Atish Choudhury, MD, PhD, on Can Patients With an Exceptional Response to ARPIs Interrupt ADT?

What we know is that adding an androgen receptor pathway inhibitor to ADT leads to much more profound and prolonged responses compared to using ADT alone, and these drugs lead to overall survival benefit in men with metastatic prostate cancer. However, in those trials, you stayed on these drugs ongoing and forever. And what we're observing in our practice is that there are many men whose PSA level, which is a measure of their cancer activity, goes to undetectable levels on these medicines. And then you're keeping them on continuously, kind of forever, for the rest of their life. And then you're subjecting them to all the toxicities and costs of staying on these treatments forever. So we asked a pretty simple question. If we take the group of patients who are experiencing exceptional response to these treatments after 18 to 24 months of treatment and then just stop, what happens? Are there patients who can actually recover testosterone? And among the patients who recover testosterone, how many can actually stay off treatment and for how long? So we designed a study where we planned to enroll 75 patients. In the end, 78 patients enrolled, where if their PSA was less than 0.2 at the 18- to 24-month time point, we stopped treatment and monitored them very carefully with PSA and testosterone checks every 3 months, scans every 6 months, and quality-of-life questionnaires every 6 months. And the primary endpoint of the study was: What is the percentage of patients who can make it out to 18 months after stopping treatment with testosterone recovery and not have to resume? And we thought anything above 30% would be interesting in terms of moving forward with further studies. And what we found was that 41% of patients who stopped treatment made it out to that 18-month time point with testosterone recovery without having to resume treatment. And more interestingly, potentially, as we've been following these men a median 26.9 months after stopping treatment. And actually 38.5% of the patients, even at that later time point, haven't needed to resume any treatment whatsoever, which is probably a higher number than what most people would have expected, even though about 35% of the patients who were in the study had actually high-volume disease to start with. So pretty remarkable off-treatment outcomes. When we look at the patients who actually died in that follow-up, there were 4 deaths, but actually only 1 was from prostate cancer. The other 3 deaths were from unrelated causes: myelodysplastic syndrome, influenza, and myocardial infarction. So there's no obvious evidence from our study that there's some negative cancer-related outcome by taking this treatment break. So what we concluded is that, you know, even in the absence of real randomized phase 3 data, if you have a patient who's struggling with side effects from treatment, if they're an exceptional responder, they could probably safely take a break and probably, if you resume the treatment, still have activity against the cancer and probably have a very low likelihood of dying of prostate cancer. So in terms of next steps, this is very challenging because do we really want to enroll patients to continuous treatment trials moving forward because of the toxicities associated with continuous treatment? So I think what we're trying to learn now, based on retrospective studies of this study incorporating some molecular analysis as well, is who are the patients who can have these very prolonged treatment-free intervals? And can we design trials to more smartly identify those patients and more smartly potentially stop treatment even earlier or in a larger subset of patients or maybe a smaller subset of patients? This is what future studies really need to determine.