Charles. J. Ryan: I want to make a few comments about this trial AFT-19, or the PRESTO study, presented by Dr. Aggarwal. I think this is a very important trial and may be underappreciated for a couple of reasons. The first is that it's the first phase three study in serologic relapse that we've seen have a positive result, at least that I can think of. There is no standard of care for patients with serologic relapse, although we know by following these patients for a long period of time that many of them are destined to experience metastatic disease, CRPC, and death from prostate cancer. And so, this is an area where we can intervene early, and we can begin to alter the trajectory of their disease, and indeed alter the trajectory of their life, by establishing more effective initial therapies. That's point number one.

Point number two is that it is a finite duration of ADT. On the other side of the spectrum, many patients are overtreated for serologic relapse. They go on ADT, their PSAs go down, and they think they're doing well. But over time, the toxicity accumulates. So, although we're looking at doublet, and maybe even triplet therapy, in this setting, and there may be more side effects from the treatment, that's for a finite duration. And then, the treatment stops, the testosterone recovers, and the patient is off treatment. So, even if the median duration of time off treatment is only slightly longer if you translate that into a population effect, you're going to see hundreds, if not thousands, of months, potentially, for a population of treatment freedom, or freedom from the side effects of treatment.

The third point is that there are going to be outliers here. And as Dr. Aggarwal said in our brief interview, there are patients who have recovered their testosterone, and their PSAs have not risen. And we've known for a long time that there are individuals out there who have a very sensitive form of this disease, a very sensitive form to ADT and that even a brief course of ADT like this may lead to prolongation or very prolonged time without therapy. So, the possibility that a patient could take ADT plus Apalutamide for a year, and have that followed by three or four years of freedom from treatment, is incredibly encouraging because when we think about the cumulative side effects of treatment, and we think about the freedom from the burden of being on therapy for that period of time, it can translate into a lot of time when patients are protected from side effects, we're preserving their good function, and they're not accumulating the toxicity of ADT.

So, perhaps I'm a little biased because I helped design this trial with the Alliance team, and I participated in it by enrolling patients. But I think we're going to see a lot of exciting developments from this space, generally, but also this trial in particular as we look at time to metastases, perhaps the role of PSMA PET imaging in the setting of recurrence, and of course, the safety of this approach considered over the full course of many years of follow up.