high number for us in the modern era to think of taking a treatment break. And then the resumption criteria was the PSA had to get above 20 or above whatever the PSA was before they started on treatment.

So patients were kept at a much higher level of disease burden throughout this intermittent process than what we're proposing here, which is really selected for the patients whose PSAs really do get to, you know, pretty much undetectable. And after 18 or 24 months of treatment, so you feel like you've really slowed down the cancer, put a good amount of the cancer to sleep, made some of those cancer cells even completely dormant so that people could get a good time off treatment. And so the primary endpoint of the study is actually time off treatment. And so how long does it take for patients to meet one of those criteria that we stipulated to then have to resume the treatment? And so the primary endpoint is the percentage of patients who can make it 18 months with recovered testosterone without having to have resumed the treatment.

Alicia Morgans: Thank you for that explanation, because I think that's so important to differentiate for clinicians who are thinking about this question and how we're really setting things apart in this situation. Really that heterogeneity of response is captured so well and the intensive hormonal therapy that you're giving and parameters that are so much tighter in terms of restarting treatment. I think it's just a really exciting study and I know that I have patients who want to come off of treatment and are going to be really excited to participate. Now for those clinicians and for those patients who are out there watching who think, you know, is this something that I could participate in? Is this study open at many centers? And how would someone find out if it might be available near them?

Atish Choudhury: Sure. So this is a cooperative group study, and it's being administered through the National Clinical Trials Network (NCTN). And so most academic centers have some NCTN affiliation, so the patient can go to clinicaltrials.gov and look up the trial and see if one of the institutions near them is participating. Any member institution of the NCTN can elect to join through a site called CTSU. And we are certainly very interested in as many people from as many different places participating in the study because certainly everyone's different experiences we wanna be able to capture.

Alicia Morgans: Fantastic. So we'll make sure that we have a clinicaltrials.gov link and really at the bottom where we can see locations, people can investigate if it might be available near them.  Very, very helpful. So what's your final message on this study, which is so exciting A-DREAM?

Atish Choudhury: Yeah, so I do think that we have so many tools and so much information that's available to be much more aggressive at the very beginning when people are starting on treatment. So there's been data that suggests that radiation to the prostate, even in metastatic disease can be helpful for survival in a subset of patients. We have the opportunity potentially to treat metastatic sites, and we have these more potent hormonal medications that can bring the cancer down to very, very low levels. And once we established a really, really good response, then we have this opportunity to, you know, have men recover their testosterone and see how long they get before they need to resume. And I think it really, you know, so many patients are looking forward to that. They feel much better about starting on treatment when they feel like there's a limited time that after this period of time I'm gonna come off and then I'll see how it goes. And I think it, this gives an evidence base to our colleagues at other institutions that this is a reasonable thing to do and we're not harming people. And I think putting that all together, we kind of try to maximize patient's quality of life as much as we can, knowing that metastatic prostate cancer is something that people can live with for years and years and years and years.

Alicia Morgans: Wonderful. So really harnessing our current technology, our current treatment paradigm, and understanding how we can help those patients with those exceptional responses to ensure that their survivorship is actually the best that it can be. So thank you so much for your time and your expertise and of course for putting together this trial.

Atish Choudhury: Thank you. Yes. Thank you so much for this opportunity to discuss it.