Matt Cooperberg:

Hello, I'm Matt Cooperberg from University of California, San Francisco, and welcome to another installment of our Journal Club for Patients in prostate cancer. This is an initiative sponsored by UroToday and the Prostate Cancer Foundation with the goal of bringing game changing and practice changing research articles to you, our patient community in language that's hopefully a little bit more accessible than the original publications themselves.

So for this installment, we are going to be talking about a major trial which came out looking at microultrasound, which is a new diagnostic modality using high resolution ultrasound as either an alternative or adjunct to MRI for guiding prostate biopsies. The OPTIMUM trial is the name of the trial. This is the full title here, "Microultrasonography-Guided versus MRI Guided Biopsy for Prostate Cancer Diagnosis."

We are privileged to be joined by the lead author on the study, Adam Kinnaird, who's the Frank and Carla Sojonky Chair in prostate cancer at the Alberta Prostate Cancer Research Institute. So he will give a presentation on the trial. And then we are further joined by Dr. Geoff Sonn at Stanford, the Associate Professor of Urology and Radiology, who has also done a huge amount of work in terms of prostate cancer diagnostics and imaging, who will give a few comments, and then we will open this up for questions. We'll have some questions from our patient advocates here at UCSF who have helped organize these sessions. And if any of you have questions who are live on the session, please use the Q&A box in Zoom and we will get to those as well.

So with that, why don't we get going? Adam, please take it away.

Adam Kinnaird:

All right. Thank you very much, Dr. Cooperberg, for the invitation to present today about this exciting trial and this exciting technology.

So I'm a urologist and a surgeon scientist from the University of Alberta in Canada. And I do have a disclosure, and that is that I have received research funding from Exact Imaging, the company that makes the microultrasound product, and I'll be talking about microultrasound in this talk.

So I want to start off by saying that I am a big believer in MRI. So MRI is like Wayne Gretzky here. It's tried, tested, and true. It is the gold standard currently. It has won Stanley Cups. It has won scoring records. It is great. But microultrasound, I want to pose here is like Connor McDavid. So he's the best hockey player right now. They both play in my hometown of Edmonton, Alberta. And so I want to pose here that MRI is wonderful and maybe microultrasound can be great as well, but we're still trying to figure out its exact position in prostate cancer diagnostics.

So my goal here is to review microultrasound technology to discuss the OPTIMUM trial, and then to briefly introduce ongoing trials to give you a sneak peek into what's going on with current global trials in biopsy decision making and active surveillance using microultrasound.

So why does microultrasound exist? It's because even though MRI is like Wayne Gretzky, it is not perfect. You need to have sophisticated imaging facilities for MRI; there are contraindications to MRI like ferromagnetic objects; pacemakers sometimes pose a problem, cochlear implants; hip arthroplasties or hip replacements can cause some distortion in the images, renal dysfunction, and claustrophobia.

There's also, while this is now controversial with a clinical trial that came out in September, there is the need for contrast enhancement for multiparametric MRI that is no longer needed with biparametric MRI.

Also, cost is a limiting feature. In Canadian dollars, in my hometown, if you want a prostate MRI, it costs you about $1,000. Whereas if you want a microultrasound, it costs the system about $200.

And then I think that this is a really, really critical point; and this is actually Dr. Sonn's research that I'm quoting here. This is only 35% of patients in the US get an MRI pre-biopsy. And that drops even further in the rural United States. So this clearly shows that even though this has been guideline recommended, in 2022, only about 35% of patients were getting MRI. So clearly we need to do something to bring technology to the patients.

So what is microultrasound? Microultrasound is a point of care device. It can be wheeled to the bedside. It can be used anywhere where you have electricity. The way that it works is it has a bunch more crystals, ultrasound crystals that let you detect ultrasound at a higher frequency. So it uses a frequency that is about three times higher than conventional ultrasound. And what that means is that you get more resolution. You can see better. It's like putting your glasses on. So what it resolves down to is 70 microns, which is about the size of a prostatic duct.

So what you're actually imaging here with microultrasound is ... I'll show you an example of both benign tissue and cancer tissue. And this comes from a friend, Jake Pensa at UCLA.

And so if you are imaging a prostate gland in the parasagittal plane, what you end up seeing here is you end up seeing the Swiss cheese pattern. This is benign. This is called a PRI-MUS 1 score. You're imaging the prostatic ducts. This is very favorable on microultrasound for it to be benign tissue. Whereas if you're imaging cancer in the same plane, you lose those ducts. And this is what prostate cancer looks like on microultrasound.

