Zachary Klaassen: Hi, my name is Zach Klaassen, Urologic Oncologist at the Georgia Cancer Center, Urologic Oncologist at the Georgia Cancer Center, and I'm delighted to be joined on UroToday by Dr. Eoin Dinneen, who is from Peter MacCallum Cancer Center, as well as UCL in London and Dr. Ricardo Almeida, who is also at UCL in London. Today, we're going to be discussing the recent publication in the Lancet Oncology, the NeuroSAFE PROOF Trial. Gentlemen, thank you so much for joining us on UroToday.

Eoin Dinneen: Thank you for having us.

Ricardo Almeida-Magana: It's a pleasure. Thank you.

Zachary Klaassen: Congratulations on just a wonderful trial. I'd love to get your presentation slides up here in a minute, but just great work. It's hard to do randomized trials in surgery, so why don't you share sort of the background, the methods, and the key results.

Ricardo Almeida-Magana: Absolutely. Happy to do so. Thank you so much for the opportunity to present this. As you mentioned, it's a randomized control trial. We run it, it's a project that it took over 10 years to develop and to get results, but we are very happy of what it turned out to be. And I'll go over some of the rationale why we did it, how we designed the trial and the results, which we are really excited about. So first of all, the big question all men ask when getting counseled for a radical prostatectomy, am I going to lose my erections?

And the answer to that relies on the fact that the nerves that control the erections go really close to the edge of the prostate. How close? I think most surgeons don't even realize it's a matter of less than a millimeter. So here in the yellow area, you can see the nerves, which are actually like a hammock. So the decision to preserve them during surgery is a very difficult one. We try to rely on the information we have beforehand, the MRI, the biopsy results, the PSA, the previous function of the patients to decide this. But this is all, let's say like gamble.

We don't have any reliable way of knowing if we took the right choice until we see the final pathology and then see if the cancer actually extended all the way to those nerves. And we know that the more we can preserve, the better the erections will be. So if you do an intrafascial nerve spare on both sides, the chances of the patient recovering erections sufficient for intercourse are very high. However, if you remove both bundles or even just one completely, the chances drop significantly. So why don't we do it more often? Because as I said, it's a balance.

If you risk getting very close to the prostate, you risk leaving cancer behind. And that's something we are really against because this is an oncological operation. However, if we have a standardized way of doing this, we might offer better outcomes for our patients. So in Germany, the Martini-Klinik, they developed this, the NeuroSAFE technique, which basically takes frozen section, which is a technique that has been there for more than a hundred years and standardizes it. So we take out the prostate while doing a full bilateral nerve sparing procedure.

And then depending on the results that we get during the frozen section, we decide on whether to leave the bundles and the nerves intact or to remove them. And this technology was described in about 2006, but it took more than 10 years to get enough evidence retrospective that it was a good idea. And it started getting adopted around the world without having a randomized control trial to support it. And here in the UK, the new technologies are very scrutinized. So if we wanted to do this, we needed to prove that it actually worked with level one evidence.

So we designed this trial. We selected patients who had good erectile function beforehand, who were continent of urine, and we offered them enrollment. In this new randomized control trial. We gave every single patient a personalized nerve sparing plan, which was prepared by a surgeon and our radiologist who were looking together at the MRI and gave them the best type of nerve sparing we could think it was safe. And then we randomized them either to have a surgery performed by that pre-surgical plan or guided by NeuroSAFE.

And our primary outcome was the 12-month erectile function as measured by the International Erectile Function questionnaire, the IIEF‐5. And we were interested in looking if we also affected other outcomes such as continence and IIEF‐6, which is a slightly different version of the Erectile Function questionnaire. So we screened more than 900 patients. We ended up randomizing 200 to each arm, and 190 had surgery guided by NeuroSAFE and 191 via the standard route. And we were very pleased to see that we got a really diverse population here in London and the rest of the centers who participated.

We did this study in five UK centers. They are big suburban centers. So we have a very diverse population and we managed to invite most patients. And I think this was a combination of the outreach we did with the patient involvement events, and also because of the type of patients that we recruited, which were younger than the average population. However, we are also pleased that most of the patients had what we call clinically significant prostate cancer as well.

So during the surgery, we realized that it took 40, about 40 minutes more to do NeuroSAFE, but what that gave us was the opportunity to do much more bilateral nerve sparing. About 80% of patients in the NeuroSAFE arm got bilateral nerve sparing compared to 56% in the standard arm. And that actually translated in clinically significant and statistically significant difference for erectile function, which is the first time actually that a randomized controlled trial shows an intervention that can improve patient outcomes in radical prostatectomy.

