Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Urologic Oncologist in Houston, Texas. And it's a pleasure to be joined today in our forum by Dr. Benjamin Maughan. Benjamin, welcome.

Benjamin Maughan: Thank you so much. It's wonderful to be here. As always, I always love visiting with you and really appreciate the amazing work that UroToday does to help with dispersing high quality information. So, thanks.

Ashish Kamat: Yeah, and speaking of high quality information, you're going to enlighten us today on something that has really taken off in the last three or four years. I mean, we've been doing liquid biopsies in one form or the other for almost 20 years, but really the evolution and the progress has really been exponential in the last several years. So, liquid biopsies in GU oncology, tell us everything we need to know.

Benjamin Maughan: Yeah, thanks. Well, I mean, I don't know I can tell you everything we need to know in our short time together, but you're right, it really has reached this inflection point, and I think that's because of really two things sort of happening simultaneously now. One, we have this increased number of treatments that are dependent on some molecular signature or whatever, like some gene mutation being present or something. And then additionally, the quality, the technology of the liquid biopsies has dramatically increased. So, for instance, about 10 years ago when I started doing this, the number of genes, for instance, that were covered was only about 70 in any given company's random commercially available liquid biopsy kit, and now it's different from one company to another, but now they're more like 500 or 700 genes. So, it's much more expansive in the depth of it is much better.

The sensitivity has dramatically increased because they're able to do these sequencing in much more sensitive ways. So, it's really the combination or pairing of both of those that are tremendously changing the role of liquid biopsies in GU oncology. So, we tried to synthesize this very recently with the review article that we were fortunate enough to be able to get published in European Urology. Even there, this really would require something more expansive, like a book chapter or something to be truly comprehensive. But we were able to highlight a few examples of that and let me share a few of those with you. But I think very briefly what we were able to do is really highlight some key reasons or examples of why liquid biopsy is clinically actionable today. So, importantly, liquid biopsy is just a way of looking for some endpoint or signature within a blood sample. I mean, technically it doesn't have to be a blood sample. Liquid biopsies is technically broader than that. It could be CSF, could be urine, whatever.

But as of today, right now, the clinically actionable liquid biopsy approaches from blood, although again, that will evolve over time in the GU space. Most notably, that's going to include urine samples eventually. But from that source, you can do a whole variety of things like you can see on the left, you can look at whole cells like measuring circulating cells or looking at metabolites or proteins or lipids. The one that's the most advanced today is DNA, looking at genomics. But even within DNA, there's other things you can do like methylation or fragment, looking at fragment pieces. So, what we did in our review is really just try to establish how clinically relevant this technology is today.

So, what we did is look through all the different sort of alerts, etc that the FDA has, and we try to identify what are all those drugs, not ... We excluded testing, imaging tests or whatever that are sort of dependent on genomics or some liquid biopsy. And we were really just looking for therapeutics. So, we identified all these therapeutic indications and there's more indications than nine, but there were specifically nine drugs that were dependent on a liquid biopsy. Now, there's more drugs that are approved based on some specific molecular feature, but some of those are like a IHC testing from a tissue sample. So, we excluded those. We were looking at how applicable is liquid biopsy testing in the clinic today. And there's a variety of applications that can be used. So, there's prognostic applications and a few examples are shown here. There's others. These are just a few examples.

And in terms of predictive applications, so the use of the therapy is dependent on the molecular testing. We've outlined how they're applicable here. And there are some, it's important to know that are tissue agnostic. So, if a patient has an NTRK fusion or a BRAF mutation, then regardless of whatever the underlying cancer disease is, then there's BRAF inhibitors that are approved or NTRK fusion therapies that are approved, etc. The ones that we are probably more familiar with in the GU space is erdafitinib for FGFR fusions or mutations, and then HRR status for prostate cancer in terms of a PARP inhibitor being indicated. But this is also evolving the current clinical trial landscape, and we give some examples of this as well.

How certain clinical trials are being developed that likely are going to show that your testing is a requisite part of determining if the patient's a candidate for that therapy. The best example of this would be the PARP inhibitor studies in prostate cancer to date. So, in summary, I would say that genetic testing is very important for changing the care for patients. And liquid biopsies are very important for obtaining a lot of this prognostic information and predictive information for how we treat our patients with GU cancers. And additionally, something that we really didn't get into that much in the manuscript just because of space and limitation issues we talked about a little bit, but they can also be used as a treatment monitoring tool. So, so far, most people think about the qualitative value of liquid biopsies.

So, trying to describe a cancer, does it have this mutation, does it have this amplification, whatever. But liquid biopsies can also be useful in a quantitative way. So, very much like PSA we use as a quantitative function, at least in therapeutic monitoring, is it going down? Is it going up? You can do a similar thing with liquid biopsies. And then again, as we alluded to, you and I at the beginning of this, there's additional large changes that are likely coming or I should say certainly coming with additional applications for this technology. But even as of today with the number of applications we have, it has an important place in clinical management today for patients, in my opinion.

