Clinical Implications of the Study Findings from the Radiotherapy Adjuvant Versus Early Salvage ((TROG 08.03/ANZUP RAVES) Trial - Andrew Kneebone and Declan Murphy

January 15, 2021

Men who undergo surgery as definitive therapy for their localized prostate cancer generally only receive subsequent radiation therapy if their surgical pathology shows high-risk adverse pathologic features (adjuvant radiotherapy) or if they experience biochemical recurrence (salvage radiotherapy). Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomized, controlled, phase 3, non-inferiority trial aimed to test the hypothesis that observation with early salvage radiotherapy (SRT) is not inferior to adjuvant radiotherapy (ART) with respect to biochemical failure in patients with high risk disease after radical prostatectomy (RP).

Andrew Kneebone (Northern Sydney LHD) and Declan Murphy of Peter Mac join Alicia Morgans, MD, MPH speaking about this collaborative study, led by the Trans Tasman Radiation Oncology Group (TROG), in collaboration with the Urological Society of Australia and New Zealand (USANZ), and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) between surgeons, and urologists, recently published in The Lancet Oncology.

Between March 2009, and Dec 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Drs. Kneebone and Murphy highlight that these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy and we now have very clear evidence to support the way we offer radiotherapy in the post-op setting.

ClinicalTrials.gov, NCT00860652

Biographies:

Andrew Kneebone, MD, Associate Professor, Senior Staff Specialist in Radiation Oncology, Royal North Shore Hospital, Sydney, Clinical Associate Professor, University of Sydney

Declan Murphy, MB, BCH, BaO, FRACS, FRCS, Urol, Professor, Consultant urological surgeon at Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Australia and Director of Outcomes Research at the Australian Prostate Cancer Research Centre. 

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so delighted to have here with me today two friends and colleagues. One, Professor Andrew Kneebone, who is a Senior Staff Specialist in Radiation Oncology at the University of Sydney, and the second is Professor Declan Murphy, who is the Director of GU Oncology at the Peter MacCallum Cancer Centre in Melbourne, both from Australia. Thank you so much, gentlemen, for being here with me today.

Andrew Kneebone: Pleasure.

Declan Murphy: Pleasure.

Alicia Morgans: Wonderful. So, I wanted to speak with you about the recently completed and nicely reported RAVES trial, wondering if you could tell us a little bit, Dr. Kneebone, about why you did the trial, really how it was constructed and what you ended up finding?

Andrew Kneebone: Yeah, I think the trial addresses an important issue in prostate cancer management, that radical prostatectomy is the most common treatment for prostate cancer and probably about a third of men have high-risk features. And 15 years ago there were three large trials that said for men with high-risk features after radical prostatectomy, that having adjuvant radiotherapy within four months has the risk of cancer recurring. And so current American/European guidelines recommend that all men with high-risk features after radical prostatectomy and that's T3 disease, positive margins, seminal vesicle invasion, that they should be considered for prostatectomy radiotherapy within four months. Now that hasn't really been a popular recommendation amongst the urology community because there's always the option of watching men closely and if the PSA starts rising, then we give radiotherapy then, and that's called early salvage radiotherapy, and the old trials really compared adjuvant radiotherapy with no radiotherapy at all.

And having the approach of early salvage [inaudible] for men, the potential side effects of treatments, and also maybe early salvage was as effective. And the RAVES trial was born and we're really proud of being an acronym: Radiotherapy Adjuvant Versus Early Salvage, so we became RAVES. And so 13 years ago the trial was born and so we've now just recently published in Lancet Oncology, the results of the RAVES trial and basically the bottom line is that it is perfectly safe for men who have high-risk features not to have adjuvant radiotherapy, to watch the irPSA closely, if it hits 0.2 and then we give salvage radiotherapy and then being free of cancer five years after that approach was plumb the same in the adjuvant versus early salvage scenarios.