So there is a scoring system that has been developed, it was developed by a radiologist in 2016 out of Toronto, called the PRI-MUS scoring system. And this is analogous to what's called the PI-RAD scoring system for MRI. And so it's a Likert scale of one to five, with one and two being considered benign findings, three being considered equivocal, and four and five being considered suspicious for prostate cancer.

And basically what you see is you see on the far left, you see lots of prostatic ducts, lots of Swiss cheese. That's good; then you see a little bit of Swiss cheese, but not that much, a complete loss of Swiss cheese in the middle; and then you start to see some features like cauliflower appearance, starry sky, and then you see irregular shadowing and actually tumors itself in the PRI-MUS 5.

So moving on to the OPTIMUM trial. The OPTIMUM trial was published in March in JAMA. It is a multicenter, international, open label, randomized, non-inferiority trial of biopsy-naive men. So in plain English, this was done around the world, patients knew whether they were getting an MRI or a microultrasound, they were randomized to different groups; and we were trying to show not that microultrasound is better than MRI, but that it is not worse than MRI at diagnosing prostate cancer.

And so in this trial, it wasn't a two-arm trial. It was really cool because it was a three-arm trial. And so what this means is that patients were randomized into one of three groups. They were either randomized into just getting a microultrasound biopsy, so no MRI whatsoever; or they were randomized to receive an MRI and a standard MRI biopsy; or they were randomized to receive an MRI to which the urologist performing the biopsy didn't know the results. We were blinded.

Then we did a standard microultrasound biopsy, and then after we'd done the microultrasound part, we turned on our brains to the MRI and we took any MRI targets that were missed potentially by microultrasound. And the primary outcome was the detection of prostate cancer that may need treatment. So this is called Gleason Grade Group 2 prostate cancer, or more, Gleason 3+4=7 prostate cancer was the primary outcome.

So now we really did have expert users as a requirement for this. We wanted to make sure we were comparing apples to apples, not apples to oranges. And so in MRI, centers had to have previously performed hundreds to thousands of MRI guided prostate biopsies; and with microultrasound, investigators were required to reach an advanced level user classification, which meant they had to have done at least 35 microultrasound cases. So clearly there is a bit of a difference here. Only 35 prior cases for microultrasound required versus hundreds to thousands of MRI guided biopsies.

So in this trial, 802 men were included in the analysis that was published. The trial was actually stopped early for success. It was stopped at the 50% mark after an interim analysis showed that it was unlikely that continuing on with the trial would change the results. This was done at 20 medical centers in eight countries around the world.

And at the end of the day, what it showed, and this is the take home message that I want everyone to take home, is that if you included microultrasound in your biopsy technique, we detected clinically significant prostate cancer 46% of the time. Whereas if you used MRI, so no microultrasound, we detected clinically significant prostate cancer about 43% of the time. So there was approximately a three to 4% difference favoring microultrasound in terms of the detection of clinically significant prostate cancer.

When looking at these plots, what you can see here is that in blue is the non-inferiority margin. This is the margin that we could not cross for this trial to be considered a success. And as you can see here, the dots and the lines do not come anywhere near that non-inferiority margin, meaning that this trial was a success. And it looked like, not statistically significantly, but it was favoring microultrasound rather than MRI.

Now, because the trial was stopped at the 50% mark, it meant that our statistical power was less, that our confidence intervals are quite wide here. So it is possible that if we had completed this trial with all 1,200 patients, these 95% confidence intervals would be shorter, and we may not have crossed this 0% line, which means we could make amazing claims about microultrasound. But because we stopped early and the confidence intervals are wide, we can just say it is not worse than MRI.

So then the question comes, there is a trend now to only do targeted biopsies, because in this trial, everybody got a targeted plus systematic biopsy. So a targeted biopsy is where you just take samples from where the imaging looks suspicious; systematic, you sort of mop everything up by taking quasi-random biopsies throughout the rest of the prostate.

So we did a secondary analysis where we looked only at the targeted biopsy and we found similar results. And so indeed, these were non-inferior as well. So when we used microultrasound only, we found clinically significant prostate cancer 38% of the time versus 34% of the time with MRI only, and 40% of the time when you combined microultrasound and MRI together.

So when we looked at the scoring systems and how good the scoring systems were, what you can see here are two graphs.

Well, the one on the right is the PI-RAD scoring system, that's the MRI scoring system, with one, two, three, four, and five across the X axis in both graphs, with this being the PI-RAD score on the right and the PRI-MUS score on the left. And what you can see here is that as the score increased, the likelihood increased of finding prostate cancer, we indeed did find prostate cancer more often.

