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Matthew Cooperberg: Hello. I'm Matt Cooperberg in the Department of Urology and in Epidemiology & Biostatistics at the UCSF Helen Diller Family Comprehensive Cancer Center. It is a pleasure to welcome you to our inaugural journal club for patients. This is an effort on behalf of UroToday, who has for many years now, been curating high-level content about emerging trends in research and patient care for prostate cancer and related conditions.

Now, this information has always been oriented toward clinicians, toward physicians, and researchers. In conversation with our patient advocates at UCSF over the years, the question has arisen as to why we can't get more information about cutting-edge research tailored to the lay public, to patients, to our patient audience. We've chosen to explore this format of a journal club.

Journal clubs are pretty common in academic medicine and even in some community practice settings. We get together periodically to go over the latest, greatest findings on major trials, major advances in research or clinical care for prostate cancer or for other conditions in urology. These may be oriented toward our trainees or just conversations amongst a group of physicians.

In this case, we are going to put on a journal club for you, oriented toward you as the patient community. The format here is that the authors of a paper will give a brief discussion of the main findings of the paper. We'll have a commentator give a bit of a second perspective. Then have questions both pre-planned from our patient advocates and from the broader community.

For our inaugural journal club, we could think of no better study than the 15-year update from the ProtecT trial, which was published earlier this year in the New England Journal of Medicine, with a companion paper in New England Journal of Medicine Evidence, detailing a randomized trial, randomized with patients between surgery, radiation therapy, and active monitoring for prostate cancer.

This was led by Professors Hamdy at the University of Oxford and Donovan at the University of Bristol. It is our great pleasure and honor that they have agreed to join us to serve as our first journal club presenters. With that, we will introduce our presenters and our panelists and launch forward.

Freddie Hamdy: Thank you very much, Matt. It is a great honor to be chosen to come and speak at your inaugural meeting, which is actually very inspiring to make that connection between the research and patients.

Jenny and I are both absolutely delighted to be here. I'm Freddie Hamdy. I'm a professor of Urology and Surgery at the University of Oxford. Jenny?

Jenny Donovan: Hi. Yes, I'm also delighted to be part of this and thanks very much for the invitation. I'm Jenny Donovan. I'm a professor of Social Medicine at the University of Bristol, a social scientist involved in ProtecT.

Leszek Izdebski: Hi, I'm Leszek Izdebski. I have actually the pleasure of co-chairing this extremely active, wonderful group of patient advocates at UCSF together with Bruce.

The group was started many, many years ago by Stan, who is also a part of it right now, a very active part of this group. Like all of us, I'm a prostate cancer patient.

Stan Rosenfeld: Yep, I'll go. Stan Rosenfeld, patient, prostate cancer survivor, and member of the Urology Patient Services Committee.

Bruce Zweig: I'm Bruce Zweig and I'm also a survivor. With Les, I'm co-chair of the UCSF Patient Services Committee.

Nathan Roundy: I'm Nathan Roundy. I'm a 19-year prostate cancer survivor. I have a slowly rising PSA and I've been involved in prostate cancer education and advocacy since I was diagnosed in 2004.

Matthew Cooperberg: Welcome to all, and thank you all for your time on this. Our format is that Professor Hamdy and Professor Donovan are going to present the updates on the ProtecT trial. I will serve as the commentator and give a bit of a second perspective. Then we have a series of questions from our advocates, which we will start the conversation with. But if anyone else has questions that come up, please use the Q&A button at the bottom of your Zoom window here.

Don't ask any specific, personal medical questions. We will not be able to answer those publicly. But if you have questions about the data, about the trial, anything that comes up as we go through here, please do use that Q&A format. We will come to those after the first set of questions. Without further ado, let me get the slides up. Professors Hamdy and Donovan, please take it away.

Freddie Hamdy: Thank you. Thank you very much, Matt, again. What we would like to do today, is to bring you up to date with a study called ProtecT. This study started because there have been very long uncertainties about the benefits of detecting prostate cancer early, followed by early, radical treatment as long as the cancer is contained to the prostate.

