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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Bashir Al Hussein and Dr. Dan Barocas talking with me from Vanderbilt about a recent CEASAR study update published in JAMA. Thank you both for being here with me today.

Daniel Barocas: Thank you so much, Alicia.

Bashir Al Hussein Al Awamlh: Thanks for having us.

Alicia Morgans: Wonderful. So, Dan, let's start with you. Can you give a little background on the CEASAR study? This has been a long-term endeavor for you and multiple collaborators across the country actually. We'd love to hear more.

Daniel Barocas: Sure. First off, I'm Dan Barocas, a urologist and researcher at Vanderbilt. The CEASAR study was designed and started by Dave Penson. The big idea was to accrue men with recently diagnosed, localized prostate cancer and follow them longitudinally to compare the effectiveness and harms of different management options for prostate cancer.

The idea is that we know that shared decision-making is the appropriate way to guide people in making treatment decisions, but the data to inform those discussions has been lacking. So, the big idea was to generate those data. What really are the side effects of contemporary treatments, things like robotic prostatectomy, intensity-modulated radiotherapy, and contemporary active surveillance strategies?

So that was the idea, and, again, Dave Penson started it, and we've been at it since 2011 and '12 when this cohort was accrued, and now we're up to just having published the 10-year quality of life outcomes. The oncologic outcomes are coming soon, as we finish up reviewing the chart review data from each patient.

Alicia Morgans: Wonderful. Well, it's a huge endeavor, thousands of patients, and really, as you said, it's data over time so it's a longitudinal study to help us really understand these outcomes.

So, Bashir, can you tell me what was the analysis that was published in JAMA? It sounds like the quality of life data. And tell us how that was designed and what you included and found.

Bashir Al Hussein Al Awamlh: Yeah. Thanks so much, first, for having us. I'm Bashir Al Hussein. I actually just finished my Vanderbilt fellowship and I'm joining Cornell.

So, as Dr. Barocas said, the idea and the premise were to see the long-term side effects for men with prostate cancer. And really, what we also want to point out is that we know that men with localized prostate cancer, as more recent evidence shows, live long-term after prostate cancer, at least 10 to 15 years. So this becomes more important and puts the study at the forefront of why this is important.

In this analysis, really, we looked at how the side effects of men are after being treated with guideline-concordant treatment. So we went by the AUA and NCCN guidelines, and what we included is almost 2,500 men. And we were able to stratify men based on their disease prognosis. So we put men in the favorable prognosis group and those men had low risk or favorable intermediate risk prostate cancer. And on the other hand, we put men in the unfavorable prognosis group, and we grouped both men with unfavorable risk prostate cancer and high-risk prostate cancer.

And the rationale behind that, which was really unique about this study, is that we had sufficient men to put in both groups, and the rationale is men are treated differently, as we know, with different intensities. So, both groups, we looked at both groups separately, and we compared the guideline-recommended treatment. So, for favorable prognosis prostate cancer, we included active surveillance, brachytherapy, and EBRT, and radical prostatectomy. And on the other hand, we included radical prostatectomy with EBRT and ADT.

I can go into the main findings if you would like now. This is the 10-year follow-up study and it really gives the landscape of the whole longitudinal follow-up for men as they started getting treatment to 10 years. So, I think the main findings, we can look first at the favorable prognosis group. One is that... Or I'll just combine them both. For radical prostatectomy, we know it's associated with urinary incontinence, and we managed to see that almost between 11 to 25 percent of men have urinary incontinence at that time, versus for EBRT, it's around four to 11 percent of men experience urinary incontinence during that timeframe. Additionally-

Daniel Barocas: Can I jump in for a second, Bashir? I think that's an important point. We used what's called the EPIC-26, which is a standardized questionnaire that assesses urinary, sexual, and bowel function, and hormone therapy side effects. And those instruments, instruments like that, are validated based on their total score or each domain, but it's hard to interpret. We end up with, "My function score is an 84." What does that really mean? The instrument is very sensitive to urinary incontinence; any bit of urinary incontinence knocks your score down pretty significantly. And, as Bashir was saying, we see those differences between surgery and the other groups, and those differences are big enough that they meet what's called the minimum clinically important difference. And that's how we interpreted whether differences were significant.

