You know, in what setting would you say if somebody already has sort of not great bowels that you would say this is a non-starter or would you just aggressively address that so they would have a shot at this medication?

Yeah, you know, I think the thing to recognize is we're dealing with an accelerated disease course.

This cancer is going to cause symptoms sooner rather than later.

So it's worth trying in these patients that have loss of P10 to see if they can tolerate it.

But in someone that's already having, say, irritable bowel or GI symptoms, this is where it might be, you know, leaning towards adding Imodium a little bit sooner rather than later, Loperamide.

And maybe even prophylactic.

The onset of diarrhea is within 12 days.

So I

And I'll ask you, Dan, In what setting would you say if somebody already has sort of not great bowels that you would say this is a non-starter or would you just aggressively address that so they would have a shot at this medication?

Yeah, you know, I think the thing to recognize is we're dealing with an accelerated disease course.

This cancer is going to cause symptoms sooner rather than later.

So it's worth trying in these patients that have loss of P10 to see if they can tolerate it.

But in someone that's already having, say, irritable bowel or GI symptoms, this is where I might be, you know, leaning towards adding Imodium a little bit sooner rather than later, Loperamide.

And maybe even prophylactic.

The onset of diarrhea is within 12 days.

So I think

Well, and Dan, I might ask you, you know, just in terms of if this actually was going to go to the clinic, how are you going to make a choice? We now have an abundance of riches of doublets and triplets and emerging other lutetium and PARPs? What do you think?

Yeah, I think that's going to be a really important question, but all of these are relative subsets.

So when you're looking at sort of 25% of patients that have this 90% or greater loss of P10, the number of those patients that are going to have a BRCA mutation or MSI-high probably going to be really low.

So I don't think we're going to see overlap of these targetable, actionable approaches too often.

But there are other less biologically defined approaches like docetaxel chemotherapy or potentially radioligand therapy that could be applied to these populations.

The truth is, is that we don't have prospective data with those approaches in this population.

I think the most important thing to recognize is that this study, Capitella 281, defined a new biologic subpopulation of prostate cancer, P10 deficiency.

Yep.

What do you think?

Yeah, I think that's gonna be a really important question, but, you know, all of these are a re- relative subset.

So when you're looking at sort of twenty-five percent of patients that have this ninety percent or greater loss of PTEN, the number of those patients that are gonna have a, a BRCA mutation or MSI high probably gonna be really low.

So I don't think we're gonna see, like, overlap of, um, these, these, these targetable, actionable, um, you know, uh, approaches too often.

Um, but there are other less, um, l- less, you know, biologically defined approaches like docetaxel chemotherapy or potentially radioligand therapy that, that, that could be applied to these populations.

Mm-hmm.

The truth is, is that we don't have prospective data with those approaches in this population.

I think the most important thing to recognize is that this study, CAPITELLO-281, defined a new biologic subpopulation of prostate cancer, PTEN deficiency.

When should this testing be done? Should it become relevant when this path either moves forward or doesn't? But I think the audience wants to know that as well as Nirmal does.

Yeah, yeah.

I, I, I'll tell you that, you know, what's been tried and true and studied for a long time is immunohistochemistry.

There's also FISH, and, and I, I showed one slide with some of that where we can kind of look at the, the nuclear chromosomal level of that gene present.

But, but probably, you know, what's newest is, um, genetic testing or next gen sequencing of, of multi-gene total tools like we see with like Foundation or, or Caris or Tempus.

So to me, I think recognizing these, uh, as, as, as different modalities of assessing P10.

But immunohistochemistry, been around the longest, is, is the direct measure of the protein.

Mm-hmm.

Go ahead,

Dan.

Thank you, Elizabeth.

Thank you all for coming this evening and enjoying, hopefully, informative information about what we see as really kind of an... an important target in prostate cancer, one that's been around for a long period of time that we haven't really taken advantage of.

And I hope in this session I can kind of walk you through that background information around this genetic alteration and what we call PTEN deficiency, its biologic and clinical implications.

Okay.

Let's start a little bit broadly to start here around biomarkers, because I think, you know, when we think of prostate cancer and where we are today, already in practice, we have a number of validated biomarkers that we're using.

What do you think?