What happened when PSA started to be used in the 1980s and '90s widely across the world, is that there was a very substantial increase in the number of patients who were diagnosed with prostate cancer. The cancer was very indolent and insignificant. These men were given the label of cancer, but they actually didn't need to know they had the cancer, and they didn't require treatment.

At the same time, paradoxically, men died of prostate cancer and continued to die of prostate cancer. We wanted to establish the effectiveness of treating PSA-detected prostate cancer at an early stage, using one of the three options that have been available and still are very much conventional treatments. One is active monitoring, a form of active surveillance.

The other is radical prostatectomy, which is radical surgery. The third one is radiation to the prostate. The rationale for comparing these options is that these were the options patients could choose. But we wanted to establish the difference between surveillance, surgery, and radiotherapy in actually having an impact on the survival of patients with prostate cancer over a long period, who have been detected by PSA.

We went out to nine centers in the UK, as you can see in the pictures on the map here. We tested almost 82,500 men aged between 50 and 69. We found 3,000 cases of cancer, or just below that, with prostate cancer. Of the cancers that were contained within the prostate, or what we would say clinically localized, we randomly allocated 1,643 men with cancer to either active monitoring, radical prostatectomy, or radical radiotherapy.

We followed them up for an average of 10 years and then an average of 15 years. We've already reported on our 10-year median outcomes. Recently, this year, we've updated everyone with a publication in April showing the results of the 15-year average follow-up. The first thing to show you is what actually happened to the patients who were allocated to one of these three treatment options.

Where you can see the men who were allocated to surgery, radiotherapy, or radiation, the majority of them received the treatment that they were allocated to. By an average of 15 years, 90% of men who were allocated to surgery received the treatment, and 92% of the men received radiotherapy. If you look at the active surveillance curve, you can see that at approximately three years, 25% of men had switched over to receive another treatment.

By 10 years, it was about 50%, to 55% who had switched over and by 15 years, it was 61%. What that shows are two things: there is a gradual switch with patients, which can be triggered by changes in the way that the biomarkers, the PSA behaves, what the imaging shows, and what the repeat biopsies show.

Or it could simply be because of the anxiety of the patient or the anxiety of the physician, who want to discontinue the active surveillance, and put the patient through an active treatment. What is quite interesting is that about 25% of men at an average of 15 years, never received any treatment or were spared any treatment for prostate cancer and remained well, and up to 40% were not receiving treatment until that time.

Now, what happens over time in terms of survival? The primary endpoint or the main objective of the trial was to try and find out whether the treatments compared to active surveillance made a difference in making people live longer. What you can see on this graph are three lines, which are superimposed, and almost flatten to a single line. The black line represents patients who received radiation.

The red line represents surgery, and the dotted green line represents active surveillance, and they are superimposed. There are three pieces of good news in that curve. The first one is that men with clinically localized prostate cancer, as long as it's low or intermediate risk, since we have a very, very small number of high-risk patients. Thus, ProtecT really cannot comment on high-risk patients.

We do believe that high-risk patients should receive treatment as early as possible and as much as possible. But what we can tell is that for patients with low and intermediate risk, the survival is very high at an average of 15 years, up to 17 years on this graph, and it's about 97%, which is the highest survival rate compared to any other cancer if you look at the long list of cancers that affect people.

The second thing that it is showing is that irrespective of the allocation, whether it is active surveillance, surgery, or radiotherapy, that doesn't seem to be impacting on that survival. The final one is that surgery and radiotherapy are equally effective as active surveillance. Now, if that is the case, then why would we discuss treatments with patients? This graph is the reason why we discuss treatment.

You can see that the lines have separated here. At the top, you've got the two radical treatment lines, groups of men who received surgery or radiotherapy, with superimposed black and red lines. You can see the dotted line, which is separated from it. What does it mean? What does it show? What it shows is that at an average of 15 to 17 years, about eight men in active surveillance stayed on active surveillance.

About 10% of men will see that their disease has spread, and it has spread either locally around the prostate or outside the prostate with metastases, and so it may have gone to the bone. That's one in 10 men. However, if men receive radical treatment within the first 12 months from the diagnosis being made, then that risk of 10% is halved to 5%. When I see a patient in my clinic, I explain to them that that is the benefit of having early treatment.

Putting it another way, one in 10 men, if they go on active surveillance, have the risk of metastases. If they have treatment, it's down to one in 20 men. That cancer benefit comes at the cost of side effects from treatment. I'll pass on to Jenny, who's done an amazing job looking at patient-reported outcomes. These are the same patients that were randomized to these three treatment options. Jenny, over to you. Thanks.

Jenny Donovan: Yes. Thanks, Freddie. Yes, we wanted to make sure that we collected the men's experiences of the treatments in detail. We asked them to fill in a very long questionnaire every year. At the moment, we've got data for a full 12 years, and they were very enthusiastic in filling in the questionnaires. The response rates were over 80%, so they were very high-response rates.

We also did some interviews with some men to capture the impacts of those treatments, so I'm going to present some of the data here, just the main findings. These are the findings for urinary leakage. If you look at the chart, first of all, this is the data where men report if they need to use one or more pads per day to protect against urinary leakage.

If you look at the left-hand side of the chart, you can see at the beginning, at baseline, that none of the men needed to wear pads in any of the groups. But if you follow the red line, which is the surgery line, immediately after treatment, about 40% of the men needed to wear at least one pad per day. Then over time, that improved a little so fewer men used pads over the next few years. But once they got to about four years onwards, that stayed level.

About 20% of men still needed to use pads every day, and that increased slightly at the end to 24%. In the other two treatment groups, you can see there was not much use of pads at the beginning in the first few years. But then gradually over time, there's some increased use as they switched to surgery or had additional treatments, as you can see at the end for the radiotherapy, but always below the surgery level.

In terms of men's experiences of these impacts, one man said, "I still wear a small pad just in case, because you don't want to have a damp patch or an accident." So it's kind of preventive use. But another man said, "It really changed my life. I couldn't go anywhere. I'm always thinking, 'What if I wet myself?' It's always in the back of my mind. If I bend forward now without thinking too much, I do still leak."

These are their experiences. These are the findings for sexual function and particularly, having erections firm enough for intercourse. Again, if you go to the left-hand side of the chart, you can see that the men started at the same level at the start of the study. Again, if you follow the line, you can see that there's an immediate effect of treatment and the reduced level of erections there in the surgical men.

There's some recovery a little after treatment, but again, the sexual function stays at a pretty low level throughout the time period. If you look at the end after about 10, 11, 12 years, it's quite interesting that the other groups actually joined the surgery group at that low level of sexual function, but their experience before that is very different.

You go back to look at the radiotherapy group in yellow here, there's an immediate effect of the hormones. But then when they stop taking the hormones, there is recovery in erections, but then a gradual decline over time in the ability to have erections firm enough for intercourse. The active monitoring group, experiences a slower decline over time so that more of the men retain their ability to get erections for longer.

But also, there's the decline gradually over time with increased treatment and time passing. In terms of the experience of that for men, one man said, "I've been married for 36 years. We've just got to the point now where we avoid the situation." She said to me, "I don't really want to do it because you're so disappointed afterwards, because it's never what it used to be." Another had a more severe impact.

"Now I'm going through a divorce. Our sex life was pretty good before, and the wife thinks that sex is an important part of marriage. Knowing now that I might not ever have sex again, I try not to think about it because it does crack me up." Those are the experiences. This is the final slide. For bowel function, you can see, again, the same level at the very beginning on the left-hand side of the chart.

But then you can see the yellow line beneath the others. That indicates that there's a little worse bowel function for the radiotherapy group, particularly in the early stages.

Freddie Hamdy: These are really some of the key messages of how ProtecT is changing things. Well, the first one, again, is a good news message that the risk of dying from clinically localized prostate cancer, as long as it's low and intermediate risk, over an average of 15 years from diagnosis, irrespective of treatment, is high. It's 97%, with a 3% risk of dying, and a 97% chance of survival.

That's great news, very reassuring information. Men whose cancer spreads outside the prostate really live quite a long time. We've seen extraordinary survival of men even with metastatic disease who survived 20 years and are still alive. They come into what we call competing causes or competing morbidities, meaning that the cancer is controlled, the treatments are working.

Let's face it, there's been so many fantastic advances in metastatic prostate cancer, that people do live a very long time. It isn't the cancer that kills them, it's a heart attack or stroke or something else. ProtecT has produced through these patients, real-life, patient-reported outcomes. We now have a fantastic profile of what happens to these patients over a long period of time, up to 12 years after the treatment.

Many people say, "Oh yes, but you did all this surgery, and it was open surgery, now there are robots. You gave radiotherapy, and it was radiotherapy using conformal. Now we have intensity-modulated radiotherapy and other methods." In fact, there have been studies to look at the patient-reported outcomes of patients receiving these more modern techniques, and they are exactly the same.

They align themselves completely with what we found in ProtecT. At the end, new patients with low to intermediate prostate cancer really can take time to decide what is the right treatment for them. Most importantly, they are able to assess the trade-off between the cancer benefit from the intervention they're going to receive, against the harms or the side effects of each individual treatment option before they're able to make a decision.

What we find in our clinics, is that every patient has different priorities. For some patients, one thing will be more important than the other, and because of that, they will make very different decisions. We cannot dictate these decisions, and at the end, it's very much a shared decision-making process between the physician and the patient. More importantly, also, it's the patient and their partner.

It's really important. We think, we hope that we are now helping them to make these well-informed decisions. I think we're going to stop there, Matt, and take questions.

Matthew Cooperberg: Thank you so much to both of you. As a reminder to all the participants, please use the Q&A or the chat with your questions, which we will come to in a few minutes. I'm going to give a couple of brief comments about the trial, starting with the fact that this has been an absolutely incredible effort. For anyone on the call who is not familiar with how difficult it is to run large, randomized trials in any context.

You should know that during the time ProtecT was running, there were multiple attempts to do similar things in the United States. They all failed dismally because patients would not accept randomization in the US. That's in large part, we think, because of the clinicians involved. The surgeons and the radiation oncologists, and the other clinicians, really couldn't get themselves to equipoise.

They could not present these treatments as equal options. The story I've heard, which I think Professor Donovan may comment on, is that part of ProtecT's success, was that before the patients who ultimately wound up in the trial met with any surgeon or any radiation oncologist, they were presented with the trial. The fact of equipoise, the fact that we do not know the best way to manage prostate cancer, and having over 1,600 men volunteer for a very difficult randomization.

This is a three-way coin toss; are you going to go down the surgery path, the radiation path, or the monitoring path? It is an incredible effort. This trial has yielded insights which would not otherwise be possible in any setting, and it really is a spectacular accomplishment. It's also a big trial and there's a lot of details in it.

Like many trials, with a lot of details and a lot of secondary papers that have come out since the original publication in the New England Journal a few years ago, everybody has their own spin on it. It's been very interesting over the years after the 10-year paper was published, to see the different ways that the data have been presented by other opinion leaders. There are those that say, "Look, these curves are superimposed."

They ignore the risk stratification and say, "We don't do any good by treating. Prostate cancer treatment doesn't save lives. There's certainly no reason to screen for it because we don't do any good when we treat it." This is completely ignoring the risk profile of the patients in the trial, but we've heard this quite frequently over the last several years.

On the other hand, others look at the metastases curve and say, "See, active monitoring leads to more metastatic disease, which eventually is going to cause lethal prostate cancer, and we need to treat every prostate cancer when we find it." We do still hear those perspectives. I still see presentations even in the past year, which put up that metastases slide as an argument against active surveillance.

Then we hear, "Well, this is now proven definitively that surgery and radiation therapy are equivalent treatments for prostate cancer." Again, a full stop, ignoring the risk stratification question. But surgery causes worse quality of life, and therefore, radiation is the better option. Again, kind of oversighting or misinterpreting the ProtecT data. I want to raise a few caveats and a few points to really emphasize here.

As Professor Hamdy already pointed out, the patients who were approached and accepted randomization in ProtecT, largely had low and intermediate-risk disease. I want to spend a few minutes just on what that means. Prostate cancer is a term that we use for an exceptionally broad spectrum of things that can happen to a prostate, ranging from completely indolent, okay?

Having basically no likelihood of spread or threat to life over a 5, 10, 20, 30-year period, to very aggressive. Even high-risk prostate cancers tend to move slowly, but high-risk prostate cancer is the second leading cause of cancer mortality among men in the United States and the fifth leading cause worldwide. It's a small proportion of all cancers diagnosed.

But because prostate cancer is so common, high-risk disease is a major cause of mortality. But those are not the patients who were in this trial. What do we mean when we talk about risk? One of the terrific things in this 15-year update, was a more granular risk stratification than the first paper using something called the CAPRA score, which we actually happened to have developed at UCSF about 15 years ago.

It looks at the PSA, the Gleason grade group, the clinical T stage, that's whether we can feel the tumor or not at the time of diagnosis, and the extent of biopsy core involvement. If we do a 10-core biopsy, do we see cancer in just one core or is it nine of the cores, and the patient age? We sum all these up to a 0 to 10 score. It's been very well validated in tens of thousands of patients around the world.

If your score is 0 to 2 out of 10, that's low risk, 3 to 5 is intermediate, 6 to 10 is high risk. A little over 70% of the patients had low-risk disease, about a quarter had intermediate risk, and very, very few patients were in the high-risk category. It's also important to note if we think about that first map in the first slide from the presentation, patients were diagnosed in a variety of practice settings.

These biopsies were done with a 10-core template in the era before we were doing image-guided biopsy. MRI was not yet standard of care, and even the quality of ultrasound was quite variable, so under-sampling was a major concern. One of the supplemental figures in the paper points out that if you look at men who had what looked like low-grade disease and went to surgery,

Therefore, we were able to determine the true grade and stage, because the whole prostate was removed, there were substantial rates of upgrading and upstaging. Men who had what looked like low-risk disease, were actually found to have much higher grade, higher stage disease. This happened; this was quite common in all practice settings in the era when patients were accrued to ProtecT.

It emphasizes the point that if we're going to reliably risk stratify men in contemporary practice, that risk stratification is based on a biopsy that is almost always image-guided. This is true in both the US and the UK in contemporary practice. What else can we say about contemporary practice now that may be different? Both imaging and treatments have evolved.

As Professor Hamdy pointed out already, radiation therapy is now given typically with IMRT or SBRT, rather than the 3D conformal treatment that was used then. Because of this, the doses are higher, maybe the targeting is a little better. The quality of life really has not changed all that much. Will the cure rates be any different? Probably not, when we're talking about such low rates of metastatic progression in the first place.

Robotic surgery, I totally agree, has not changed the world relative to open surgery. However, the practice setting makes an enormous difference. When surgery, whether open or robotic, is done in a high-volume center of excellence, outcomes are markedly different than they are when surgeries are performed in a low-volume setting. These days, we've really seen trends toward consolidation of management of prostate cancer, again, both in the UK and the US.

Such that treatment is increasingly done in high-volume centers where the outcomes are very reasonably expected to be better than what was observed in ProtecT. I think the evolution in imaging is actually a bigger deal than the evolution in treatment, because of this under-sampling issue that I raised a minute ago. It is pretty uncommon; it's almost unheard of in the UK.

In many parts of the US, it's uncommon these days to go to a biopsy without having an MRI first. Even the ultrasounds that we do are much better quality than they were in the days when patients were being recruited to ProtecT. The likelihood of under-sampling is much less. A contemporary cohort today that goes down an active surveillance strategy is much more tightly risk-selected to be low risk.

They're actually going to have an even lower risk of metastatic progression than the ProtecT active monitoring cohort would have. The other point to make about the active monitoring cohort in ProtecT, is that it did not include programmed downstream imaging or biopsy. The patients were followed primarily with PSA and had imaging and biopsies done only if the PSA was not behaving itself, which we know is not necessarily the optimal way to follow prostate cancers today.

The final point I want to make here is that it was an incredible success to have over 1,600 men agree to randomization. However, there was a reasonably substantial proportion of those men, a little over 20%, who did change their minds after randomization. The most common decision there was they got randomized to surgery or radiation and said, "Actually, I'd rather go on monitoring."

Then there were a smaller number of men who were assigned to monitoring or radiation and decided to have surgery. A smaller proportion still, who were assigned to monitoring or surgery, and decided to have radiation. This matters because when we look at the way the data are presented in any major publication, the trial is always presented according to what's called an intent to treat.

Meaning all these curves, everything we've looked at for both the survival curves and the quality of life curves, are based on which group you were assigned to, no matter what actually happened. This is the standard way of reporting major trials. It's inherently and by design, a little bit conservative if we're looking for differences between groups.

This is mostly because when early, major drug trials were reported, if you only report the outcomes according to who actually got the drug, and some patients go off a drug because of toxicity, and you don't include those men in the trial, you're going to obscure some of the adverse effects of the drug. On the other hand, a man wants to know what will happen if he undergoes surgery, not necessarily what happens if he chooses surgery and there's an 80% chance he gets it.

This is important because if you look at the original ProtecT publication, there was an editorial written, which suggested, "Well, there's a trend favoring better outcomes among radiation." This was based on five events in the radiation arm, five deaths. Four cancer deaths in the surgical arm, which by the way, is much too small a number to draw any conclusions.

There's a principle in research that the absence of proof of a difference, does not in any way prove the absence of a difference, okay? When the event rates are very small, we can't necessarily say things are equivalent. There was a later publication from ProtecT, that actually showed that of the four men in the radiation arm that died of prostate cancer, they all got radiation.

The five men in the surgical arm who died of prostate cancer, only two of them actually got the surgery. In terms of what can we say about surgery versus radiation therapy? For low-risk disease, sure, they're equivalent because they're equivalent to active monitoring, and patients don't need any of the above. For high-risk disease, we can't say anything about surgery versus radiation therapy based on the ProtecT trial.

There are other trials ongoing in Scandinavia that will eventually answer that question. In summary, it is essential that prostate cancer be very, very carefully risk stratified at diagnosis. That we appropriately target the intensity of treatment to an individual man's cancer based on the PSA, the Gleason grade, the number of cores involved, and other factors like that.

It is also essential that contemporary diagnosis be guided by high-quality imaging, ultrasound, MRI, and other imaging modalities. By the way, there's already been questions about PET scan. PSMA PET is a terrific way to stage prostate cancer distantly. I would expect that the vast majority of men in the ProtecT trial, would have had a negative PSMA PET scan in terms of trying to find distant, metastatic disease at diagnosis.

There would've been some, but very few. As far as using PSMA PET to stage the cancer locally, meaning to find the cancer within the prostate, there are studies ongoing that suggest PSMA PET may be comparable to MRI, maybe even a little bit better, but that's all very much emerging. I don't think PET would've made as much of a difference here as MRI and contemporary ultrasound.

I think we can all agree, and the guidelines are very consistent on this now, that in 2023, low-risk prostate cancer should be managed by active surveillance or active monitoring, full stop. The same is true for selected, intermediate-risk patients. This is where the devil is in the details in terms of which intermediate-risk patients are eligible for AS.

Many men that started surveillance are ultimately going to be treated. We saw that the transition to treatment curve in the ProtecT trial. Those transition rates are lower in most contemporary, active surveillance cohorts in the US and elsewhere. That's because we're selecting patients more carefully who have low-risk disease. Finally, treatment must be of high quality.

You need to ask your team of doctors and other clinicians what their own cancer outcomes and quality of life outcomes are, and seek care where those outcomes are very high quality. The other point I would make is that no one should suffer in silence. The vignettes that Professor Donovan presented of men that feel like they can't leave the house because of urinary leakage or have relationships affected by erectile problems,

These are problems that can be corrected. I have a colleague whose entire research agenda is on the undermanagement of complications of prostate cancer treatment. When treatment is necessary, it may still carry the risk of side effects, but we can absolutely intervene to manage many, not all, but many, many of these side effects. Do not suffer in silence, is the last point I'll make.

With that, we're going to turn it over to our patient advocate panel to go through the first set of questions.