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Matthew Cooperberg: Welcome to another installment in the UroToday Center of Excellence on Localized Prostate Cancer Interview Series. It is a great pleasure today to introduce you all to someone you've all seen on other Centers of Excellence before, Dr. Todd Morgan, who is a Professor of Urology at The University of Michigan and Chief of Urologic Oncology. I've had the pleasure of knowing Todd for many years and have been a huge fan of the work that he and his group have done across the state of Michigan in terms of really defining what quality of care should look like in urology, and specifically what sort of research we should be doing in the biomarker arena. So I look forward to the conversation. Todd, welcome.

Todd Morgan: Thanks, Matt. It's good to be here with you.

Matthew Cooperberg: Yeah, it's a pleasure. So maybe just to kick off, I would hope that most people watching this have some knowledge of MUSIC and all that has been going on. But maybe you could give us a bit of an overview. And actually for those that do not know how you got to where you are in Michigan and where MUSIC has been and where it is going in broad terms.

Todd Morgan: Yeah. MUSIC is a Blue Cross Blue Shield of Michigan, a physician-driven, quality collaborative initiative. There are multiple of these in Michigan, that these CQIs, across a variety of specialties, and this one was started by David Miller and Jim Monty back in 2012. You just can't say enough about what they did to bring this to fruition, because I think if you said, "Okay, we've got this idea, and we're going to bring community docs and academic docs, and bring everybody together around prostate cancer care, and we're going to track all this patient data. And oh, by the way, we're all going to get together a few times a year and think about what are the most pressing issues, and what are the areas that we can drive improvement as a group and not really compete, but think about how to raise the tide to lift all the boats.

We're going to do this, and everybody's going to share data and work well together, and change the quality of prostate cancer and neurologic in this whole state, you'd say, "That's, okay, pie in the sky, not possible." It was right when I started at U of M, it was 2012, and I thought, what in the world are these guys doing? That's not possible. Then I started going to these meetings, and it's three times a year, 100 urologists all across the state getting together, deciding together what is really important, decreasing infections, for example, around prostate biopsy. Okay. Let's change how people do that. Let's change from TRUS biopsies to transperineal biopsies, okay. How are we going to do that and work together and track all the data and show that it matters? So that's been going on, again, since 2012, and now has expanded to kidney cancer and stone diseases as well.

Matthew Cooperberg: That's fantastic. What do you think have been the key elements of success? How much of it relies on personal communication, personal interaction? I mean obviously, these are all important. But the support of Blue Cross, and the buy-in from the insurers? How much is made, obviously, of Dr. Monty's personality, and respect across the state? What do you think were the key elements?

Todd Morgan: Yeah. I think some guiding principles from the get-go were that it's not about competition. It's not about billboards. It's about raising the level of prostate cancer care at the time, and now, again, to these other diseases. That is really Dr. Monty, and his reputation carries a massive amount of weight. And also David Miller and his talent and ability to communicate carried a lot of weight. Ultimately, you can't do this without serious investment. It costs a lot of money to run MUSIC. The budget number is so sizable. And yet, I've seen Blue Cross Blue Shield of Michigan talk about the amount of money that they save on an annual basis through MUSIC. For them, it's in the tens of millions of dollars by their count. Because if you reduce sepsis after a prostate biopsy, well that's a lot of dollars saved, right?

So I think those are some really key elements. Picking problems that are solvable, potentially, as a group where you really can make inroads from a quality improvement standpoint, that's another key piece.

Matthew Cooperberg: Do you think this would be possible if it were not for Blue Cross being so dominant in the state? This has come up a lot as we've launched the AQUA registry nationally with AUA, with the thought of trying to feed data to regional collaboratives. It seems like there have been a lot of attempts, and none has quite stuck the way MUSIC and the other CQIs in the state have, in part because it's hard to get insurers to buy in if they see their competition is going to benefit, too, which has never made a lot of sense to me. But I went to one of your meetings the first time they ran it and met one of the Blue Cross folks and asked what they were investing in.

Todd Morgan: What'd they say?

