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Alicia Morgans: Hi, I am so excited to be here with Professor David Penson who's joining us as the Professor and Chair of Urology at Vanderbilt University Medical Center. Thank you so much for being here with me today, David.

David Penson: Thanks, Alicia. It's always good to talk to you.

Alicia Morgans: It's always good to talk to you too. And I think today we want to talk about the ProtecT trial and what your perspective is as a urologist, lots of talk about it, and I think that there can be some confusion about how to best incorporate the results of the ProtecT trial into our clinical practices. What do you think?

David Penson: Well, first of all, you've got to hand it to the folks in the UK for doing the study. This is a very difficult study to accrue to, we've tried it in the US in various forms and have failed miserably. And to their credit, they enrolled 1,500 men into a trial that randomized surgery, radiation, and conservative management. And so they deserve congratulations for that. The study when it was last reported out, it was 10 years follow up, if I remember correctly. It was pretty clear that there was no difference in outcomes between the three arms. And now we get to about 15 years of outcomes and we're finding some different things.

And the reason is because we're learning more about the cohort and what we've learned about the cohort is we thought it was low risk and favorable intermediate risk disease, but now they've reclassified some of the men. And in fact, only two-thirds of the men are low risk, the remaining third are either intermediate or high risk disease, and about 10 to 20% are actually high risk. And so it really makes it a very confusing study for us because we're not going to discuss active surveillance in a 50-something-year-old healthy man with high risk disease. And yet in this study, a lot of these men went into that. So when you look at it at 15 years, you see no differences between the three arms. You see a trend towards worse outcomes in the active monitoring group in terms of metastatic free survival, but no differences in prostate cancer specific survival.

So at first blush, you think, "Oh my gosh, why are we treating any of these guys?" But when you really start to get into the data, you start to realize there are some problems here. Number one, it's an older cohort and things have changed. Most of these guys were accrued from 1999 to 2009. Particularly radiotherapy has changed a lot since the turn of the century, to the credit of my colleagues in radiation oncology. So that's the first piece. The second piece is that if you look at specifically the active monitoring group, it's not the same as active surveillance that we see in the US in 2023. It's really much more like watchful waiting. And that's reflected in the fact that more than half the men in that group end up getting aggressive therapy over the course of the study. Whereas if we look at American populations who are truly low risk and on active surveillance, you'll go out to 10 years and the vast majority of them remain on active surveillance. We've seen this in CESAR, the Toronto group shows this, UCSF has shown this when they look at their Gleason 6s. So that's a difference too.

And the other thing is, remember that in the radiation arm for ProtecT, everyone got androgen deprivation therapy. And a lot of those patients, particularly for treating Gleason 6s with radiation, which we shouldn't be doing, by the way, I want to go on record saying that we should be putting all of our Gleason 6s on active surveillance, they're getting ADT in this study, which is also not reflective of what we do. So then you end up in this situation where you have, it's a dated cohort, you have the interventions are maybe not as contemporary as we'd like, but then you throw in this last piece about, "Oh, it's really only two-thirds low risk," and it makes it really hard to figure out. The way I'm taking this home as a urologist is I'm looking at ProtecT, and I'm looking at it in conjunction with the active surveillance cohorts, which are out there, which I had mentioned before, the UCSF cohort, the Canary Group. And what it tells me is this is more proof that in low risk patients, and you don't really see a good subgroup analysis of the truly low risk patients with enough sample size to make really definitive statements, but what it tells me is in low risk patients, which I think these data probably apply to, there's certainly no difference between surgery and radiation. And there's probably no difference between surgery, radiation, and active surveillance.

But I think the important point is there are going to be patients out there with high risk disease who can look at this and say, "Oh, whoa, whoa. I don't want to be treated because this shows me that I can get away with that." And the reality of it is that you have to tell them, "No," because that really only represents the minority of patients in the study. And if you do subgroup analyses on those high-risk patients, you're not going to have enough statistical power to make definitive statements. And you see this trend towards worse metastatic free survival in the active monitoring group in ProtecT. And I'm convinced that's being driven by those high-risk and unfavorable intermediate risk patients, which make up up to a third of the cohort. So that's how I'm parsing it.

The other thing, which is going to make me very unpopular with many of my colleagues in urology, is if you look at the accompanying study from ProtecT in NEJM Evidence in the online journal where they report their patient reported outcomes... And by the way, if you look at data from CESAR, which is under review, well, these patients who have surgery, they have incontinence 10, 15 years later. And so it's hard to justify surgery, certainly in low risk patients. And if you're comparing surgery to radiation in low risk, in favorable intermediate risk patients, you should still be doing active surveillance. Let's go out there and say that. But if you're not, you can make the argument that if there's no difference in cancer outcomes and there's a big difference in PRO outcomes, then maybe we should be going in a different direction. And we can talk, you know high-risk disease probably better than I do. But the reality of it is is that there's a different argument in high-risk disease. It's a much more nuanced discussion. So that's my take home with it is for low risk patients, it makes a lot of sense, but we have to be really careful not to apply it to these high risk patients because it's not applicable.