But actually, the more digestible way to present the information is based on some of the individual items that capture what patients most want to know. And what Bashir was referring to is people reporting at least a moderate or even a big problem with urinary leakage. And it's pretty interesting in the favorable prognosis men, it's about 14 percent of men who have long-term, bothersome leakage after prostatectomy. And that compares with about four or five or a little bit more percent in the radiation groups. And so, when you think about the magnitude of difference in that light, it doesn't feel as large. Certainly, there's a risk that's bigger with surgery than it is with radiation, but the magnitude of that risk is perhaps not as big as people think and may be quite different in specialty centers where results are tracked and so forth.

Bashir Al Hussein Al Awamlh: Thank you. That's actually a great clarification. And this also brings a point that this is a population-based study. So, it's pretty interesting that this represents the community and what happens in the general public as well. So, that's, I think, one of the biggest advantages of this study.

So, we spoke about urinary incontinence. The next domain is the sexual function domain, and we found that for the favorable prognosis group, radical prostatectomy is associated with sexual impairment for the first three to five years compared to the other treatments for those men with favorable prognosis. But after five years, we noted that the sexual function converges or becomes not that different with the other treatments, and that can be related to age-related side effects or age-related decline in function for the most part.

And then, however, the other interesting finding for the sexual function, when we looked at the unfavorable prognosis, was that we didn't find any differences that meet the validated or the predefined clinically minimal clinically important differences for the sexual function between EBRT with androgen deprivation therapy and radical prostatectomy. And that was a very interesting finding and is important in a clinical context that we can talk about in a little bit, but that also can inform decision-making or help in that.

And one of the other findings that we found is, over 10 years, at the end of the follow-up for men with an unfavorable prognosis group, there was a slight but significant difference that met the threshold for hormone-related side effects and for bowel-related side effects for men with unfavorable prognosis cancer in the ADT with the EBRT group.

Alicia Morgans: It's so interesting because, as you point out in that discussion, radiation comes with hormonal therapy in this poor prognosis group, and so there are all of those side effects as well that can be contributing.

Bashir Al Hussein Al Awamlh: Right.

Alicia Morgans: And I think it's always been so valuable to see the team put these longitudinal studies out because this is what, to Dan's point, this is what patients want to know. They want that granular level, and they are all expecting to live at least 10 years, if not forever. So we do need to be able to provide this information.

Now, if you had a patient in clinic this year and the patient was trying to decide, maybe, let's say, a favorable case of more favorable risk prostate cancer between surgery and radiation, let's give this patient a very neutral age of, say, 68. Let's say that this patient really has the opportunity to go in either direction when it comes to surgery or radiation, is a good surgical candidate, would be a fine radiation candidate as well. How do you use this information to actually have that conversation with the patient and explain what he should expect when it comes to these domains of quality of life?

Bashir Al Hussein Al Awamlh: I think this is the dilemma that we deal with probably every day as urologists, radiation oncologists, and medical oncologists, which treatment to do. I think one thing I would notice here is that active surveillance, if that patient is a candidate, this data really supports active surveillance because you can see, provided it's safe in that particular scenario, you can see the side effects for all these treatments and how active surveillance compares to that. And so it truly is beneficial. So that is probably the number one thing I would focus on.

Daniel Barocas: Well said. Well said. The best treatment to preserve your function is no treatment, as long as that's a safe maneuver oncologically.

Bashir Al Hussein Al Awamlh: Yeah. So I think that's the one thing that we would focus on the most. However, patient preference is such an important thing, and it depends on really what the patient, to them, is important. Some patients will focus on sexual function, and that's the most important thing to them. Some patients can't fathom the idea of having urinary incontinence; that's another thing. But it's important to put things into context, and their baseline function is really important as well.

These data are important, and it gives you a general trajectory of things, but different patients have different priorities. And maybe we can talk about this in a second too, but it's important for patients to see how they would pan out in terms of function in a personalized manner, and this is where nomograms come in and prediction tools using data such as this. And that is an important topic for us.

