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Daniel Lin: So, switching to active surveillance now.

And, I would first say the first slide is in the current setting, Grade Group 1 equals cancer.

Okay?

In this setting right now, we know that grade reclassification is the primary driver. It's in terminal lung. Many people in this room have shown this. Although Grade Group 1 and Grade Group 2 is a gross oversimplification, we know that Grade Group 2 unto itself can still be active surveillance.

There are a lot more granular endpoints we can use. This was discussed in the plenary by many people, whether they're percent pattern 4, histologic patterns that are cribriform or otherwise. We do know that Grade Group 1 and Grade Group 3, I would say, is an unquestioned significant endpoint. This happens. This happens more than one thinks.

In the Canary cohort, of the upgrading events that are in the Canary cohort, a third of them are upgrading to Grade Group 3. This has been shown in other cohorts as well. I'm aware of some data from UCEF showing the same thing, especially in the form of biopsies.

There are other endpoints. Matt has promoted this change in CAPRA, from low risk, from 0.2 to intermediate, to greater than 3. I would point out, though, that you can get one point from a secondary pattern 4 to grade 4, one point for age over 50, one point for PSA over 6. I think that might have been modified to sum it up.

There are multinomial risk calculators, we have them. But then where's the reasonable cut point for risk at that endpoint? It's a very difficult one.

At this point, there's no MRI or PSA criteria. Maybe Declan will enlighten us and give us better insight on how we can go forward with that later today. There's no PSA criteria either. I think there's some community versus academic considerations.

We're all in the academic world, we are GU pathologists, we work with, we're talking about percent pattern 4, histologic patterns, cribriform and so forth, really that's going to be some big considerations for the GU pathology. I think biopsy compliance, in our setting, is much different than in the community, and then there are socioeconomic issues that impact the carers.

So the second slide is just now going to say that there is a nomenclature change. Grade Group 1 is no longer a cancer.

What is that going to look like in active surveillance for endpoints?

First of all, we don't know how to monitor yet. We're going to come across that, I think, today.

What's the biopsy schedule?

We have few predictors to predict reclassification. There's not going to be a clear trigger for biopsies. At least I'm not sure of one yet. We can use similar volume metrics and PSA density. We know that those are correlated. Poor biopsy compliance is already full right now as we speak. Could it get worse? I think it might, if we change the nomenclature.

What about the triggers for treatment for Grade Group 1?

What is going to trigger us to have treatment?

Well, certainly, maybe a higher grade. I'm not sure, and there are others that I list up there.

I think, Scott, you were the lead author on a paper for Aspall, a white paper saying high grade, high volume Grade Group 1.

We saw a slide earlier today about pack breakthrough, when it happens, not very often, but it does.

Is that going to be a trigger? We don't know, and of course you can't have a CAPRA of zero anymore if, say, they had a Pattern 4 so you have to change the CAPRA scale if we change the nomenclature.

Grade Group 1 to 2 will represent a new cancer diagnosis since it's going from no cancer to cancer. There might be some unintended consequences now all of a sudden we are going to have decreasing AS in favorable intermediate risk if we now call a Grade Group 2 a new cancer.

And then again, prostate cancer surveillance, unto itself, will only be in Grade Group 2.

So upgrading to Grade Group 3 or higher will be very much less relevant.

Matt, you asked to end on something, some future directions.

This is certainly one. What is that breakpoint between an aggressive and an indolent? And we heard Al Cerves give a great talk. Is it just this simplistic transition here? Is there some sort of percentage of Grade Group 2 that when we talk about Grade Group 3, if Grade Group 1 goes away?

And I think all this is certainly not probably going to be just a simplistic histologic diagnosis. There are other things we can use. Again, there is a list there. Many of us who are involved in some of these endeavors, somewhere in their findings, even within Grade Group 1, something genomically. Germline, somatically, AI.

And then I'll end by saying, I still think that we need, you can just advance and open.

I still think that we need extended outcomes in Grade Group 1 for clinically relevant disease, not just adverse pathology or treatment, not upgrading rates, not BCR, but we can talk about that later.