Alicia Morgans: So thank you so much for going through that and clearly very important and I have to say as a medical oncologist, I'm less incorporated into these discussions, but it is absolutely not necessarily the preference of the urologist to say in that adjuvant setting, "Hey, you're still having some urinary incontinence, you're still recovering, but we're going to really push to get you to get adjuvant radiation," and of course they have because that's what the data suggested. But really interesting and important that you actually looked at this question, not just at adjuvant versus nothing, but adjuvant versus early salvage. Declan, can you tell us from your perspective as a urologist, what are the reasons that you might not want to go right into this adjuvant approach to radiation?

Declan Murphy: So urologists have always been of course, very keen to offer our patients a multimodal approach when we are concerned that surgery on its own may not give them a good cancer outcome and hence we always have had an interest in offering adjuvant or early salvage treatment when it's appropriate. But the challenge has been, and we know that if we offer adjuvant to every person who has slightly ugly looking features at their prostatectomy, so as Andrew said, maybe there's some extracapsular extension or some high-grade disease or positive surgical margins if we offer radiation within a few months to all of those patients, the concern we have is number one, we may be over-treating a bunch of patients who despite having some, for example, extracapsular extension, but maybe a negative surgical margin who maybe are not going to go on and have biochemical recurrence in the future. So they will be over-treated.

And so there's a bunch of men that perhaps may be harmed by that because the second concern is, of course, putting radiotherapy into that surgical field will mean a small number of patients may have some quite significant side effects either in the GU tract or in the GI tract. So I think there's a competing thing here. Yes, we want to make sure patients do receive that additional treatment if it's going to be important for their longer-term cancer outcome but we want to make sure that we're not over-treating a bunch of men and exposing them perhaps to side effects they wouldn't need to.

And the prior trials that have looked at the question of post-operative radiotherapy because if you put it under that framework, that these are men who've had surgery and they're having radiotherapy sometime post-operatively, they have not had the same rigor as this particular trial had because if we said, "Okay, this is a bunch of men with some adverse features, we're going to watch them", half of them will have the radiotherapy I think it was within three or four months of surgery, in other words, adjuvant when their PSA has not yet reached 0.1, or we're going to watch them carefully and when their PSA gets to 0.2, so a low bar, then they will have their salvage radiotherapy.

I feel this is a much better trial design than some of the older trials where men did not get the salvage radiotherapy early, they got it later and later and later. So that was one of the attractions of this trial, it was truly testing early salvage at a PSA of 0.2 versus adjuvant. And I think that's ended up what has been our practice, Alicia, in recent years is we have increasingly moved towards the early salvage approach and what RAVES and indeed RADICALS and the GETUG trial that read-out at the same time has shown us is that early salvage seems to number one, offer us that good security that their cancer management is not compromised and we can ask Andrew to talk to that primary endpoint of biochemical recurrence-free survival, so early salvage seems to deliver the same as if you gave everybody adjuvant. And secondly, very importantly, on the side effect profile, we see that patients do well if you offer them early salvage because it's at a later time point, then treat everybody within a few months with radiotherapy.

Alicia Morgans: Well, thank you for going through that for us, Declan, and Andrew, can you go through really just the specifics of that biochemical recurrence-free survival, that primary endpoint? Can you speak to that a little bit, let us know how the different groups did? You said they were right on top of each other. What does that mean?

Andrew Kneebone: Yeah, and there's a couple of provisos and we'll talk later about limitations, but there were no negative patients and they had to have an undetectable PSA at entry. And so they each had 64 Gray in 32 fractions just to the prostate bed, no hormones were used, and there had to be a trigger at 0.2, we didn't let it get up to 0.4, 0.5, or higher. And if anything, the salvage was 87% biochemically disease-free at five years and the adjuvant was 86%, so the curves absolutely overline each other. At eight years, and the confidence intervals are getting a bit wider when you're out that far, but we had 75% biochemically disease-free at eight years in the salvage group and 79% in the adjuvant group. So if you, at eight years only had a 4% difference in biochemical control then the likelihood of any clinically meaningful difference between the two arms, such as metastasis or survival endpoints is going to be piddly-squat.

