Charles J. Ryan: Hello from ESMO 2022 in Paris. I'm very excited today to be speaking with Rahul Aggarwal, my friend, and colleague from the University of California San Francisco. Dr. Aggarwal has led a really important study that I've known as AFT-19, or the PRESTO study, in serologic relapse and just reported on the top-line data at ESMO. Rahul, welcome. Great to see you. Congratulations.

Rahul Aggarwal: Thanks, Chuck. It's great to see you.

Charles J. Ryan: Tell us about the study and what you found.

Rahul Aggarwal: Yeah. This study was basically looking at a finite duration of treatment for patients with a rising PSA after prior surgery. So basically the biochemically recurrent, hormone-sensitive setting. There was three treatment arms. The standard of care was ADT monotherapy, so Lupron or an analog, the combination was Lupron plus apalutamide, so that was one experimental arm, and then the second was a triplet, Lupron, apalutamide, and then abiraterone with prednisone. In all three arms, patients were treated for a year, and then treatment was stopped and patients were followed for PSA progression, which was the primary endpoint of the study. The goal being to see whether intensification of ADT can really prolong PSA progression-free survival, and that might translate into longer treatment-free intervals in this setting.

Charles J. Ryan: This is a really important space because serologic relapse is so common and there's really no standard of care in this setting. As an oncologist myself, I worry, are we undertreating some people and are we overusing ADT? So this finite duration is really key. But also the risk determination of who should actually get treated in the first place. That was based on PSA doubling time. Let's talk a little bit about that.

Rahul Aggarwal: Yeah, absolutely. Risk stratification is huge for these patients. Patients with a slow PSA doubling time really ought to be observed and not necessarily need any form of systemic therapy. We chose to select the high-risk patients that basically had a doubling time of 9 months or less. We know that that's a group of patients that's at higher risk of development and metastasis and prostate cancer related mortality.

Charles J. Ryan: The primary endpoint was PSA progression-free survival. What you find in terms of hazard ratio, et cetera?

Rahul Aggarwal: Yeah. We basically reported the results today of our first interim analysis. So this was after about 50% of our PSA-PFS events, and we see a statistically significant improvement in PSA progression-free survival in both experimental arms compared to the control. So with ADT plus apalutamide, we see a median improvement from 24.9 versus 20.3 months, with a hazard ratio of 0.52 and a p-value that met the efficacy boundary. Similarly, for the triplet versus the monotherapy, we see a median of 26 versus 20 months and a hazard ratio of 0.48, also meeting the efficacy boundary.

Charles J. Ryan: How did you incorporate testosterone recovery into those findings?

Rahul Aggarwal: As a secondary endpoint, we actually looked at PSA-PFS in the testosterone evaluable population, those group of patients that recover their serum testosterone after treatment completion. Similarly, in that group of patients, we also see a significant improvement in PSA progression-free survival, and we looked separately at time to testosterone recovery and did not see any meaningful difference between the treatment arms.

Charles J. Ryan: Oh, interesting. And good. There's always more to learn and more to follow here we need to look at metastasis-free survival, et cetera, I'm sure, but how do you expect these subsequent findings to be found and for us to hear about them?

Rahul Aggarwal: Yeah, absolutely. I think the longer-term follow-up is very critical to look at metastasis-free survival, time to castration resistance, and even time to subsequent therapy. We chose a pretty stringent definition of PSA progression of 0.2 or higher. Not all patients are restarted on treatment at that level, and so looking at those longer-term outcomes are really help to better define how broad of an impact this the study results will have on standard of care.

Charles J. Ryan: Do you have preliminary safety outcome data?

Rahul Aggarwal: We have preliminary safety data that basically shows good tolerability, especially with the doublet versus monotherapy. With the further addition of abiraterone, we do see a higher rate of grade 3 hypertension as one would expect.

Charles J. Ryan: Right. But we're also on the flip side. If we're showing that a finite duration is going to lead to a reduction in the long-term use of these therapies, we might see a safety advantage over time because patients are going to be potentially off therapy for a greater period of time, one would hope.

Rahul Aggarwal: That's exactly right. It's trying to strike that balance of enriching for a high-risk population, but then trying to improve the quality life by extending that treatment-free interval. We are going to be looking at patient-reported outcomes, both on and off treatment, and hopefully, see a benefit there.

Charles J. Ryan: I've enrolled patients onto this trial myself, and my discussion was always, we're looking to see whether an investment, perhaps, in more intense therapy, taking more therapy, potentially facing more side effects, leads to a payoff, a return on that investment in your time. That leads me to wonder, do you know yet, are there outlier patients who take the therapy for a year and then years are seeming to pass and they're not having PSA recurrence?

Rahul Aggarwal: Yeah, absolutely. These outliers are fascinating. What makes their cancer so hormone sensitive that their testosterone recovers in its years before the PSA starts to come, we did see those patients. Whether there's a big difference between treatment arms there, we need longer follow-up to see, but the biology of those patients, regardless of treatment arm, I think is going to be very important.

Charles J. Ryan: I totally agree, and I think we're going to have to look at, if we can, androgen receptor status, androgen metabolism status, obviously tumor genomics may drive a lot of this as well. A great top-line data. Congratulations, really important study. I think it accrued well, rapidly, and with a very good patient selection criteria. Obviously, a lot more to learn from this trial.

Rahul Aggarwal: Yeah. Thanks, Chuck. Appreciate it.

Charles J. Ryan: My pleasure.