Matthew Cooperberg: [crosstalk 00:05:14] in the industry, I said, "No." He said, "Do you know the term decimal dust?" I said, "Not really." He said, "I don't know, we put in a few million, we don't even notice." Because they know that they're going to save tens of millions. But aside from that, you do need those millions to get going. Do you think this would be possible if it were Blue Cross plus United plus Aetna [crosstalk 00:05:33]?

Todd Morgan: People have tried this, right, in different states. I think that's a key barrier. So their dominance must play a big role. On the other hand, this is the part that I really didn't understand at first. I wish I'd have asked that question. Because again, I got here like, "Wait, so is this only for Blue Cross Blue Shield patients that they are covering, and all the costs for it?" No, no, no, this is everybody. It's like, what? They're helping everybody? That's a huge amount of money. And from patients, which I don't want to discount that at some level when you see Blue Cross and the representatives at these meetings, they really care about patients. We don't stand up for the insurance companies, I think, very often because we have a lot of negative experiences with trying to get patients covered for different things. But they invest, and what they are doing is really benefiting patients in this state.

Matthew Cooperberg: Yeah, no, it's phenomenal. What are some of the most exciting ongoing developments?

Todd Morgan: In MUSIC as a whole, the biggest new things are the ROCKS Initiative, so pushing forward stone care in ways that I don't think we've ever really done. And the new development of MUSIC, KIDNEY. My own bias is towards these two clinical trials that we've been running, and hopefully, we can talk about it.

Matthew Cooperberg: Yep, that's where we're going next, yep.

Todd Morgan: So maybe I'll use this as a chance to segue into that, which is the G-MINOR Trial and the G-MAJOR trial. Which is at some level, kind of taking advantage of the MUSIC infrastructure to then almost make it a cooperative group, to be able to run trials.  Because now we collect data on so many prostate cancer patients, to almost really over 90% of localized prostate cancer patients in the state, their data is included in the MUSIC registry, including whether they undergo surgery or radiation, their follow-up, PSA recurrence, quality of life data. Every patient undergoing prostatectomy in the state, basically, gets a baseline EPIC questionnaire, gets 3 months, 6 months, 12 months, 24 months.

Every four months, I get a report of all my patients. For an individual patient, I can walk into a room with a piece of paper, and I do, that says, "Here's where you were at baseline, here's where you were at three months, here's where you were at six months, for urinary sexual [inaudible 00:08:07] gains, quality of life. Here's where we expect you to go, we hope over time. That is pretty useful. But then we say, "Do we know our own data?" No, that's where you were really pushing for it in AQUA, there are not a lot of urologists, not a lot of urologic oncologists that really know their own data. I know my own data. So if a patient asks me, I could show it to them actually.

So, that's the infrastructure. Anyway, that's kind of the backbone of infrastructure. Then we've asked on top of that, okay, can we use that infrastructure than to run randomized control trials? So the first one we ran was G MINOR. This trial focused on the post-prostatectomy setting. As you know, there are reams of data around these gene expression classifiers. Like DECIPHER, and we know that they perform really well for the endpoints that they're meant to predict. There are tons of retrospective data demonstrating the performance of these classifiers. But there is virtually no prospective data validating that they change decisions, that they change outcomes. So this was a trial that we conceived of back in 2000 probably '13, '14.

Along with Michael Cher, who's a co-PI with me on the G MINOR trial, it was, again, focused on that post-prostatectomy setting, where there is a test.  DECIPHER intended to help with decisions around adjuvant radiation for patients who we might consider for adjuvant radiation, and that landscape, was, of course, changed in the last year. But we can talk more about that. But the question we posed was for patients, say, with pT3 disease, at prostatectomy, or for patients with a positive margin, patients you might consider for radiation because certainly, they are at high risk of local recurrence, does a classifier, in this case, Decipher change decisions around radiation? And then ultimately, does that change outcomes? Which is, of course, really important. Does it change rates of metastasis? Does it change rates of death for prostate cancer over time?