And it's really nice to see that when the scoring system was completely negative, PRI-MUS 1 in the microultrasound arm, we did not find any prostate cancer whatsoever. So this is very reassuring to us.

So that's basically the crux of the trial. What I want to give you a snapshot now in the next two minutes is just a glimpse into the future of what we're doing.

So one of the important things here is to make a decision as to ... So in this trial, a limitation is that every single patient got biopsied, which is not standard practice. In standard practice, if your MRI is negative, you typically avoid a prostate biopsy. And if your MRI is positive, you get a prostate biopsy. So we wanted to take the next step and study what happens in terms of, can you use the imaging technology to say you do not need a prostate biopsy?

And so we are [inaudible 00:12:48] 25 centers around the world in North America, South America, Europe, and Asia. We've received funding for this. And we have one site open, my site, and we are about to open in about six more centers in the next month or two.

And so in this trial, it's men who are at risk of prostate cancer aged 50 to 70 with an elevated PSA and who've never had any imaging or biopsy are randomized one to one to receive either an MRI or a microultrasound. In this trial, if the imaging is negative and your PSA density is low, then you avoid prostate biopsy. Whereas if the imaging is suspicious for prostate cancer or your PSA density is just too high, you receive a biopsy.

And this is, again, the same primary endpoint, the detection of Grade Group 2 or more prostate cancer. And so where we are with this trial so far is we've screened 201 patients, we have enrolled 150 patients and we are going up to 1,284 patients around the world.

The other place where microultrasound is being tested is in active surveillance. And so this is called MUSIC-AS, Microultrasound and Cancer Active Surveillance. This is another investigator-initiated trial that's a prospective paired diagnostic trial; and I'll show you what that means in a second. This is, we're getting 210 men from six international sites in North America and Europe.

And in this trial, what happens is men who are diagnosed with low risk prostate cancer who need confirmatory biopsy end up getting enrolled in the trial, undergoing an MRI to which the urologist is blinded; in the biopsy session, you take microultrasound targets, you unblind yourself to the MRI, you take MRI targets, systematic biopsies, and then we look for how many men get upgraded on this confirmatory biopsy.

And where we are here is we have 169 out of 210 patients enrolled. And so I'm hoping that this study wraps up in the next six months and it is another non-inferiority trial.

So we're testing microultrasound not only in, "Is it good for biopsy?", but, "Is it good for biopsy decision making? Is it good for active surveillance?"

And the final slide I want to show you is, can artificial intelligence be used for microultrasound? And this is some early work that we're doing here collaborating with researchers at Queens University in Ontario. And what you can see here is you can see that this is what the microultrasound images look like on the left, the top panel being a benign image, the bottom panel being prostate cancer. And when you apply artificial intelligence to this and let it analyze the images, it comes up with a heat map. And the heat map shows blue in the benign saying that you don't need to take a biopsy, whereas in the bottom it shows a hotspot where you should take a biopsy from. And so this is a really exciting next step in microultrasound that I hope will advance the technology.

So in conclusion, MRI set the bar. It's Wayne Gretzky; microultrasound or Connor McDavid is quickly closing the gap with fewer contraindications and potentially improved cost savings. We showed in the OPTIMUM trial that microultrasound is non-inferior to MRI for detection of clinically significant prostate cancer, and then we have ongoing trials and using AI.

So thank you very much for the opportunity to present here and I'm happy to take any questions.

Matthew Cooperberg:

Fantastic. Thanks so much, Adam. And I love the hockey analogies. Wayne Gresky, of course, was also famous for saying you really need to skate to where the puck is going as opposed to where the puck is. And I think that's exactly the mode of thinking here that you and the collaborators at OPTIMUM have kind of set with this trial.

So before we go to questions, let's go over to Geoff, to Dr. Sonn to give us a few comments and counterpoint on the trials.

You're muted, Geoff.

Geoffery Sonn:

Yeah. All right.

Thanks, Matt. I appreciate the opportunity to be here. And Adam, great presentation. You hit on a number of the points that I wanted to discuss. So some of it's just going to be reinforcing my thoughts of things that you mentioned too.

So first of all, I'd want to congratulate you, Dr. Klotz, and the rest of the OPTIMUM investigators for successfully completing this trial. RCTs like this are many years in the making and a tremendous amount of work, but they go a long way in changing guidelines in the way that we ultimately take care of patients. You know, this trial was quite rigorous in its methodology, and I think there are a lot of important insights that come out of the study.

