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Neal Shore: So maybe I'll start with you first, Martin. Excellent presentation. Maybe comment more about the challenges in the intraobserver variability, particularly when thinking about staging as it relates to histopathology and imaging. And even the DRE, as Declan did a really nice job reviewing that, whether it's primary care-based or urology-based. It seems the only thing that is truly not subjective is the PSA.

Martin Gleave: Well, I think the DRE, as Declan pointed out, is still useful as a surgeon in terms of defining the disease, deciding on nerve-sparing versus non-nerve-sparing. But there is, again, intraobserver variability in how to describe it. In general, surgeons have a tendency to, if you're at the T2b/T3 level, I think, underestimate stage. And I think that, and this is debatable, it's hard to say because it's all so interobserver. But there's at least, in my experience, a tendency for a radiation oncologist to call a T2b what a surgeon would call up to a T3a.

So there is this shift in terms of interpretation, and that's limiting. I think the MRI we all incorporate, if you've got evidence from an MRI that there's extracapsular extension, that's going to change what you think your finger is feeling as well and affect ultimately clinical stage. And similarly, volume of high-grade disease. If you've got a nodule with multiple cores of a higher-grade cancer, you're going to predict as a clinician that this will be extracapsular and perhaps use your finger to drift from a T2 to a T3 as well.

So I think that's why the DRE is somewhat driftable in terms of categorization. And something we have to interpret with care, in that it shouldn't be a singular cutoff between risk. You shouldn't be high-risk T2b versus a high-tier intermediate risk T2b, and then all of a sudden high-risk because you're T3 with no other risk factor to support that.

Neal Shore: So Declan, maybe you could add to that. And also the challenge that we have, this is such a great conference in that it's global. And you make the great point that not everyone has the paradisiacal accessibility to MR. You're very lucky in Australia. I think you have it fairly ubiquitous there. But as you point out in the US, we don't. Here we have discrepancies. So help us understand how you think about this selection and the stratification, especially not just with DRE, but throughout all the other variables.

Declan Murphy: I think if we could only do one thing in the high-income countries to improve overall outcomes of men with prostate cancer, it would be to make sure we have MRI in the early detection pathways. Because it will reduce the over-detection of insignificant disease. And that's been clearly shown in countries where there is widespread access. We do less biopsies and therefore we find less insignificant cancer.

So I think, for example, things like biparametric MRI being equivalent to multiparametric, as we saw in the PRIME study at EAU recently, will help. Having a 20-minute scan instead of a 34-minute scan with contrast and having to have a doctor there—all these little things will help. But I think that's the number one thing that will improve outcomes is having MRI in the early detection pathway. And that's what the Lancet Commission pretty much called for.

And I think the point about primary care is still really, really important. Maybe David will comment on it, but that data shows that men genuinely have concerns about DRE such that many of them won't go in and have a chat with their doctor. So I think we can do more to remove DRE from the recommendations for early detection in primary care. David.

David Matheson: Just to pick up on Declan's point. Certainly my experience in doing awareness talks on prostate cancer, the DRE is something which I would say is a large turn-off for the men. And it's very interesting, I think, to compare how men react to the thought of this to how women react to the thought of similar intimate examinations. But one of the problems that there is, is that the DRE, in my experience, is completely misunderstood by the prospective patient. They seem to see something much more dramatic and even traumatic than it actually is.

And when it's pointed out to them that nowadays, let's say it's done with feeling. Whereas my initial experience of such things when I had prostatitis in my 30s, it was an absolute trial. Getting this education across there so that you can actually see, well, what is the point to this? What's the payoff? What's the benefit? What's the potential loss and so on. And the limitations of it. There's just increased understanding, increased education. I think there'd be much less resistance. And of course, it's certainly as an initial way of trying to feel at least a bit of the prostate, it seems to be rather important.

Speaker 5: You have a question at the microphone.

Speaker 6: It's a question to Dan. So thanks for the lecture. The Decipher test—you show profound value in discriminating the prognosis and the treatment, but it's a very expensive test. Like in Brazil, there is no way around to send the material to the test. So my question is, for other solid tumors, is there a specific test, cheaper, easier for a marker that adds to refine the prognosis and the treatment for prostate cancer instead of expensive and not available tests for many countries?

Daniel Spratt: So I can present the data, but 100%, I think I took the slide out for time. But I think that if this was free, there's really no discussion, in my opinion—I'm happy to have that—that this should just be standardly done. But because there's a cost component, and that's where I think if it is used to change a decision, that's why I always say do not order any of these tests if it's not going to change your decision.

To some patients, and we have a patient here, I will tell you that in the US, out of pocket, there's a financial program—it's $400 if insurance won't cover it in the US. Most patients—and I live in Cleveland, Ohio, it's not the wealthiest city—patients will happily, if there's a chance at omitting ADT, which has costs, some of it's being far more than $400. I think that that's one of the promises of the digital pathology is in the US, I think the cost is far cheaper, and I do think that's going to be globally more rapidly adopted. And probably have—I don't think they'll ever be compared head to head, but I think that it probably can capture at least a lot of the prognostic value.

So I'm hoping that that can be—we have a number of grants doing some things out, actually not with exactly Artera, but in India at Tata Memorial with other cancer types as well for AI. But in prostate, you've got a lot of valuable tools. I would say PSA density, I think percent positive cores—it is a shame when I see targeted-only biopsies because it's actually more prognostic than T stage. It's almost as prognostic as a Gleason score. So use what you have available, but happy to talk. I do have international patients that get Decipher testing, but I know the company is trying to internationalize to provide a cheaper option.