That data will continue to evolve. We enrolled 350 patients, as planned. Half the patients underwent Decipher testing, half the patients did not undergo Decipher testing, at least clinical Decipher testing. Although their tissue was still sent off for ultimate Decipher testing to be available at the end of the study for comparison. That is kind of the lay of the land on that.

Matthew Cooperberg: You gave an update at ASCO GU, give us the high level so far.

Todd Morgan: [crosstalk 00:10:51], so the way it was designed, the primary endpoint which was the first thing we could measure, is asking the question of whether decisions were changed. A lot of these questions around utility get, what would you do beforehand? And what do you think you would do after you have a test result? But this was real-world, not like a referral to radiation oncology. It was the receipt of adjuvant treatment, radiation or ADT, or both, and did Decipher appear to change those decisions? And sure enough, yeah, as we presented at ASCO GU ... patients who had high Decipher scores, and were in the Decipher arm, were much more likely to undergo radiation than patients who had low Decipher scores and also in the Decipher arm.

In patients in the control arm, not surprisingly, Decipher scores were not associated with decisions with the use of adjuvant radiation, okay. That is, they didn't have the scores available, but it's a good comparison. You'll be interested in, maybe you saw this, CAPRA-S was also associated.  One of the things included in the trial that I think was really important was, we wanted to ask the question, not just ... we don't just want to get at, does use of some kind of quantitative risk, incorporation of that into counseling, does that seem to drive decisions? Because there is a lot of controversies, I think, around this, that I'd love to hear your thoughts on.

But some people would say that what these gene expression classifiers do is provide you with a quantitative risk assessment and that's it. Well, we can get that through something like CAPRA-S, and it's free. So CAPRA-S scores were discussed with all patients in both arms of the trial, to kind of lay the foundation. What I was getting at is, sure enough, CAPRA-S scores were associated with treatment decisions. But Decipher, its effect was independent of the CAPRA-S score.

Matthew Cooperberg: Which is honestly really exciting. As you say, there have been a ton of these utility studies done that are usually kind of marginal in terms of quality. There are exceptions. But like you said, a lot of it is a kind of retrospective survey or even a prospective survey, what would you have done if? Sort of things. It's amazing you have the prospective data. Are you going to be supported to follow the clinical endpoints? To mets and ...

Todd Morgan: Yeah, yeah. That was, we were able to get an NIH grant around that, so that's an R01 ran by me and Dan Spratt together.

Matthew Cooperberg: Okay.

Todd Morgan: One of the aims is a long-term follow-up of G MINOR, to allow us to continue to follow-up for mets and death, which I think anybody would say, "Okay, that's kind of the fact that DECIPHER seemed to change decisions, that's necessary but not sufficient for these tests to be clinically impactful." Of course, it's going to take a few more years to get that data, but it is a high-risk cohort and we are powered to be able to get that. So from the get-go, we powered it knowing that of course, even though the primary endpoint was decisions, we powered it to be able to get the oncologic outcomes eventually, so we will get there.

Matthew Cooperberg: Very, very cool. How does it change given, I think you were starting to allude to this, given now RADICALS-RT and RAVES and GETUG-AFU 17, and the RCTs for adjuvant versus salvage radiation, should we still give adjuvant radiation to somebody with a high Decipher? I know it's a controversial question.

Todd Morgan: Yeah. It's unknown, I think. The data around those trials is very compelling for the endpoints that have been reported so far. There are issues with the trial, but especially if you look at the ARTISTIC meta-analysis, there's not really a signal for a benefit for adjuvant radiation. But it's still early days. There are more important endpoints, metastasis, death yet to be reported. I think it is plausible, we will see that there's a high-risk population that still could benefit from adjuvant radiation, to be determined. I'm sure you, me, we err on the side of early salvage radiation for the vast majority of patients. I think those trials, as we get more data, there's no doubt we are going to learn more.

I think no matter what, having the data from the G MINOR trial, especially the oncologic outcomes down the road, it's going to be new and kind of an important question that we still do not have an answer to.

Matthew Cooperberg: I wonder if you'll be able to get ... I mean, it'll take more than one R01 five-year period, but I've always finished in the negative predictive value of Decipher. Meaning, we had a study out with the CISNET group a few years ago, that estimated the rate of overdiagnosis of recurrent prostate cancer by 30%. There are all these guys that their PSA rises after surgery. But that's it, and nobody ever dies of a PSA.

