Alicia Morgans: Hi. My name is Alicia Morgans, and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today a friend and colleague, Dr. Cora Sternberg, who's a Professor of Medicine and the Clinical Director of the Englander Institute for Precision Medicine at Weill Cornell in New York, New York. Thank you so much for being here with us today, Dr. Sternberg.

Cora Sternberg: Thank you, Alicia. It's my pleasure.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about an abstract that you're presenting at GU ASCO 2021, an assessment of "Overall Survival and Metastasis-Free Survival by Depth of PSA Decline in the PROSPER Trial", and this was, of course, in patients with non-metastatic CRPC who were treated with enzalutamide. Can you tell us a little bit about that work?

Cora Sternberg: Okay, so the PROSPER trial, as I think you well know, was a trial in patients with non-metastatic CRPC, and this occurs in the United States in about 50-60,000 men a year, which is, if you think about it, that can kind of fill a whole football field, those 50-60,000 men, so it's not an uncommon disease. And before this trial and other trials like this came around, there really was no specific treatment for these men.

In this trial, we took patients with non-metastatic CRPC by CT scan and bone scan, with rising PSA, with a PSA doubling time of less than 10 months, and randomized them 2:1 to either receive ADT and enzalutamide or ADT alone. There were 1,401 men who were randomized into this study. In this study, we saw an improvement first in metastasis-free survival of 71%, which led to an almost two-year improvement in metastasis-free survival, an important improvement in time to chemotherapy, and a very important 27% reduction in the risk of death, which was almost a year difference improvement in overall survival.

So, what we looked at here was to try to investigate the association between the depth of PSA decline and both overall survival and metastasis-free survival in men with metastatic CRPC who were treated with enzalutamide in this PROSPER Phase III trial. And we looked at different levels, looking at a 50% decline, a 90% decline, and then we looked at patients who had a 90% decline in PSA with a nadir of greater than 0.2 or nadir of less than 0.2.

What we found in this trial was very few patients in the placebo and ADT arm had a PSA decline, and more than 80-some percent of patients, 90% actually, had a PSA response of greater than 50% in the enzalutamide arm, and some 65% had a PSA nadir of greater than 90% in the enzalutamide arm. And then when you look at the PSA nadir of more than 90%, and those of also less than 0.2, you can see that there was really a huge difference in terms of overall survival and metastasis-free survival.

So, the best group was, as you'd imagine, the ones with that greater than 90% PSA decline and a nadir of less than 0.2 in their PSA. Patients were not allowed on this trial if they didn't start with a PSA of at least 2. But their overall survival of this group of patients, the median has not yet been reached and the metastasis-free survival has not yet been reached.

If we look at the patients with a greater than 90% decline in PSA but the nadir was greater than 0.2, we still have quite a long overall survival of 64 months and metastasis-free survival of 37 months. And again, even the patients who had a greater than 50% decline, between 50 and 90% had an overall survival of 50 months and 26.2 months.

So, what this study shows you is that the relationship between PSA percentage decline from baseline and the actual decline below 0.2 ng/mL is important, and it emphasized the importance of PSA decline as an intermediate biomarker of risk of progression in non-metastatic CRPC. Thank you.

Alicia Morgans: Yes, of course. And thank you, and thank you to you and your team for putting this together. I think that as we take care of these patients and we see some PSA decline in, as you said, a vast majority of these patients, it's so important for us to be able to understand which patients have a really meaningful decline and what that number might be, and I so appreciate this point too, this cut off to help us try to understand that because we still have heterogeneous outcomes within our population, which this study really helps us understand. How do you use these kinds of figures in thinking about patients in your own clinic, and do you ever think about these types of things as you counsel men as they're being followed for their non-metastatic CRPC?

Cora Sternberg: Well, I mean, with patients with non-metastatic CRPC, I treat them with enzalutamide. When I first was writing this protocol, I was back in Barcelona a while ago, and I was asked to speak in a meeting, and there was no Phase III trial, no treatment. And now we have three Phase III trials that all show an improvement in metastasis-free survival and improvement in overall survival. So, I really believe that it's true, that each one of the trials shows the same similar results, and that it's important to treat these men earlier.

I must say that this data is very new in terms of the PSA decline, and I don't think that I would stop anyone if their PSA was declining because it wasn't a nadir of 0.2 yet, but I think I would think about it more that maybe these are the patients that will progress now that we know this new data.

Alicia Morgans: Absolutely, and I certainly would never encourage someone to do that. To be clear, we want to continue these patients on therapy for as long as they're benefiting, and certainly that would in most cases be until radiographic progression or development of a symptom, which is unusual in this patient population that's non-metastatic, but if a symptom developed, certainly we would want to make a change. And maybe it's just that we want to scan patients who don't get down to that nadir or patients who have a drifting PSA that seems to be coming up. Maybe it's that we want to keep a closer eye on their radiographic evidence of disease to make sure that we understand if the treatment's failing when it is.

Cora Sternberg: Within a clinical trial, we do a lot of scans. We're blinded to who's on enzalutamide and who was on placebo. But I think in real life now when we're treating patients, we're not blinded. We know what we're doing. And perhaps the scans are not as rigid as they were in a clinical trial, but one can look at this PSA and it's an easy way to understand what's going on, so I think it's important work.

Alicia Morgans: Absolutely. Well, if you had to give a summary, I guess, to those who are watching and trying to learn all that they can from the PROSPER trial, and congratulations on that work that you did all the way back in Barcelona coming to such an incredible fruition for patients in helping them not only prolong time to metastasis but also live longer regardless of subsequent therapies in the mCRPC space, what would your summary or your assessment of this work be?

Cora Sternberg: In men with the non-metastatic CRPC and a rapidly rising PSA, when they're treated with enzalutamide, there's a correlation between the depth of the PSA decline following treatment and improved outcomes for both overall survival and metastasis-free survival. So, I think looking at PSA response is very important, and it's important to look at both 50% decline, 90% decline, and also the depth of the nadir if it's less than 0.2.

Alicia Morgans: Great. Well, thank you so much for doing this work and for sharing your expertise with us today.

Cora Sternberg: My pleasure. Thank you.