Daniel Barocas: Let me just chime in and say that we have illuminated one aspect, and a very important aspect, of this decision. The ProtecT trial gives us really good information on survival and metastasis out to 15 years, albeit with older-style treatments, but in a different setting. And our oncologic results will be forthcoming, as I said. But there are many other facets to the decision.

If somebody has committed to treatment and is thinking about surgery or radiation, beyond the side effects, I think the things that people dwell on are how they're going to feel about the interpretation of the PSA afterwards. It's pretty simple after prostatectomy and can be a little confusing after radiation. And some people don't tolerate that uncertainty well from an anxiety perspective. And, again, notwithstanding the ProtecT trial showing really equivalent oncologic outcomes long-term, people feel differently about having the opportunity to use salvage radiotherapy if there's local recurrence and acknowledging that the risks of salvage surgery after radiation go way up.

And so I think there are, as Bashir said, personal preferences in those regards that also factor into decision-making. Certainly, the impact on sexual function, at least in the favorable prognosis people, is more immediate. It evens out by five years, but that means that the people who get radiation have preserved function for longer. And, again, it depends on how much people value that. It's something like 40 percent of the patients in the study had poor sexual function at diagnosis. And so, for those patients, that issue comes off the table pretty much. And, as Bashir said, in the unfavorable prognosis patients, there's really no difference in sexual function outcomes that we could detect. And so there were differences in some of the individual items, but the main analysis with the domain scores really didn't show, didn't meet, that minimum clinically important difference. So for those men, again, that aspect of the decision comes out of play.

Alicia Morgans: I see. I think it's so important, as you mentioned, the baseline function, and that, I think, is something that can be challenging for people to think through sometimes, that maybe they're not perfect at baseline going into it. And everyone wants to maintain, but if you're already in a limited capacity when it comes to sexual function or already have some urinary complaints, this can be challenging. So, for each of you, I'd love to hear what your message would be to listeners as they're considering this paper, and hopefully, they all go read it in JAMA, but if they had to have that take-home message from you without reading it quite yet, what would that be, Bashir?

Bashir Al Hussein Al Awamlh: Well, that would be prostate cancer treatment has side effects, and it's important to go into treatment for patients and understand these side effects. As we know, patients live for a long time after and hopefully live forever, like you said. And it's important to categorize patients into favorable and unfavorable. I think that is an important part of this paper. It depends on the risk. Knowing what risk you are going into that and seeing what side effects are important to you is important. That's pretty much it. Yeah.

Alicia Morgans: Great. Thank you. And, Dan, what would your message be?

Daniel Barocas: I guess what I would say is that the shared decision-making process is really important, and the data that we've produced here helps to inform that process. The details here are things that we can individualize and we can generalize, but I think it's important to deliver the information to the patients and important for the providers to understand it so they can explain it well and give patients reasonable expectations about their future function.

Some of the other analyses that we've done in the CEASAR dataset show that a certain proportion, 10, 15 percent or so, actually regret their treatment choice afterward. And a lot of that is driven by this difference between expectations and real outcomes. And so, to the extent that we can provide better information at the outset, we hope to reduce that kind of decision regret.

Bashir Al Hussein Al Awamlh: Yeah. I'd like to add just one point. It's an important study we also did using the 10-year data, or the patients who participated in it. It was a qualitative analysis actually. And when we looked at patients and interviewed them, one of the important themes that came out from this analysis is that patients would advise other patients or other providers to have important baseline information, set the expectations right. And I think that's so important, I think, like Dr. Barocas said. So, we hope this data will help set the expectations right and we would like to implement it so it's personalized. So that it comes in handy actually, not just stay in general.

Alicia Morgans: Well, that is wonderful, and I commend you and the team for doing this work. I think it's so important that this kind of work informs what patients may expect, as they can go through these treatments and try to live their lives as normally as possible on the other side.

So, thank you so much for your time and expertise today.

Daniel Barocas: Thank you, Alicia. It was really nice talking with you.

Bashir Al Hussein Al Awamlh: Thank you so much for having us. It was great.