Zachary Klaassen: Hi, my name is Zach Klaassen, urologist at Augusta, Georgia. I'm joined on UroToday by Dr. Steve Freedland, who is a urologist at Cedars-Sinai in Los Angeles, California. We're both in Chicago for ASCO 2025, and we'll be discussing some really interesting data that Steve presented at ASCO, looking at the importance of a PSA nadir of less than 0.2 in metastatic hormone-sensitive prostate cancer specific to the VA population. So Steve, thanks as always for carving time out of your busy meeting to join us on UroToday.

Stephen Freedland: No, thanks so much for having me, Zach. It's great to be here.

Zachary Klaassen: So we've seen just recently with ARANOTE, we've seen it in TITAN, ARASENS, ARCHES, all of these big mHSPC trials have looked at subgroup or post hoc analysis, looking at the importance of 0.2 or less for PSA. This is really an important discussion point with patients when we sit there and we say, we're not trying to get your PSA to 1 or 0.5. We're really trying to drive it as low as we can. So maybe just highlight in your thoughts why this is so important and why that message is important to get out.

Stephen Freedland: Yeah, no, it's a great question. And I think it goes down to physician education. So you and I did a study with Neeraj Agarwal, Dan George, others published in JAMA Network Open, where we did a survey of physicians and said, what are your goals in treating mHSPC? And the majority of physicians actually picked a percent decline in PSA, not an absolute number. And the median decline that they would have been happy with was 50%.

Zachary Klaassen: Not great.

Stephen Freedland: Not great. And when we asked them an exact number, the median PSA, their target was 2.

Zachary Klaassen: Yeah, also not great.

Stephen Freedland: No, no. And so the question is, if you got a 90% drop in PSA, intuitively, that's pretty good, right? You would think, OK, I'm pretty happy with that 90% drop. But the question is, is that good enough? And how low do we need to go? I think of the limbo, how low can you go? And we saw some nice data from ARANOTE Neal Shore presented to AUA. Really, as low as possible. So that was the question we had was if you got a 90% drop, was that good enough, or do you really need to hit that 0.2?

Zachary Klaassen: And just tell us about the study design because this is really important. This is not a trial. This is real world evidence. I believe the first real world evidence has looked at this importance of 0.2. Just tell us about the design and the database.

Stephen Freedland: Yeah, so we use the VA database, VA-Wide, using claims data to identify patients with metastatic hormone-sensitive prostate cancer that were getting ADT plus minus other things, real world. A lot got ADT alone which they shouldn't be in the modern world but are ADT plus an ARPI, various treatments. And regardless of how they got there, we said did your PSA drop 90%, yes or no, by nine months? Give them nine months to get there. And then we said did your PSA get to less than 0.2 by 9 months, yes, no?

And then from that nine months on, what were your outcomes? And what we found is if you dropped 90% which again, sounds pretty good. You had a 22% lower risk of death, no difference in survival or progression. So 22% is kind of modest. Whereas if you hit the 0.2, there's over 50% reduction in death and over a 50% reduction in progression. Really saying below 0.2 really separates out good or better, I should say not good, but better from worse. 90% drop just doesn't give you that separation.

Zachary Klaassen: And no OS benefit with that 90 versus 0.2, right? You've got to get to that 0.2 to get the OS benefit.

Stephen Freedland: You had a little bit at 90%, but statistically significant but relatively modest. Nothing to write home about.

Zachary Klaassen: I'm going to give you the platform to basically hammer home what we've been talking about. We just saw 90% response versus 0.2 isn't good enough. 0.02 is better than 0.2, like you just said, we've heard a month ago. So in a month we've seen these are very different metrics. So what are you going to tell our listeners about what we got to do to get it as low as possible?

Stephen Freedland: And that's the nice thing is we actually looked at what's the likelihood you got to that less than 0.2. It's much higher with ADT plus an ARPI. So I think that's the decision that you have to make early when you're seeing that patient. You can't say, well, let's start with ADT and if we don't get where we want we're going to add an ARPI. That doesn't cut it. You really got to start with the combination up front, drive that PSA as low as possible. Even if you got 0.1, I'm not thrilled with that. I'm an ultra sensitive guy. I want it less than 0.01. That is really where I want to drive it down.

And that's where we're seeing the best outcomes for our patients. And we're seeing some updated data here on ARCHES and ENZAMET, doublet therapy being presented at ASCO. The outcomes for the doublet for some of those patients can be really good. And so as we start to think about the next step of do you really need doublet for life in some of these patients. Can we withdraw doublet? And after a year or two, nine months, none of us really know that answer.

But if we're going to consider that, which I think can probably have a lot of quality of life benefits, I want that PSA, not 90% drop, not a 50%, certainly less than 0.2. But I would like it even lower than that.

Zachary Klaassen: Great point. The last thing I want to hit on just before we wrap up, because I think it's really important for this study because of the population and because this hasn't been looked at in a real world situation. We've seen it again in the trials, is just the generalizability of it. 28.5% African-American, just talk to how important that result is in terms of dispersing to the population.

Stephen Freedland: Yeah, and that's to me, one of the beauties of the VA data is I think it does better represent the general population out there. The US population in general is 13% Black. We know there are 2/3 more likely to get prostate cancer, twice as likely to die. So as we get to advanced prostate cancer, it should be about double those 13%. So when you're hitting 28%, that actually is pretty representative of the general population. And we know they have good access to care through the VA equal access system.

So obviously we would love to see this replicated in other data sets. But I do think this probably is generalizable to the general population and it fits the clinical trial data. It makes sense, intuitively. So to me, it is a broad statement now that we can say that really, if we're not getting below 0.2, and we can debate how low below 0.2, but if you're not getting to even 0.2, that's bad.

Zachary Klaassen: That's a problem. Steve, lots of great teaching points in this discussion. Thank you for your time, as always.

Stephen Freedland: Thanks for having me.