We were also really pleased and pleasantly surprised to see that ICIQ was also improved at three months. However, we saw that these differences diluted as time went on. At six months, there was no difference. And one of the questions we get when we present these results is, "Okay, but what does this mean for patient?" So we use this, the standardized effect size. So the result was 0.41, that's a moderate effect size, and that's actually higher than some of the medications we use for erectile function. And we also classified patients categorically. So we see that if you were randomized to the NeuroSAFE arm, you had a 40% chance of having either no or mild erectile dysfunction compared to 22% in the standard arm.

So almost doubling the chances of you having a good outcome after surgery. The big question is we were not powered to detect a difference in oncological outcomes. However, we still wanted to present this. We saw a slightly higher number of patients having PSA persistence and biochemical recurrence. However, we believe these numbers are very low still compared to the benefit that you get in terms of functional outcomes. And we will follow patients along because we know this is really early and our aim is to really know if this is both effective and safe.

So I think that now surgeons have this option to tell patients when they're worried, "Okay, I have good erectile function, I have clinically significant prostate cancer, and you're telling me that you're going to do a surgery where you don't know if you're going to preserve my nerves?" You can tell them, "Okay, we have an intervention that has level one evidence that can help us guiding this decision." So in summary, the NeuroSAFE results in better erectile function at one year improved their urinary continence at three months.

And we did some analysis that I didn't present here, but it seems that these benefit is even greater in patients who would not otherwise have received nerve sparing based on the preoperative plan. We see similar oncological outcomes at 12 months. And to our knowledge, this is the first randomized controlled trial to show an improvement in erectile function. So thank you so much for the opportunity to present these results.

Zachary Klaassen: Ricardo, great presentation. Again, congratulations on just really, really impressive results. I'll start asking you the first question. I think when you look at the baseline demographics of this trial, it's really impressive. We know that minorities and black patients are underrepresented in the majority of clinical trials, not just in GU oncology, but across all oncology. So almost 30%. What does this speak to in terms of recruitment, in terms of generalizability of these results? And I look at this as somebody who treats a lot of African-American patients in the United States.

Eoin Dinneen: Thank you for the question. Yeah, we're really proud as a trial team to have achieved that landmark actually as well. Not only the first trial to show an improvement in erectile function, a radical prostatectomy, but way outperforming the recruitment in terms of a proportion of black and Afro-Caribbean men. Africa being population in the UK is about 4%, but we know that over the course of a man's lifetime, black and Afro-Caribbean men are at double the risk of prostate cancer compared to their Caucasian contemporaries.

So that means one in four instead of one in eight. And the Prostate Cancer Commission on the Future of Prostate Cancer pointed out that under recruitment of ethnic minorities in the past has been a big stumbling block to equitable access to good care. And indeed, in fact, the whole beginning of the NeuroSAFE PROOF story for Ricardo and my boss, Professor Greg Shaw at UCL consultant neurologist and high volume prostatectomist, was that he was not uncommonly confronted with young black and Afro-Caribbean men diagnosed with localized prostate cancer at a curable or certainly a treatable phase of the disease history, but who did not return back for treatment.

And they were either by way of surgery or radiotherapy because they were worried about the sexual wellbeing side effects. And so to see that run through to 30% in our trial population, we're really proud of that. And as Ricardo correctly points out, it's also partly due to the fact that the five big recruiting centers in the UK were all big cities. So we've got a much higher proportion of Afro-Caribbean men compared to the rest of the UK.
Zachary Klaassen: Yeah, great answer. And I think it just speaks to the, like you said, the trial team, generalizability of results, especially in parts of Europe or the UK and certainly the United States as well.

Ricardo Almeida-Magana: And if I can add to that, just say that.

Zachary Klaassen: Absolutely. Absolutely.

Ricardo Almeida-Magana: We actually reach out to the population actively. So I think it shows that it's not that black men don't want to participate in research. If you ask them, they're happy to do so. You just need to explain everything.

Zachary Klaassen: Yeah, a hundred percent agree. That's well said, Ricardo. Second question is along the lines on oncological outcomes, I know you presented it, Ricardo, in terms of the 12 month and maybe a slight uptake in PSA persistence in BCR, what's the plan in terms of the trial team following forward? What are some additional endpoints from an oncological aspect? I agree, I think it's a small percentage. And again, you're increasing your bilateral nerve spare by almost 30% absolute improvement in bilateral nerve spares. So what's that plan just to see if there's more of a signal from oncological aspect?

Eoin Dinneen: Yeah, thank you. Again, really, really important question and one that we get a lot now that the results of the 12 months functional outcome have come out. Look, really the really simple answer is you'll be seeing a publication and presentations before too long and the 24-month outcomes that will include erectile function again, which was a key secondary outcome and the oncological outcomes you might expect as well.

