Phillip Koo:

We’re going to go on to the next study about DNA damage repair gene variants, and some interesting data presented. I believe it was GU ASCO.

Zachary Klaassen:

Yeah, so sort of on the same line of thoughts, you know, we're seeing… you mentioned precision medicine, we're hopefully going to have a pTEN target here soon. We've had BRCA mutations, talked about these for 15 years now, roughly. We have PARP inhibitors that do well with these patients.

So, to your point, Phil, we're starting to see target, target, target, can we treat with certain medicines? And this is a little more information based off of that sort of line of thought. So, this is metastatic patients, as you mentioned, ASCO GU, looking at these 3 specific ones, BRCA, ATM, and CHEK2.

This was 3,000 patients with metastatic prostate cancer. And what's interesting is, of those 3,005, 9% of them had one of these mutations. Most commonly was BRCA2, 2.8% ATM, 1.2%, and CHEK2, 1.1%. And so, we'll turn our attention to the bottom left of this slide.

The BRCA mutation patients were historically younger than those that did not have a BRCA mutation. We kind of knew that already, and we see that the Gleason grade group is significantly higher with BRCA2 compared to other patients that don't have these mutations.

Again, not too surprising. What I think's interesting is the CRPC progression in less than 1 year. 26 out of 46 patients with BRCA2 had CRPC progression, which means that their cancer went from a hormone-sensitive state to a hormone-insensitive state, and into another category of more aggressive and more potentially lethal prostate cancer, over half of those patients in less than 1 year.

And then the final thing on the right side is looking at the different mutations. We can see that purple dot is the bracket 2. This was the strongest predictor of worst mortality, when looking at ATM and CHEK2 and some of these other mutations.

And then that clearly correlated to the overall survival curve on the right. Median overall survival for BRCA2 was about 5 years compared to, 10 years with the patient that did not have BRCA2. So, really kind of already sort of confirming what we knew about these mutations.

But looking at it again in a big cohort of patients, this is an opportunity to always talk about genomic testing and genetic testing with our patients, and we've known for a while BRCA 2 is important. This continues to highlight that.

Phillip Koo:

Great, so, you know, to clarify for the patients online, this is germline testing, this is the genes that you might have inherited from your parents, and it's showing that, you know, having these DDR variants, BRCA, ATM, and CHEK means you probably have a more aggressive prostate cancer. 

There was a question about Decipher and Polaris. They're… they're similar, there's some subtle differences, but those fall into the genomic classifiers, which is different from the germline. So, different testing, but similar concepts of trying to identify the aggressives from maybe perhaps the intermediate versus not as aggressive. So, where do you foresee this going. I mean, I know we talk about BRCA a lot, you know, BRCA then allows you to receive certain treatments.

How will this impact what treatments they're given?

Zachary Klaassen:

Yeah, I think, you know, we typically, if you look at our guidelines, everybody with clinically localized high-risk prostate cancer, that's Gleason 8 and above, and everybody metastatic should be… should have a discussion about somatic, testing the tumor, or doing germline testing on these patients. The way I think about somatic versus germline is, if you're the only person in your family that has this cancer, I typically start with somatic.

If your brother had it, your uncle, your dad, your son even has it, potentially. There's something going on there. I typically will talk about getting both, somatic and germline testing, because this has implications for family members.

How should we inform this? I think just because you have a localized prostate cancer that has a BRCA2 mutation, doesn't mean you're immediately going to get a PARP inhibitor, but it will tell your provider that this is a higher risk tumor.

We're gonna treat this aggressively. We know we have this in our back pocket when we get to a point where PARPs are already approved, which was down the line. And so, it'll inform… Maybe surveillance regimens, maybe how aggressive the initial treatment is, and then subsequently will be a bullet in the holster when we need it in perhaps a metastatic setting.

Phillip Koo:

Great. I love that. I think it's important to have the information, to have a plan, work the plan. It's so informative, and you're right, being able… being two steps ahead all the time.