Todd Morgan: Right.

Matthew Cooperberg: So you're right, we get very little early salvage. But where I have used Decipher clinically is the patients who have a fairly favorable pathology report, low CAPRA-S, and rising PSA, and a low Decipher, we tend to let the PSA drift more, and the question is, well can you just stop checking the PSA at some point and just say that this patient will never have metastatic disease? I'm curious, we're not at the point of doing that. I'm curious if you are. Ultimately, I think a lot of these patients do get radiation, because of PSA anxiety. But I wonder if there is a point where we can use the genomics to really tailor how much we are even looking in the post-treatment setting.

Todd Morgan: That makes a lot of sense. I mean, we have that paper, PCAN paper, using the CAPSA Registry, different definitions of biochemical recurrence depending on the baseline of risk.

Matthew Cooperberg: That one.

Todd Morgan: Same concept, that many patients, especially those with lower disease risk, don't have pre-PSA progression despite hitting a PSA of 0.1 or 0.2.

Matthew Cooperberg: Yeah.

Todd Morgan: Now of course, we would say, well patients in general who hit those PSA values around 0.2 typically should get early salvage. But I agree, there's a population that doesn't need it and we have to figure out who that population is. Interestingly, I'll tell you, one of the cool things about MUSIC, to sidetrack us one sec, is in partnership with BCBSM, every year there are new value-based reimbursement metrics, practices based on whatever is agreed upon by the collaborative, hitting certain metrics that are pre-specified, areas that we want to focus on, getting an increase in payments, okay? Take for, say, prostate cancer care, for example. One of the ones this year we identified a key issue around is the use of salvage radiation, in particular, the use of early salvage radiation.

Yeah, so the upside is that one of the VBR metrics this year is a referral to radiation oncology for patients who have the biochemical recurrence for early salvage radiation. We identified that as an area, a kind of weakness.  We published some data around that, kind of the magic of MUSIC is then you can say, "Okay, this is an area where we want to focus our improvement on, and we're not just going to do it through education and training." But we are also going to incentivize and pay for the quality of care, which is amazing.

Matthew Cooperberg: And then G MAJOR is coming up, right?

Todd Morgan: Yeah, it's open. 

Matthew Cooperberg: Or G MAJOR is accruing, right?

Todd Morgan: G MAJOR is open. G MAJOR is our RCT, also was part of that R01, an RCT in the initial diagnosis setting. So patients with favorable-risk prostate cancer excluding very low risk. So we said, "Okay, very low-risk patients, the vast majority, or actually 100%, really, we would recommend being on surveillance. We don't really need additional information, necessarily, out of the gate to guide that recommendation." So we excluded patients with very low-risk prostate cancer.  So it's kind of the higher low risk, and favorable intermediate-risk more or less, Gleason 3+4, PSA less than 20 are eligible, if they are within nine months of their initial diagnosis.

It's a 900 patient clinical trial, multi-site within MUSIC, asking a very similar question. In this trial, we are including all three of the gene expression classifiers, Prolaris, Oncotype, and Decipher, all on board. Each site is picking the test of their choice to use for the duration of the study.

Matthew Cooperberg: And test [crosstalk 00:19:30].

Todd Morgan: And again, patients in the control arm will also get a test sent, matched up based on that site. So we will still have some comparative data at the end of the study. But the patient and provider do not know, obviously, the control arm data. Just like G MINOR, everybody is exposed to a free clinical nomogram, in this case, MUSIC has its own risk calculator that's online, Ask MUSIC, just developed, based on the MUSIC data. So that is kind of our way of accounting for just the quantitating risk from the outset. And we are looking at, the primary endpoint is decisions around ... is the use of surveillance versus primary treatment, and secondary endpoints around biochemical recurrence, quality of life, I mentioned that we've got [inaudible 00:20:22] data. So that's just integrated for all these patients.