Ashish Kamat: Thanks so much, Benjamin. That was a nice review. And of course we'll have the link to the entire manuscript at the bottom of this UroToday video. What you say makes a lot of sense. And oftentimes you'll have patients, and I'm sure you face this too, that sit in the office and say, "Can you do a blood test? Do I need the scans? Do I need a biopsy of this lymph node, et cetera? Can I just do a blood test and can you figure out if I have cancer or not?" We're not there yet, right? But we are long ways away from 15, 20 years ago when I would be asked that by patients and I have to say, "No, we don't have a PSA for bladder cancer or kidney cancer, or something like that." Tell us a little bit, looking in the future, where do you think this liquid biopsy is headed as far as tissue agnostic? And we'll still say with GU, but really tissue agnostic detection of cancer?

Benjamin Maughan: Yeah, that's a really great point. So, when I think about liquid biopsies, the value really depends on what the application is. So, we talking about as a diagnostic tool that's in the example that you alluded to, that's much harder to accomplish and improve. But in terms of therapeutic monitoring or treatment selection, that's really where the application is presently. I suspect at some point we'll be able to do the diagnostic piece from liquid biopsies as well. But there's so much information that we obtained from a path specimen, it's going to take a lot of innovation to sort of supersede that value from purely a liquid biopsy. I really see all of these technologies as complimentary because fundamentally with cancer in terms of treatment selection or treatment planning for a patient, it really comes down fundamentally to the disease biology, how aggressive or less aggressive is the cancer, and secondly, what's the extent of the problem presently.

And so to answer those two fundamental components, we use a bunch of orthogonal testing to really help us arrive at that comprehensive assessment. And so I see liquid biopsies as really being a very useful augment to everything that we do currently. But again, over the next five years, today, plus the next five years, the greatest advancements with liquid biopsy in my opinion, will be in therapeutic monitoring and treatment selection. For instance, in prostate cancer, we've been able to dramatically improve the survival for patients where the median survival is somewhere in ... the median survival for patients with metastatic or unsensitive prostate cancer is somewhere about five to eight years given the underlying disease biology variance. But now that's long enough that we really have to start thinking about the long-term consequences of the treatments that we're employing, especially if you're talking about triplet the versus doublet therapies.

And so one useful tool that we found is looking to better define disease biology is like SPOP mutations, right? Cancers that have these SPOP mutations are very sensitive to the hormone therapy manipulation. And so in clinic today, I use that as one of the, not the only, but one of the selection factors that I look to decide, should I do triplet therapy versus doublet therapy, or conversely, if they have a lot of molecular features associated with very aggressive disease biology, like PTEN mutations, p53 mutations, et cetera. So, again, over the next five to 10 years, I think treatment monitoring and treatment selection is where we're going to see the biggest advances with this technology.

Ashish Kamat: Yeah, no, I agree. Because like you said, right now it's complimentary, but when you have tissue and you can come up and do assay for all these mutations, the liquid biopsy is more of like a supplement in some ways or confirmatory. But when you don't have tissue, for example, a patient who's had, say a radical cystectomy and an [inaudible 00:12:14] was coming up and there's some press releases out there, which I'm sure we're going to hear the data, but when you don't have tissue per se, and you're just monitoring patients and you're looking at, for example, ctDNA, that liquid biopsy of sorts is a really good way to figure out which patients need either escalation or de-escalation of therapy that can be toxic even though it's less toxic than say, systemic chemo. And also what's interesting is that there's a lead time.

You have your ctDNA detection, for example, in patients with bladder cancer, and it leads the radiological detection of tumor by at least three to six months if you look at some of the data that's come up. So, it's a way to identify early, which patients may need acceleration of therapy, but also a way to figure out which patients don't need intensification and de-intensification of therapy. So, I think, like you said, the manuscript couldn't cover everything, and I was kidding when I said you're going to tell us everything we need to know about liquid biopsies, but there's a lot more to be done, and hopefully when we do this again in a year, we'll have you back to give us an update.

Benjamin Maughan: Yeah, agreed. Yeah, that's a great point is that there's two fundamental applications to liquid biopsies, a qualitative component, and a quantitative component. The quantitative component really can be used as a very sensitive assay, very similar to how we approach PSA in terms of trying to find minimal residual disease that's too small to be seen on whatever imaging technology that we have. So, yeah, there's lots of applications for this technology and it's exciting to see the advances that we have made with it to make it clinically useful today. But also it's exciting to think about the advances that are going to happen over the next short time period of just a couple of years.

Ashish Kamat: Great. Thanks so much, Benjamin, for taking the time. Always good to have you.

Benjamin Maughan: Great to be here and great to visit with you.