Speaker 5: Nick, you have a question?

Speaker 8: Yeah, it's a great session. You've kind of half answered my question, Dan, but it was for Martin around percentage of positive cores. Because what we've seen in our practice where everybody has an MR first is that we put lots of needles in the PIRADS whatever positive lesion and hardly any anywhere else. So you end up with lots of positive cores, lots of high-grade cancer, and I'm sure we're seeing a big stage migration off the back of it. So I just would question the value of quoting the number of positive cores because it's very contingent on your MRI practice.

Daniel Spratt: Yeah, I would say the way we at least do it, and I'm curious of you all, is that if it's an ROI, it's just one core, right? If you just shove five needles into the same. So for us, we do a systematic and targeted. And even if there's three out of three positive in ROI, it's just one. We haven't moved away, though. I mean, that systematic biopsy from the prognostic standpoint, it's incredibly prognostic. It's in almost every other cancer. When you think of T-stage, it's true like tumor size and depth of invasion. And so just be mindful, I guess, giving up that prognostic info unless we are relying more on the actual volume of the MRI.

Martin Gleave: So can I follow up on that, Nick and Dan? I think that I do TP biopsies in our clinic now, transperineal, MRI-directed. I think that obviously we rarely do biopsies without an MRI now unless PSA is high and DRE is abnormal. And we mainly target regions of interest. But I think that I do treat it like a battleship—the Battleship game anyways. And I try to increase the number of cores through and around the ROI because we're not as good as we think we are in terms of targeting the ROI. And we want more cores that are positive. The TP approach reduces the risk of infection—not particularly. It is uncomfortable, but with appropriate freezing, it's less uncomfortable. And by getting more cores that are positive, it allows you to gain access to a better estimate of the heterogeneity of what we have to deal with.

Speaker 8: I agree with all of that. It's just that you end up with a lot of positive cores. I'm interested, I'll stop talking.

Andrea Gallina: Andrea Gallina, Lugano. Very great session. I just have one question regarding nodal staging and how to deal with this nodal staging. In the new guidelines, as Dr. Walz showed, there is the indication for doing an extended lymphadenectomy if we do the lymphadenectomy. What is not so clear, at least in the last version, is when should we perform a lymphadenectomy? I would like to have a statement from the panel on what to do. Because I think that the role of lymphadenectomy is not passed out. And I think we should, especially with the new data coming from SKCC, we need to discuss about this. Because now there is no indication in the guidelines. So that's my personal opinion, of course. And so I would like to have your opinion on that, especially Jochen and Dr. Murphy, Alberto, whoever else. Thank you very much.

Jochen Walz: Thank you, Andrea, for the question. Indeed, when I was looking up the updated guidelines from 2024, they say that you should do an extended one, but they do not specify when and how to decide. And I think it's getting now more and more complicated. We learn more about the effect of this treatment. The first time we have a clear sign that it is curative, not only staging, which probably will change the indications for it. Karim Touijer during his presentation in Paris said, "All patients should undergo lymph node dissection." That was challenged by Freddie Hamdy saying, "No, we should select."

I think for the time being, we have the excellent tool from Giorgio Gandaglia and from Alberto Briganti integrating imaging, which seems to be so important—targeted biopsies—into the decision-making. Nomograms, I think, are the way to go to decide who should undergo a lymph node dissection or not. Personally, I like to do it or I do it when in doubt, but I'm happy to skip the lymph node dissection whenever I can. But it just takes so much time, it needs to be done meticulously in order to have the real effect. So select your patients, and I think the best tool right now is the Briganti Nomogram or the updated one from Giorgio Gandaglia. That's my point.

Declan Murphy: I have a slightly different view on lymph node dissection, and we haven't done lymph node dissection for PSMA-negative patients for many, many years now. And the EAU guidelines this year, very, very different. So Jochen showed what they say about high risk. If you're going to do a node dissection, do it extended. But last year it said do an extended pelvic lymph node dissection. So the EAU has dialed right back. Why? There's no evidence lymph node dissection improves survival and it causes complications, right?

And in the intermediate risk category, it's completely dropped lymph node dissection. It used to say nomogram-driven, now it's not even mentioned. There's no talk of nomograms. And it's not even about PSMA. PSMA is part of the conversation, but they've dropped it completely. So I think we're seeing a sea change away from futile nomogram-driven lymph node dissection that doesn't help patients. And PSMA will help select patients even more, but I don't regret not doing lymph node dissection with PSMA-negative patients because it doesn't improve survival.

Speaker 5: We have time for one last quick question.

Speaker 11: Quick question for Dr. Gleave. Great talk. I'm not familiar with the N2 classification. I don't believe it's part of AJCC. Can you elaborate on that? N2?

Martin Gleave: You mean in the N1, N2 status?

Speaker 11: Yep.

Martin Gleave: I think that it's just whether or not you have size of lymph node and bilateral outer lymph nodes. Is it a small volume versus larger volume regional lymph nodes? I think that they intend to staging. Is it small volume regional versus larger volume regional? Interpelvic versus extrapelvic? Extrapelvic would be M1a. Is that the question that you had?

Speaker 11: Like I said, it's not part of AJCC that I know of, but what classification system is that?

Martin Gleave: Just trying to estimate better. This is an evolving concept of how we better determine volume along with grade that ultimately predicts need to intensify versus de-intensify.

Speaker 11: Great. Thank you.