Alicia Morgans: Well, and that's so important and I so appreciate you highlighting that because I do think that, at least in my practice, there have been patients who have reached out and there's been a lot of media buzz around this study and how essentially perhaps we don't need to treat prostate cancer. And I feel like I don't want us to slip back into a situation that we were in with the USPSTF in 2012. I don't want us to slip back and say, "We don't need to screen. We don't need to treat, we don't need deal with this," because you and I both know when we see high risk prostate cancer and it comes back and it does at a much higher rate than low risk prostate cancer, as we both know, it's not good. It's not something we can cure. And it is something that limits someone's life expectancy and certainly affects the quality of their survival. And so I am very, very much opposed to us slipping back into that kind of a conversation. So I really appreciate you highlighting this. And in your practice when you see someone with higher risk disease who comes in and says, "Well, the ProtecT study says that I actually don't need to treat my prostate cancer," what do you say?

David Penson: Well, I'll start by saying exactly what you just mentioned, which is this is not something that you want to just observe because when it gets worse, you're going to suffer clinically significant symptoms and it's not going to take long for that to happen. The other point that I've made to patients is you look at ProtecT and ProtecT is great for low risk patients, but if you look at the ongoing studies in high risk patients, you don't see surveillance arms. You look at the Scandinavian study comparing radiation up front to surgery upfront. And you look at radiation in high-risk patients and you see that the addition of ADT to radiation, we know this, creates much better survival outcomes. So to me, what that tells me talking to my patients is we have evidence that clearly shows that multimodal therapy is better than single modal therapy in high risk disease. So why the heck would you ever do no therapy?

And I think that's the take home message to these patients is I know that I am probably going to require multimodal therapy, whether it's radiation and ADT right up front for your high-risk disease, or if you're going down the surgery road, there's a real possibility you're going to need early salvage XRT or maybe even adjuvant XRT. None of these studies discuss observing high-risk disease and there's a reason for that, because we know better. And I think that's a key point to make to patients to say, "Listen, this study is a good study, but it is far from perfect and it's really only applicable to you if you're Gleason 6 or if you're lucky, favorable intermediate risk disease. But if you're beyond favorable intermediate risk disease and you're young and healthy, you don't want to mess with observation." And that's what I tell my patients.

Alicia Morgans: I think that's the perfect message. And so as we sum up and round this out, it is another piece of evidence that active surveillance for low risk disease is absolutely a viable strategy and actually a preferred strategy when we think about the complications of treatment and certainly the complications reported in the patient reported outcomes associated with the ProtecT trial in the New England Journal of Medicine Evidence study manuscript that was also published. When we think about high-risk diseases, it's probably not the way to go, observation, and that treatment makes sense and actually intensified treatment makes sense as we have multiple studies to show that. So what is your final message for folks who are thinking about ProtecT and just trying to figure out, "How do I talk to patients? What do I say?"

David Penson: So my message to particularly American urologists, because we still don't have adequate penetration of active surveillance in low risk populations, they do better in Europe and Canada, my message is if you're applying ProtecT to your low risk patients, this is another important piece of evidence that supports active surveillance as the preferred, not sort of preferred, but the treatment option that should be offered first. And when your patients are uncomfortable with that, and American patients are uncomfortable with the word cancer, which by the way is another discussion as you know, but if your patients are uncomfortable with it, you can point to ProtecT and say, "Look, here's a randomized clinical trial, and it doesn't show any differences." And any trends that you're seeing are related to the higher risk patients.

If you're a low risk patient, this study should make you sleep a whole lot better at night knowing that you're going to do active surveillance. Because in fact, the active surveillance that we're going to put you on in 2023 is even better than what we saw in ProtecT with the addition of prostate MRI, more regular biopsies, genomic testing. So to me, that's the great take home about this. And if someone says, "Well, I still want to do treatment," go read that paper about patient reported outcomes, because radiation is less morbid in certain regards, but it's not a free lunch either. So that's the take home I would tell my colleagues is this is more ammunition to support the argument that active surveillance is the way to go in low risk disease.

Alicia Morgans: Well, I so appreciate you taking the time. And I know it's been a long day in the OR so to put it in context, you're recommending active surveillance for these patients despite spending a day in the OR taking out prostates. So this is the world in which we live. And actually the data speaks for itself, right?

David Penson: Listen, first of all, if I'm taking out a prostate, I'm taking it out in someone who needs it, in high-risk disease.

Alicia Morgans: Absolutely.

David Penson: And I think that's the key. But that is the world we live in. And there are still a lot of people out there who are looking at this and the evidence isn't clear, and they're looking in situations and they're going, "Well, maybe I should be treating low-risk disease." And now they're going to be patients saying, "Maybe I shouldn't be treating high risk disease." And both of those things, in my opinion, are wrong. And so hopefully that's the lesson we'll take home from all this.

Alicia Morgans: Well, thank you for being our true north and for explaining the ProtecT trial. We so appreciate your expertise, Professor Penson, and always appreciate your insights. Thank you so much for your time.

David Penson: Thank you, Dr. Morgans. It's always a pleasure to see you.