And so it wouldn't justify the additional toxicity of going through radiotherapy and it's really lovely doing a trial that's practice-changing. I knew the results of the trial about a year and a half ago, I was seeing patients their PSAs had gone from 0.03 to 0.06, they're still incontinent wearing a pad and I said, "Look mate, you can take it easy, you don't need to have any treatment, we can just watch to see if your PSA is continuing to rise, I can see how long it takes to rise up to 0.2, sometimes if rise 0.2 takes a decade to rise then we don't need to treat." And sometimes I can reassure them, "It's safe to wait, your chances of any clinically meaningful difference in your outcome, eight, 10 years down the track is incredibly small."

Alicia Morgans: So let's dig into that a little bit more because I love that. We're not just helping patients to remain cancer-free and helping at least to prevent that cancer from coming back if it will, but we're also really managing and preventing hopefully complications, allowing them to heal and allowing them to minimize those long-term problems. I mean, incontinence is something that is absolutely felt every single day and if you continue to be a man working or even a man who just wants to live his life, being incontinent is a problem. So can you tell us a little bit about the side effects? It was interesting, it looked like there was this little bit of a composite figure where you put all the side effects together and I think there were Grade 3 side effects that were GU side effects altogether and really show the difference between those patients with an early salvage versus adjuvant and it really nicely separated with those patients who had the early salvage, having significantly fewer side effects. Was that your experience in practice, Declan, because I'm sure you were seeing some of these patients?

Declan Murphy: Yeah, it really is and this is one of the most important parts of this study that they measure the side effects, of course, per protocol as they went on and there's a very nice table in the supplements that describes these GI and GU side effects in the adjuvant arm and in the salvage arm. And it confirms what we might think intuitively, which is this. If you take a man after a radical prostatectomy and you offer him a course of post-operative radiotherapy into the prostate bed, and you do that at about four months after surgery when the pelvic floor is still settling down, these are the side effects you will experience. Whereas if you do the exact same dose of radiation, but deliver it at a later time point, Andrew, remind me, when was the salvage given on average?

Andrew Kneebone: Yeah, so it was a fairly uniform rate of giving salvage over time, but the mean was three to four years.

Declan Murphy: Three to four years, so if you give that radiotherapy three or four years later, the same dose of radiotherapy, the side effects are dramatically less in my view, so there's a really good trade-off there and remember the primary endpoint was about the cancer, about the biochemical recurrence-free survival. It was the same whether you had the cancer treated four months afterward or years afterward, but there was a really big trade-off in the way we counsel our patients about the side effects of radiotherapy. And importantly, of course, what it effectively meant is that half of the men did not need salvage radiotherapy then. Although you can look at it the other way, I mean half of them did need salvage radiotherapy. We mustn't lose track of that fact, but it meant that you're sparing half the group from getting radiotherapy at all, and of those who got it in the early salvage setting, they get it years later and that's a much better-tolerated thing especially GU side effects, I think that's what this trial tells us.

Alicia Morgans: Absolutely. Just from a practical standpoint, Andrew, can you tell us how are PSAs monitored? Were they predominantly monitored by radiation oncology teams? Were they predominantly monitored by the primary urologists? How did this practically work in your systems?

Andrew Kneebone: Yeah and that's all part of a clinical trial, it doesn't necessarily reflect real-world, does it? You have data managers in a salvage arm. We actually recommended three monthly PSAs for the first five years. We wanted to watch men closely and really they probably didn't need to be that closely and so when they went onto the RAVES trial, they were predominantly managed in radiation oncology units. And so the radiation oncologist monitored them and three monthly PSAs up until five years, then six-monthly after that. So there was quite an intensive PSA monitoring program which was probably more intense than what it needed to be.

Alicia Morgans: Great. Well, I think that may be similar to standard in some practices, at least for urologists here in the U.S., I'm sure that in the beginning, it might be three months and then, as you said, it definitely backs off maybe a little more quickly than the timeframe that you mentioned. But Declan, from your perspective, I know you have a wonderfully multidisciplinary approach in Australia, whether you're in Sydney or Melbourne, I think this is something that you've prioritized. If you were practicing in the U.S. in more of a community practice or even Australia if you're in more of a community practice, is this something you think urologists could enact and monitor before they need to send off to the radiation oncologist? Or would you suggest that they engage sooner? How would you suggest that work?

Declan Murphy: Look, you've raised a really valuable point, and let's give ourselves a very clear message here, in this group of men who have adverse pathological features at their prostatectomy, it's always of value to have a multidisciplinary discussion here because what Andrew's trial, what RAVES showed is that even if you opt for early salvage as your paradigm, half of the men will need that early salvage actually with these adverse features. So of course, I think it's of value to have that conversation early on and patients may even choose to say, "Well, I would prefer to be more closely monitored and have my radiotherapy really early, maybe 0.1, 0.2." So I think the number one message is, of course, it's of value because half of these men will need radiotherapy at the PSA getting to 0.2.

But the second message I would give to community urologists, many of our listeners here on UroToday who look after these sorts of patients is to feel very confident about the results that this trial plus the RADICALS trials plus GETUG plus the meta-analysis that was also published. It was a big week in the Lancet when all these trials read-out, big week for prostate cancer, very clear message across all of them. In men with adverse features at radical prostatectomy, early salvage is now the preferred recommendation.

So I honestly think for this group of men, with these particular adverse features, we mentioned earlier, the ship has sailed. We should not offer these men adjuvant radiotherapy at all as a standard of care. Now look I know that this provokes a bit of discussion and some might still feel that, "Look, all this hype, this T3 positive margin," even if the PSA is undetectable, I really feel we should be offering adjuvant. But look, that's not what the trial says. The trial says, if you wait until the PSA gets to 0.2, your patient is going to do just as well, plus you are going to mean his side effect profile will be better, plus half of the patients don't need radiotherapy.

So I think it's a really clear message. I don't think there's any really great controversy here in this trial population. So extracapsular disease, positive margins, and nasty high-grade cancer, early salvage radiotherapy should be the standard of care and I think that's a really clear message for all of us urologists around the world to hear. I think we should go on in a moment and discuss some other situations like, for example, this is not patients who were pathologically node-positive, that's a different population. But I think for the population we discussed in these three trials, it's very clear early salvage is what we should be doing. We should not be doing adjuvant in my view.

Alicia Morgans: Absolutely. Andrew, go ahead.

Andrew Kneebone: Yeah, I was just going to ask Declan, that's something that I agonize a little bit, and one of the criticisms of all the trials, the RAVES, GETUG, and RADICALS was, only about 20% was the super high-risk category, like Gleason 8 to 10, and seminal vesicle involvement, and none of it, and only 2%, but no positives. So we haven't had the super high-risk sort of patients, and maybe do they benefit? But to be honest, I am still comfortable. If I had a node-positive patient, 0.03, and the PSA, I'm still comfortable at the 0.2. Are you, Declan, if you had a node-positive patient, just because I know that toxicity is higher if you give it earlier, I'm still comfortable waiting until 0.2. Yourself, Declan?

Declan Murphy: Yeah, totally right. And Andrew, I think that's why the toxicity data in the supplemental tables here is really, really important. It helps us counsel the patients about maybe the price we might pay by doing very early salvage before a PSA becomes undetectable.

What we also know in the pathological node-positive population is that it's not a uniform population. If you have very low volume, less than two nodes involved, microscopic disease, that's very different to having 10 nodes involved in nodes up to one centimeter, they are more likely to have a full-on biochemical recurrence, or biochemical persistence, actually. Whereas if you have a pathological node-positive, low volume, and your PSA is undetectable, I do agree with you. But I suppose that was, just to be clear, that wasn't exactly the trial population that was studied here. I think pN1 is a slightly different thing. In these trials, you were talking about bed radiation, radiation to the prostate bed, so for that local recurrence. Whereas, we know that if it's nodal irradiation, we're talking about it. It is a different population.

Also in my experience, I think nodal radiation to the prostate bed is well tolerated. I have less concerns about the toxicity of node radiation to the prostate bed than I do about bed radiation. Even though my concern is they're really very low nowadays as well.

Alicia Morgans: So I'm wondering what the two of you have to say and what you think about more sensitive imaging. Because as you know, in the United States, we don't have as much access to PSMA imaging, for example, as you do, but certainly you have access. And I'm wondering, where are the patients who might've been included in this, who have gotten PSMA scans, who have identified? It's such a low PSA, and so perhaps there was nothing to be identified in those scans. But how do you think about these scans when you're thinking about this sort of approach? Do you think that you'll evolve to a setting where you would want the scan to make sure that there's nothing else outside of it, even despite that low PSA? What do you think? We could start with Andrew.

Andrew Kneebone: All right, then. Because both of us have a special interest in PSMAs as being a real game-changer for us in prostate cancer management, and very grappling when to do the scans. But our attitude is one, and we've just written some national radiation oncology guidelines about the timing of PSMA scans, but we don't do it routinely, a PSMA scan under 0.2. We just find the reliability just gets too low, and you get too many equivocal results. But it is very common practice for us now, when the PSA hits the 0.2 mark, we will get a PSMA scan, and maybe that'll change management in a quarter of patients, I tend to say to them. And obviously, you tailor that to the risk profile of what you see of the patient. So, PSMA scanning is coming into play.

There's a very interesting article that I think, by Louise Emmett, from St. Vincent's Hospital in Sydney, that the PMSA scan is pretty unreliable for detecting local recurrences. She had a significant cohort of PSMA-negative patients. They get prostate bed radiation, and 85% were biochemically disease-free for three years. Meaning the PSMA scan missed local disease. So, we know that that's one of its limitations, PSA under 0.2. We also know that it's not all that good at picking up local recurrences. You just got to keep that in mind when interpreting the scan. Declan, when do you do your first PSMA scan? What are your thoughts?

Declan Murphy: Yeah. I agree with you. We struggle of course almost, in Australia, because we have community-wide access to PSMA, patients come in with these scans all the time. But what we don't have is really rigorous clinical trials to show that acting on a PSMA PET at a very low PSA, actually is the right thing to do. But it's an emerging area, and there is data coming all the time, especially from around here in Australia.

But yeah, our view, we published a big systematic review in European Urology a couple of years ago, which we updated last year, looking at the performance of PSMA in biochemical recurrence. So we see about 20 or 25% of scans will be positive at a PSA of 0.2 to 0.4. So that is interesting, isn't it? This is a level where no other imaging will pick up disease, but yet, in about one in four scans, as you say, there will be, for example, a pelvic lymph node, or something else on a scan. And it's very difficult to un-see that when you have it. And it does modify, it does impact management, even though the trials haven't shown that the management impact is actually improving outcomes. So for example, adding that nodal radiation, or having some stereotactic radiotherapy, because there are trials we are recruiting into based on oligometastatic PET-avid disease. So it's inevitable that that area of using novel imaging for biochemical recurrence, so the RAVES population, is something that will become increasingly, our understanding will increasingly expand, I think, in the coming years.

I would caution that we just have to be careful. Just because you see something and you change your management, doesn't mean it will help with patients. And Alicia, we are expecting FDA approval of PSMA in the next four weeks, actually in the US, so. I'm doing a talk at ASCO GU where the title will be something along the lines of "Welcome to the Wild West". Once PSMA PET gets reimbursed in the US, you're going to get exposed to what we have had here for five or six years, which is probably widespread, maybe somewhat, not always the right thing to do, or not always helpful use of PSMA. It's coming soon to you.

Alicia Morgans: Yes, I've heard. And I'm also, we're very excited for your upcoming talk. We'll have to chat with you on UroToday after that talk because I think that there's a lot to learn. It would be really interesting, Andrew, if you are able, if you can go back into the database of patients who are in the trial ended up having PSMA scans. You could pull the scans that are available, and you could look back and say, "Oh, these patients met criteria, and here's their scan", and you could give us a sense. Although it would definitely be, there'd be a selection bias issue, but perhaps there's a way to have the statisticians look at it, given the wild West that has been Sydney, and Melbourne, and everywhere else in Australia, with those scans, perhaps some of them have them, that we could look.

Andrew Kneebone: Yeah. I think PMSA scans became available at the beginning of 2015, was probably when the big influx came. And that was more towards the tail end. Recruitment had closed, and it was more to the tail end of the study. So it's confirming a bit more about local recurrence data. So most people whose PSA recur after radiotherapy, we'll get a PMSA scan. So it'll give us more reliable on our patterns of failure, but not for our original staging of our patients who have relapsed.

Alicia Morgans: True.

Andrew Kneebone: And I suppose, I'll get Declan's view on this, but I think the RAVES trial and the other trials, are showing it's very safe to wait till 0.2, but with the PMSA scans, there's a temptation, oh, let it wait a bit higher, so we can see to scan. And that's what gets me nervous a little bit, that patients being held on by urologists and then say, look, let's wait till we can see it. And that worries me.

I think the RAVES said it's fine to wait till 0.2, but there's a temptation, the scan's negative, as it is in 75% of the cases, they keep waiting longer. And that's part of the issues we've been grappling with this new technology. I don't know whether Declan's seeing that in Melbourne, but it's something we're very much seeing in Sydney, that people aren't being referred when a PSA hits 0.2, and that worries me.

Alicia Morgans: What do you think, Declan?

Declan Murphy: Yeah. Andrew raises a very important point. Let's not forget the reason the pace that this trial readout very well is that the salvage patients got early salvage. They got salvage radiotherapy when the PSA got to 0.2, that's when they went on. Hence, they did just as well. But if you allow that to drift, if, for example, and he's just given the classic example, you do a PSMA-PET/CT at a PSA of 0.2, 0.3, that happens all the time here, and the scan is negative, some people will have a look at that and say, "Oh, good, great. We can just keep an eye on things." And then you repeat the PSMA when it's at 0.5, still negative. Great, good news. And then you repeat the PSMA at 0.8, and now you see disease.

And remember, post-operative therapy is not going to work as well at a PSA of 0.8. So it can be quite disruptive, this type of novel imaging in this setting. We've gone to great lengths to say that, respect to findings in this trial, the reason patients do well is because they got early salvage radiotherapy. Not medium, not late, they got it early. And if you do embrace novel imaging in your workup for these patients, you must still be very respectful of the fact that patients do well when they have early salvage radiotherapy.

Alicia Morgans: Great. Well, I'm glad that you're emphasizing that message. I think we've had to do that a little bit in the US with our old fashioned conventional imaging. That just because you can't see something, doesn't mean you shouldn't use pelvic radiation in these recurrences, but that's in a later setting. So certainly we wouldn't want to compromise what you've just defined as this early salvage.

So, as you're thinking about these things, Andrew, what are the limitations that you want us to be aware of as we do try to implement the findings from the study?

Andrew Kneebone: Well, and so we're all happy that we should be considered for salvage treatment when the PSA is 0.2, but then what is that salvage treatment? Is it the raised prostate bed alone? But there's a very influential trial in front of US, by Alan Pollack, the SPPORT trial, and that looked at giving prostate bed and nodal treatment with hormonal therapy. And so the landscape is getting very murky there. And there are also some patients that the very influential EAU guidelines that don't need treatment at all. So when the PSA point hits 0.2, there are going to be some that we think don't need any treatment that could be probably safely continued to be observed. Some that may benefit from prostate bed alone. And there are some that might benefit from what I call the "kitchen sink", our prostate bed, nodes, and hormonal therapy. Or maybe even consider avoiding the prostate bed, if you say no it's involved.

Because I agree with Declan, it's a prostate bed nodal treatment that gets me worried. So it hasn't answered all questions about post-prostatectomy management. It's just one piece in a sort of puzzle, and we're going to have to continue to learn and do studies in that field.

Alicia Morgans: I agree. Along those lines to both of you, we'll ask Declan first, and then we'll come back to you, Andrew. The group, the ANZUP group, the wonderful collaborations that have come out of Australia, these Phase IIIs that are literally practice-changing when we hear the data, have been so helpful to the field, and have been really, I think, energizing, in that these are not industry-led trials. These are trials that are investigator-initiated, they're collaborative. They are the academics who put them together, and then the communities to carry them out. But that comes with challenges. So what are the challenges that you face? You certainly must be getting good at dealing with them, since you have all of these studies coming out so beautifully. But what are some of the challenges that you do have to face, Declan, and how do you overcome them?

Declan Murphy: Well, as I'm sure Andrew will agree, doing any sort of trial in early prostate cancer is so challenging, isn't it? As you well know, the problem is to reach those meaningful endpoints, you're talking years and years and years later. And oftentimes, the question has changed by the time you get to five years in or eight years in. So, they are challenging, and you see trials reading out 15 years after they were started, and very disappointing when they read out because the question has changed dramatically. So I think that's the number one thing, the big challenge in early prostate cancer, is identifying those endpoints in a time in which it's feasible. But I think these trials have certainly done that, and that's really good to see.

But you referred to the way people recruit well. It's not always easy to recruit and on track for trials. But I think here in Australia, because we have good cooperative groups like ANZUP, and the TROG, the radiation group, USANZ, the urology group, work well together. It's a big country, but it actually, the community works well together. The links are very strong in the prostate cancer community, I would say in particular. And these cooperative groups deserve a lot of credit for getting people together and getting good recruitment into these trials.

Alicia Morgans: Fantastic. And Andrew?

Andrew Kneebone: Well, I'm 54, and Strickland's group has sort of been, sort of talking about what's the next study, and de-escalating some. And I said, "Well, it took me 15 years to do RAVES." And that makes me pretty close to 70, I think time out at 70. So I'm saying leave it to the younger ones. But yeah, it's bizarre. You only have one or two trials in you in your career, don't you, unless you're some [15:42] Bollard or Pollack. Most of us mortals can't do that many, can we?

Alicia Morgans: Well, you can certainly live on in trainees. And I hear you, I've got an adjuvant study that's about to launch. It's been eight, nine, years in the launching, and then you know, it'll be 15 years or so. So I'm going to retire right after that. I'm going to retire at Napa, as Maha], my colleague, and I say, we'll just go out and be hostesses in a wine bar.

So in any event, congratulations, it was worth the wait, the data is fantastic. And I sincerely appreciate the two of you talking to us all about how we actually are going to implement this in our daily clinical practice. Any parting thoughts as we wrap up?

Andrew Kneebone: No, I think it's a study I'm proud of. And it was really a nice collaborative study between surgeons, urologists, the trials group, and ANZUP. And it's also patients. Patients had no, they weren't getting any sexy drug. They'd lost their choice, in patients committed to a study like this. So it is the study when I'm on my rocking chair, when I retire, I'll be proud of.

Alicia Morgans: Well, maybe no sexy drug, but a fantastic outcome for them, and an improvement in their quality of life, or at least a stabilization. So wonderful, wonderful work. Declan?

Declan Murphy: Yeah. And I think clarity, clarity is the word I use here. I think we now have very clear evidence to support the way we offer radiotherapy in the post-op setting. It's not always the case with these localized prostate cancer trials, because the question has changed, or technology changes. But here we have really good clarity. If your patient post-prostatectomy has the adverse features we saw in these trials, you should offer that patient early salvage radiotherapy, not adjuvant radiotherapy, and your patient's going to do very well.

Alicia Morgans: Well, thank you for lending the clarity that you both have lent to us today for this conversation. And I wish you luck as you continue to change the paradigm of how we take care of men with prostate cancer. Thank you both for your time and your expertise.

Andrew Kneebone: Absolutely.

Declan Murphy: Take care.

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