Phillip Koo: Hello, my name is Phillip Koo. Welcome to Uro Today. Today we're very honored to have with us, Evan Yu, who's a GU medical oncologist and Professor of Medicine at the University of Washington. So today we're going to be talking about the new term that we've been hearing a lot about phenotypic precision medicine. And it's a term that I think is sort of becoming more socialized in the GU community in large part due to a lot of the advancements that we're seeing with PSMA.

So first off, thank you Evan for joining us. And could you explain to us what phenotypic precision medicine means?

Evan Yu: Yeah. Thanks Phil. It's great to be here again. I think the reason this term has been adopted recently is the fact that when people use the term precision medicine, it's really a springboard that comes from what I would say is genotypic precision medicine, which is everyone thinks about next-generation sequencing, you find a specific gene mutation and you might have a drug that mutation confers extreme sensitivity to that drug. And so that's what we're all trying to do. That's the holy grail, right? Okay. You have a EGFR kinase domain mutation in lung cancer, you're going to come in with an EGFR targeted therapy. And so I think when people talk about precision medicine, that's where they're going. In prostate cancer, let's say BRCA2 and then they'll talk about a PARP inhibitor.

But I think what people don't think as much about is the term phenotypic, which is not what's going on with a gene level, what's going on with the mutational level. With phenotypic really is his characteristics that the tumor shows or expresses. So one simple thing to think about is just the protein expression of the tumor. So for instance, there can be certain proteins that are highly expressed, highly conserved, expressed on the tumor cell, on the cell membrane, and that aren't excreted, it might be great targets for therapy. And so, and if it's expressed very specifically on the cancer cell and not so much on normal cells then it might be a great target to send different types of therapies in there. And I think in prostate cancer that's where a prostate-specific membrane antigen or PSMA fits perfectly into that term phenotypic precision medicine.

Phillip Koo: Great. Well, thank you very much, that explains a lot. So the question I have is with the VISION trial that was presented and obviously, that's based on PSMA targeted therapy, the topic of PSMA imaging comes up. 87% of those patients were PSMA positive. So this idea of the value of PSMA imaging, the value of actually knowing the phenotype, comes into question. What are your thoughts on the importance of PSMA imaging in that setting based on what we know from that trial?

Evan Yu: So I'll just tell you, I have mixed feelings on it, and I'm going to tell you why I have mixed feelings on it. The academic intellectual in me says, absolutely we want more information, we want to get as much information as possible and have some sort of a biomarker that selects patients potentially for therapy and that hopefully we might be able to use as a marker of a pharmacodynamic response and select out mechanisms of resistance, mechanisms of sensitivity, et cetera. So more seems better. But I can also see the flip side, is that if it's 87% were positive by their definitions and allowed onto the study, that's such a high rate that one wonders whether you need to do this. Whether you need to get that study, that isn't going to be completely cheap, it's not going to be free. Do we need to have that expense, that costs there if the vast majority of people are going to express that phenotypic biomarker there? And it's a really valuable question, I think the FDA will help guide us here in the near future.

But one thing I will bring out is the fact that their requirements for entry onto the study VISION trial were not just PSMA PET-positive, right? They excluded patients that had large PSMA negative lesions. And so one might take a deep dive into that 13% that screen failed due to PSMA PET imaging and look and see of that 13%. Some of those patients might've had a large number of lesions that were still PSMA PET positive. Maybe there was just one or two lesions that were negative and they were excluded for that reason. It's possible that those patients might still gain some benefit from lutetium treatment. And one wonders whether the actual PSMA PET positivity rates technically a lot higher, it's just that some people had some heterogeneous lesions and one or two might not have expressed that. I mean, the concern obviously is that they're heading down some sort of lineage plasticity neuroendocrine pathway, but we don't truly know that without a biopsy. So it could be an even a higher rate than 87%, in which case, then you'd make the argument easier to say maybe we don't need the image of these folks. But I have mixed feelings.

Phillip Koo: Yeah. Yeah. I tend to agree with you. I think we're only scratching the surface when it comes to the phenotype of these patients and the expression of PSMA. And I think we're still learning what PSMA means, what does the degree of expression of PSMA mean with regards to the patient's outcome? Does that mean more aggressive, less aggressive disease? I think we all assume that more PSMA positivity, probably less likely to be FDG positive. And that ties into the therapy trial from Mike Kauffman in Australia that use both of those. I think I would be sad and disappointed for us to sort of throw away imaging as a biomarker right now. I think it's a little too early, so I hope it is included as a companion diagnostic. And I hope we continue to study and learn more about it before we come to some more of those conclusions.

So moving forward, where do you think we're headed with regards to phenotypic precision medicine within PSMA imaging and also beyond PSMA?

Evan Yu: Well, that's a really great question. And I think that if PSMA PET imaging is not included as a companion diagnostic, we won't move as far forward. The academic in me says, is totally with you, because if you include it as a companion diagnostic for selection of therapy your next logical step, to answer your question, is that you're going to want to see what happens as a response marker, treatment response marker. And right now we're using PET imaging in prostate cancer to kind of find the lesion, maybe for earlier stages of disease, for staging, for identifying lesions, for potential oligometastatic directed therapy.

If, as a companion diagnostic for lutetium, it'll be a treatment selection marker. But really the next step is if we start doing that, we got to go beyond the baseline marker, we got to start imaging for treatment response and trying to understand what it means. What we're seeing what does that mean in regards to long-term outcomes? Might we be able to select out patients that are going to be extreme responders or patients that are not going to be good responders or even identify heterogeneous disease and find the bad actors, maybe the clones that are going to drive resistance and maybe we'll design a whole set of studies where we go in and radiate those resistant clones and that makes a big difference down the road. We aren't going to know that without this as a companion diagnostic biomarker there. So I think that's where we're going to go. But first we have to see that it gets incorporated in as a companion diagnostic and we'll wait and see what the regulatory agencies say.

Phillip Koo: That's great, lots of great points. I've no doubt you'll be answering a lot of those questions. And I often joke that Evan, you is more of a diagnostic imager than I am because your knowledge of imaging over the past decade has been really, really cutting edge. So thank you very much for your time and a pleasure to speak with you.

Evan Yu: Thanks so much, Phil. It's always great to be here at Uro Today. Have a great day.