We're looking at rates of indolent pathology of prostatectomy, so kind of what we would consider an unnecessary prostatectomy, meaning somebody has a Gleason 6, organ-confined disease of prostatectomy, that's probably an unnecessary prostatectomy, by in large. So we are looking to see if rates of that type of indolent pathology if they change with the use of a classifier.

Matthew Cooperberg: Pathologically, I agree completely. That should almost be a never event in practice in 2021. But of course, it's not, it's not, and we know about it, right?

Todd Morgan: Yeah.

Matthew Cooperberg: So no, but it's terrific to be taking that on state-wide.

Todd Morgan: Yeah.

Matthew Cooperberg: This actually raises one other question I wanted to ask you about MUSIC. Is there talk about transparency? About public reporting, by name? I know it's kind of the third rail. But on the other hand, the British Association of Urological Surgeons, you can go to their website, by name, all kinds of things are there, complication rates, the volume of surgery for high-grade versus low-grade. Some of it, I think you have to be very careful. You say you're going to put everybody's urinary and sexual function outcomes on the website without risk adjustment, that you're going to start operating on a bunch of 52-year-olds with Gleason 6, so you have to be careful. But things like rates of surveillance for low-risk disease, I don't know. Have you had discussions about this?

Todd Morgan: It's been discussed for years. We hosted a conference, there are so many concerns around risk adjustment and gaming, just like you said. And also, you worry about urologists just starting out their career, right? It's so complex. Honestly, some days, I think it's an amazing idea, and what any of us would want as a patient. Some days I think, I don't know, why do we need to do that? It's a challenge. I will say, one thing we've done in our group is sharing our data amongst ourselves. And every MUSIC practice can do that, like if they decide amongst themselves, and it's really good data, right? We can share our margin rates, we can learn from each other, we can share. So there's a lot we can do, share [inaudible 00:22:40] continents right?

It takes a leap, even within your own group that you are friends with and colleagues, and everybody trusts each other. Still, surgical outcomes are so personal for all of us, that it takes a big leap. Then to put that just publicly on a website, I think a lot of people won't be happy about that. In general, it goes against the key principles of MUSIC. But I think in many ways people feel that it's maybe inevitable in the long term but I'm not sure. Do you think it's inevitable in the long term?

Matthew Cooperberg: My one-liner is, if we don't do it, somebody's going to do it to us or for us. You just have to look at that God-awful surgeon scorecard that ProPublica put up there, which is substantially worse than nothing. But they defended on the grounds that there's otherwise no transparency. Again, theirs is so bad, I think it is worse than nothing. But ultimately, there will be more things like that, if we don't figure out some way to do this from inside.

Todd Morgan: Yeah. [crosstalk 00:23:43] patients say, okay, you guys collect all this data, can I see it?

Matthew Cooperberg: Yeah.

Todd Morgan: That's not its intended use.

Matthew Cooperberg: Yeah, definitely. It's a conversation we keep having, I think, for sure.

Todd Morgan: Sure. That's a great question.

Matthew Cooperberg: Thoughts? Where else do you think, where's the field heading in terms of biomarker trials and MUSIC? Including thoughts on future directions?

Todd Morgan: I think MUSIC, it's been so successful, I think it will continue to get serious investment from BCBSM, (BCBS of Michigan). I think that leveraging its whole infrastructure for clinical trials is a big deal. It's doable. We're actively doing it. I think you're going to see a potential trial around kidney stones coming down the pike. We don't see a lot of big RCTs, key questions around stone disease, yeah, led by Khurshid Ghani. I'd be on the lookout for that. My hope is that it will just continue to grow and stay strong. Khurshid Ghani is now the director of MUSIC. The whole team is really amazing and committed. I think, still, so much more ahead to improve care not just in Michigan, but hopefully throughout the US and elsewhere.

Matthew Cooperberg: Terrific. It's been a great journey to watch, and I hope to follow you guys for the next steps and continue the conversation.

Todd Morgan: Thanks, man.

Matthew Cooperberg: Thanks for spending time with us. And I hope to see you in person sometime in 2021.

Todd Morgan: Yes, yeah.