But we have the ethical permission to follow these men with questionnaires and updates on their oncological outcomes to five years. So you'll be seeing it then. But I dare say that in the fullness of time, it's going to take a decade, maybe even 15 or 20 years to see whether this has an effect on overall survival and progression free metastasis free survival.

And looking at the big data sets on overall survival in men who have radical prostatectomy with disease characteristics that you see in our study, which is essentially a Gleason seven disease, either ISUP two or 3. 96 to 98 percent of men are still alive at 23 years from radical prostatectomy. So we do not expect to see an overall survival difference. But yeah, look, those other more surrogate and still very important oncological outcomes. They are incredibly important to us and we'll be updating the urological community in the coming years.

Zachary Klaassen: No, that's great. I think when you look at just that slight percentage, you're right, this is a curable disease for the majority of men. I think you guys are doing a great job with that five year follow up. I think my, I don't know, my most important question or my most excited question to ask you guys is that we've certainly seen this taken up in Germany, in Europe, UK for sure, perhaps other parts of the world.

Looking at the United States where I practice, and maybe this is a bit of a come to Jesus moment of, "Hey, this is something we should be doing. We have level one evidence now." What do you guys see as maybe barriers? When I look at this, I think, "Okay, maybe a little bit longer operative time, consulting closely with the geopathologist." What do you guys see as barriers as to full implementation across the globe?

Eoin Dinneen: I'll answer that one first, and I know Ricardo's got some great thoughts on it too.

Zachary Klaassen: Yeah.

Eoin Dinneen: Yeah. So look, 43 minutes extra for an operation. That's probably not going to be a deal breaker for most places. We found, and we heard in the UK when we were setting up the trial, there was lots of interest from different units, but the pathological technical and the histopathologist on site at the drop of a hat, and these were the barriers that we came up. We would've loved to have more sites recruiting and performing this in the UK, but that was what we heard from many different centers.

And indeed that's what we hear now around the world where people say, "We would love this frozen sections, but we can't do it. We'll never be able to do it." But there is some, in terms of the future for intraoperative margin assessment, and particularly at the posterior lateral neurovascular bundle adjacent margin, there are some exciting technologies coming and they're going to have worldwide reach, I'm sure. And with that kind of introduction, I think I'll let Ricardo say a little bit more about it, because he's actually back in London and doing some pioneering work on this.

Zachary Klaassen: Excellent.

Ricardo Almeida-Magana: So yeah, so two thoughts come to my mind. So one is if you can do the NeuroSAFE, definitely that's an option, especially for young men with good erectile function. I think if the pathology is available, that's a key thing and they have the expertise as well to process the sample in time because it's not easy. Now to really propagate this across the world as Eoin mentioned. There are some exciting technologies coming up. Some of them are, I think already in the US being trialed.

So one is Raman spectroscopy, but the one that we have been working on is called fluorescence confocal microscopy, which basically allows you to do the same thing. So the idea is the same thing. Look at the margins instead of relying on something that you have before the operation, have evidence that there are no glands on the surface of the prostate. So yeah, I think this is an exciting field. It's getting a lot of attention lately. We will be presenting some feasibility trial soon that we run with this new technology and we are really excited because yeah, this is much simpler and much quicker to perform, so it'll allow more centers to do it.

Zachary Klaassen: That's awesome.

Eoin Dinneen: I might just say one other thing on that.

Zachary Klaassen: Sure.

Eoin Dinneen: I think some of the feedback that I hear from people when they see our results and they see the proportion of men having nerve sparing and bilateral nerve sparing is that however you get there, we should be considering to do more nerve sparing during radical prostatectomy.

Zachary Klaassen: Sure.

Eoin Dinneen: And in the UK, almost every single patient would have a prebiopsy MRI. And if it's a reasonable time period from their MRI to their operation, you can, and arguably you should be using that to inform your preoperative plan for nerve sparing. And in many men with anterior diseases or small focal lesions, you can still do your nerve spares.

So it's also about thinking about this precious resource and using it wisely. And perhaps it's not for all men, but for a man who's preoperatively with good erectile function, who you're sitting on the fence and thinking, "Is it safe to do a bilateral nerve spare for him?" and you had say, one NeuroSAFE of the day, then consider that man for it rather than anybody else.

Zachary Klaassen: Yeah. No, outstanding. Gentlemen, phenomenal contribution to the neurological literature. Congratulations again. Was really excited to get you on UroToday to talk about it. So just want to say thanks for your time and thank you for joining us on UroToday.

Ricardo Almeida-Magana: Thank you so much.

Eoin Dinneen: Absolutely. My pleasure. Thank you very much.