I also want to applaud Exact Imaging for really putting their money where their mouth is and paying to conduct this trial. It's really easy for a company to put all its resources in marketing rather than in conducting trials, and I think they really should be rewarded for this commitment. It shows a tremendous self-belief to do this because a trial like this is a big risk. Imagine if it showed an opposite result and MRI was shown to be clearly better than microultrasound. Where does that put them? So it's a big risk, it panned out, and I think they should be rewarded then for that.

The highlight to me from this study, as you said, is that in the hands of experienced users, microultrasound guided biopsy works as well as conventional MRI ultrasound fusion guided biopsy in finding significant prostate cancer. And I just wanted to have four key points; again, a number of these that you've discussed already.

One, I think that microultrasound is a great resource when patients can't get an MRI. You mentioned some of the medical reasons, like an incompatible pacemaker, or lack of insurance coverage, or if you just live in an area where you just don't have access to MRI.

You highlighted the work that we had done. It's surprising, when we published that paper last year, a lot of us in academic centers were really surprised because we think of MRI as a ubiquitous technology, because it is. In our hands, everybody that I biopsy gets an MRI. But in fact, that's not the case. So we have a lot of work to do as a field bringing these advanced technologies, whether it be MRI or microultrasound, or both, to more patients.

Second, as is pointed out in the article, becoming an expert reader is very important. As you said in the study, all the investigators had to be their advance or expert level of certification in microultrasound prior to the trial. So the results of this trial are only applicable to urologists who are using this who get that sort of training.

Fortunately, I think that Exact has terrific resources that are available on their website, sample cases that come out regularly. So all of the material is there for urologists to learn how to do this. When you buy a machine, they don't just drop it off and leave. They're really with you for the long haul. So that really puts the impetus, the onus on us as urologists to actually take the time and effort to learn how to use this technology to fully realize its potential.

Number three, getting to what you said as well, we all agree on the importance of quality interpretation. You know, AI is a tremendously hot topic in society in general and in healthcare is no different. We're seeing use of AI clinically for prostate MRI interpretation, still in its relatively early days. And it's my view that we will see this in microultrasound as well.

Just another plug for work that we've done, one of our chief residents, Steve Zau, just published a paper last month in the British Journal of Urology that compared human readers of microultrasound to an AI model, and showed that the AI model found more significant prostate cancer than the human users. That certainly requires more perspective validation, but I think it's tremendously promising and something that we will see more in the future.

And then the last point gets to some of the trials that you're working on right now, and I'm excited to see the results of that. And that is that one of the great qualities of MRI is to be able to reduce the number of men who need a biopsy in the first place. In the PRECISION trial, it was about 30% of guys who were on that trial that had an MRI that was normal and therefore were able to avoid an invasive biopsy procedure, which is a big win for men with an elevated PSA.

Just because of the design of OPTIMUM, we didn't get a direct answer to that question to what extent microultrasound is able to reduce the number of men who need a biopsy. I know you provide a number that said it was like 83% of people with normal microultrasound didn't have a significant cancer. So I think that these future trials will be really interesting to see that.

And then we'll just have to think about, "What is the clinical implementation?" Are we going to be doing a diagnostic microultrasound in everybody who comes in with an elevated PSA? Because it is a bit of a more invasive test than something like a blood-based or a urine-based biomarker, or even an MRI; although there is the advantage that it can all be done then at the same time.

So I think figuring out what is the role of MRI versus microultrasound versus some of the other biomarkers in deciding who needs a biopsy in the first place is something that we'll continue to see the field evolve.

So those are my general thoughts. And again, I think this is a great trial, and I congratulate Adam and the rest of the investigators in conducting it.

Biographies:

Stan Rosenfeld, Prostate Cancer Patient Advocate, University of California San Francisco, San Francisco, CA

Nathan Roundy, Prostate Cancer Patient Advocate, University of California San Francisco, San Francisco, CA

Leszek Izdebski, Prostate Cancer Patient Advocate, University of California San Francisco, San Francisco, CA

Bruce Zweig, Co-Chair of the UCSF Patient Services Committee, University of California San Francisco, San Francisco, CA

Jim White, Prostate Cancer Patient Advocate, University of California San Francisco, San Francisco, CA

Geoffrey Sonn, MD, Cortland T. Hill Memorial Scholar, Associate Professor of Urology, Stanford University, Stanford, CA

Adam Kinnaird, MD, PhD, FRCSC, Surgeon, Scientist, Chair of APCaRI, Frank and Carla Sojonky Chair in Prostate Cancer Research, Division of Urology, Department of Surgery, Alberta Prostate Cancer Research Institute, University of Alberta, Alberta, Canada

Matthew R. Cooperberg, MD, MPH, Professor of Urology; Epidemiology & Biostatistics, Helen Diller Family Chair in Urology, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA