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Zach Klaassen: Hi. My name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are recording live at the American Urological Association 2024 meeting in San Antonio, Texas. I'm delighted to be joined by Dr. Jack Tay, who is a senior consultant urologist at Singapore General Hospital. Dr. Tay, thanks so much for joining us today.

Kae Jack Tay: Thank you, Zach. It's my honor to be on UroToday.

Zach Klaassen: It's great to have you. We're going to talk about a great topic today, the epidemiology of focal therapy. We'll delve into the talk that you're giving on this topic, but really highlighting focal therapy in general. For our listeners, by way of background, what focal therapy options are out there currently?

Kae Jack Tay: The concept of focal therapy really is to treat just the area of cancer within the prostate and leave the uninvolved prostate tissue, or perhaps where the non-clinically significant cancer is, untouched because those can be on surveillance and just monitored. In that sense, the toxicity from whole gland treatment is reduced. For example, if we treat near one nerve, that's better than having the whole prostate removed or irradiated around both neurovascular bundles. That's the concept of focal therapy.

There are many different energy modalities that can be used to deliver focal therapy today. The traditional ones would be cryotherapy or HIFU. Those have been around for a long time. But what's new is that with more understanding, more usage of MRIs and targeted biopsies, and the understanding of the biology of prostate cancer, now we know where to focus those energies. The newer energies would be irreversible electroporation, which is NanoKnife. People are using lasers. There's TULSA, Transurethral Ultrasound Ablation. There are many, many modalities that are available now. But at the end of the day, the concept is what's important. We are treating the area of cancer within the prostate and leaving the uninvolved prostate tissue alone.

The real question is, does this concept work? There's a lot of discussion about that at the meeting this year, and also at the focal therapy session that's coming up on Sunday morning. For those interested, I definitely invite you to come down to that session and contribute your views. There's a lot of science that supports treating just the focus of cancer within the prostate, but there's also a lot of science that needs to be done, which is why in major guidelines, there is still a recommendation that focal therapy be done either within a clinical trial or at least within a prospective cohort study so that the outcomes can be recorded.

Zach Klaassen: Yeah, it's a great introductory statement. That's great. In terms of the patient selection, let's talk about that. I know you've done some work with Decipher. We'll get into that. What's the appropriate patient, and then maybe dovetail that into some of the work you've done with the Decipher Genomic Classifier.

Kae Jack Tay: A lot of the work on patient selection comes from our understanding of prostate cancer biology. So it goes all the way back to those studies that were published on the natural history of prostate cancer. That helps us understand that really it's the higher-grade and higher-stage prostate cancers that are lethal. And a lot of the low-grade, low-stage cancers are actually the indolent ones and probably constitute the five out of six men who are diagnosed with prostate cancer but never die from it.

With that understanding as a beginning, there are also a group of randomized trials, and I'm going to speak about this in my talk on Sunday morning, which show that truly when you treat localized prostate cancer, it's really those that have intermediate and high-risk disease, mainly those with intermediate-risk disease, that actually benefit from it. And this was shown in SPCG-4 and other trials.

In fact, if you look at the more recent trials with a high enrichment of low-grade, low-stage populations such as PRO-TECT or even the PIVOT study, then one would find that actually the effect of treating the disease in its localized state is actually reduced. We actually are not seeing such a strong signal.

Zach Klaassen: I see.

Kae Jack Tay: Yeah. That gives us a clue that really it's patients with more high-grade cancers and perhaps those with limited volume, clinically significant prostate cancers, that really are candidates for focal therapy.

So in fact, we have several expert consensuses on this done through the Focal Therapy Society, and I think our most recent consensus is that intermediate-risk disease really is the sweet spot for focal therapy. And there are some more detailed parameters that experts have been discussing. There is some consensus that perhaps we should treat limited volume less than three milliliters for a single lesion, perhaps up to 1.5 milliliters when there are two lesions to be treated with focal therapy. And there's a very, very strong consensus now that you definitely want to do an MRI beforehand so that we can identify the targets, define the volume of targets for adequate ablation, and do targeted biopsies of the lesion.

And there's also increasing data that doing halo biopsies around the lesion will help us define what is the extent of that particular lesion so that we can decide on how much ablation to do and then go deliver that ablation.

Zach Klaassen: Excellent.

Kae Jack Tay: So I think patient selection has really come down to radiological and pathological assessment. And there's also increasing data to show that a multidisciplinary discussion between the treating urologist, a pathologist, and a radiologist really is crucial along with, of course, other modalities such as radiation specialists and other surgical oncologists to deliver the best outcomes for the patient.

Zach Klaassen: And how about Decipher? Are you guys incorporating that into sort of understanding truly the risk of these patients? Because you're right, if you've got a nice MRI lesion, we've got targeted biopsies, but Decipher maybe gives us an example or at least some information as to what may be going on with the rest of the prostate. Is that how you're using it?

Kae Jack Tay: Exactly. The entire problem with the field of focal therapy really is that it sounds really promising. It looks really good. Now we can see the lesion, we can treat it, but where are the long-term outcomes? We don't have long-term outcomes yet, and if we wait for long-term outcomes, that's going to be 20 years before we can get survival data.

So in lieu of that, what do we have? And there are many, many prospective cohort studies out there. Some of them are really well conducted that are able to give us some kind of surrogate endpoint. And I think those with a repeat MRI and biopsy are really critical for us to look at those results. If we are treating a lesion that we see on the MRI and proved on the targeted biopsy, then one way that we could look at how successful our treatment was is to go back and do another MRI, biopsy that area again, and biopsy the other areas to see whether there are any new lesions that occurred. So oncologically, I think that would tell us about the biology of the disease and the adequacy of our ablation.

So I think the whole issue is that if you look at those particular cohorts who have mandated a repeat MRI and repeat biopsy, the failure rate overall is something like 20%. There's a 20% persistence of clinically significant prostate cancer after focal therapy, whether it is within the treated area, which is what we call in-field, or outside the treated area, which is what we'll call out-field.
And there are some technical differences between these two labels. In-field recurrence could be because there was inadequate ablation, then we might have to go look back into like, did we deliver enough energy? Did we deliver into the right spot? Was there some technical factor? Whereas with out-field recurrence, we are concerned about the biology of the cancer. There were some really nice talks today on looking at are there cancers that can cause intraprostatic metastasis? And that could be a cancer that has a fate that its future is going to be multifocal.

Now, if we could identify these patients early, these patients shouldn't go through focal, they should just go straight to radical therapy. So that's the big divide here. Are we actually able... Despite our rigorous selection criteria, now we are seeing a 20% failure rate. So can we identify these 20% from the get-go based on the biology of their disease? And that's where Decipher comes in.
We've used the Decipher platform to really look into the molecular profile of the lesions. So in fact, in our cohort in Singapore, we have accrued 52 men as an initial pilot study, who have all had focal cryotherapy and they have received a one-year repeat MRI and repeat biopsy. And that's where our part of the study looked at when we profile every single lesion in these 52 men, we profiled 83 lesions in these patients. These were detected using MR and biopsy, and we took the highest grade core in each particular lesion and did Decipher on them. And Decipher has been around for a long time. We know its value in predicting response to radiation therapy after biochemical recurrence after prostatectomy. And there's been some work on it in the active surveillance space as well.

But there really is no biomarker for focal therapy at present. And the Focal Therapy Society actually published a consensus paper on this. We looked at all the biomarkers and there was no evidence for the use of biomarkers in focal therapy. So I think this particular work with Decipher is really exciting because for the first time we've shown that the classifier score provided by Decipher actually does predict... We've found a higher GC score, which is genomic classifier. The GC score correlates to clinically significant prostate cancer recurrence one year after therapy.

Zach Klaassen: I see.

Kae Jack Tay: And beyond that, the platform actually allows us to look into the why.

Zach Klaassen: Yes.

Kae Jack Tay: So there's a gene set enrichment analysis based on their grid database where we can look at cancer hallmark pathways, and the tumor immune microenvironment that's around the tumor. And at the same time, there are several classifiers to look at the luminal basal subtypes of cancers. Because we feel that prostate cancer is very similar to breast cancer, for example, because they are basal and luminal cells and cells of origin and that they have different mechanisms in terms of resistance to therapy.

So we did find in our work that some luminal basal molecular subtypes, there's a particular luminal differentiated subtype that do particularly well with focal therapy. We found a 0% recurrence rate in this group. Whereas in the other groups, in the luminal proliferated group, they have the highest rate of recurrence, something more than 30%. And there were other basal immune and basal neuroendocrine groups that fell somewhere in between.

Zach Klaassen: I see.

Kae Jack Tay: So it wasn't just a score that was generated. The score is what people most commonly use when they do a commercial Decipher test, but also the underlying pathways. We also found that the DNA repair hallmark pathway, for example, was correlated with a higher rate of recurrence. So I think altogether, Decipher is just one platform.

Zach Klaassen: Sure.

Kae Jack Tay: But I think that altogether these tell us that in the molecular universe, there's going to be added value for us to profile these lesions that are going to add to our clinical profiling as well. So I think that moving forward with this work, we continue to triangulate the radiology, the pathology, and the molecular profiles. That's going to be really exciting to help us better select patients for focal therapy.

Zach Klaassen: Yeah, that's really well said. And I think to your point, you're trying to not do focal therapy on those 20% that aren't going to do well, and this is where Decipher can come in and help with classifying these patients. I want you to maybe give us a couple of take-home messages from your talk that you're giving this weekend on epidemiology. What sort of highlights can you give our listeners from that talk?

Kae Jack Tay: Yeah, going to cover some of what I said. We're going to touch on the natural history and our understanding. The talk is on epidemiology, and which patients seem to be suitable. Very interesting work on what's been published currently and showing that 20% recurrence rate. Also work that's very interesting from a prostatectomy series looking at people who looked at large databases of prostatectomy and then gone back and said, pretend that we've tried to select some of these patients with focal therapy and how many of them would've been suitable on the end prostatectomy?

Zach Klaassen: Yes.

Kae Jack Tay: And they actually found that it was something like out of all comers, only one in six men became eligible for focal therapy. So one of the key messages is that focal therapy is not for everyone. It's going to be something very attractive. I think physicians are going to feel a lot of pressure to offer focal therapy. And we should offer focal therapy because it is a very good option in the well-selected patient. But we are going to have to talk to the patient and show them very clearly evidence that only when you fulfill certain criteria, then one's going to be a suitable candidate.

The other part of the talk is about changing epidemiology in the world. And there have been some really nice data published on that which show that first prostate cancer is increasing.

Zach Klaassen: Yes.

Kae Jack Tay: Why? I think the aging population is a huge thing. Every developed country is aging with a lower birth rate. So we're going to see a really higher proportion of prostate cancers. And so we really have to get this patient selection down pat, because how much of our taxes going to healthcare dollars are going to be spent on this population problem of prostate cancer? And if we are unable to be selective and to know who to treat, then we're going to generate huge healthcare costs. So that's going to be very important for our communities and our economies as well. Really a clarion call to everybody to look clearly at the science and also look into advances in the science such as molecular profiling.

Zach Klaassen: That's great. Last question before we wrap up. I want you to give just a quick overview about what somebody should be looking for if they're looking to start a focal therapy program? Should they stick to one sort of, I guess, thermal energy? What's your advice for somebody looking to start a program?

Kae Jack Tay: I've done quite a fair bit of focal therapy over the years, and I was very blessed to have very good mentors and teachers. And yet I would say that what I do really depends on what I was exposed to as well. So I'm quite clear of that particular bias. I did an SUO fellowship at Duke University in 2015 and 2016. We have an excellent group of faculty at Duke University. One of those was Dr. Thomas Polascik, who was really a leader in the field of focal therapy. He did cryotherapy. So that's where I got started. But at the same time, I did have exposure to other modalities, HIFU, irreversible electroporation, and there's so many new technologies coming up right now.

I would say that the best focal therapy is what you have available to you. That's number one. Number two, what are you trained in? If you are familiar with that particular technology, you will know the ins and outs of it. For example, for cryotherapy, people always say that it's safe to do it for anterior, and that's all it's good at. But really if you know how to manipulate the probe, if you know how to place your temperature probes and monitor the ice ball, you want to do it for posterior lesions as well.

Zach Klaassen: Sure.

Kae Jack Tay: And number three is that, know the limitations of a technology. When I did cryo, I realized that I can't treat well periurethral and 40% of tumors are periurethral. So that becomes the important part of my patient selection and my MDT. If I identify a periurethral tumor within five mm of the urethra, I don't offer them focal therapy. But that's how I expanded my program as well. So after I hit about a hundred cryos, I started doing irreversible electroporation. And that technique kind of builds on the earlier technique because cryo was about transperineal needle placement. So I'm very comfortable with placing needles transperineally and doing biopsies transperineally. So placing a transperineal IRE needle really was the next step up. So it like we just built-

Zach Klaassen: It feeds itself.

Kae Jack Tay: Exactly. Yeah. Then you just need to learn a little bit more about the technology and how it ablates. For example, you don't even learn the whole thing from scratch. So having a second modality, after you had a first one, really it's a smaller step than getting that first one in the first place.

So for example, I took on IRE as a secondary energy source because I felt that it could be used to treat the periurethral tumors that I was missing out on previously so I could extend the number of locations that I could do focal therapy. So that was my particular journey. And I've seen colleagues having different journeys, and that's perfectly fine. A lot of people start with HIFU because that's what they're comfortable with in their training. And then they add on some other modality when they realize that, hey, there's some spots we can't reach or some scenarios we can't do.

So I think that to summarize, number one, what's available to you? Number two, what you have training in. And number three, I think that getting into a formal training program is really important. Spending a certain amount of time with a mentor and going through not just doing the treatment, but from the start to the end, how do we do patient selection? How do we decide who to treat? How do we decide where to treat? How we deliver that treatment is just one step. And how do we do surveillance? Because I think that's really important. We will never know how well we've done the treatment if we don't do the surveillance properly.

Zach Klaassen: That's right.

Kae Jack Tay: And more importantly, if we want to offer the patient something like focal, which is not currently the gold standard treatment. In case I didn't mention this earlier, the gold standard of treatment is still radical prostatectomy and radiation. So if we are going to offer the patient something newer that preserves their quality of life, as physicians, we have a responsibility to make sure that we take care of their long-term oncological care as well.

Zach Klaassen: That's right.

Kae Jack Tay: We don't want them to lose options down the road. And if they do have a recurrence, if they are in the 20%, we want to be able to pull the trigger, do the prostatectomy, do the radiation therapy, perhaps do a repeat focal in a very limited number of cases. And that takes a very good surveillance program for us to identify them.

Zach Klaassen: It's been a great conversation. So maybe provide a couple of take-home messages for our listeners.

Kae Jack Tay: Take-home messages are that I think focal therapy is going to stay. It's here to stay because it's an important option that preserves men's quality of life. At the same time, we have to be very selective in whom we apply focal therapy. And I think that having a good program and having every urologist get on board with knowing what an MRI is, what a targeted biopsy is, how to interpret these findings is going to be really important.

And the last point would be that to advance the field, we are going to have to look into the molecular profiles of these lesions. And I think that's going to give us an all-rounded understanding of that particular cancer in that particular patient so that we can customize the treatment to the patient.

Zach Klaassen: That's great, Jack. Very holistic view of focal therapy. This will be very beneficial to our listeners. Thanks so much for your time and expertise.

Kae Jack Tay: Thank you so much, Zach. Really my pleasure to be here.