NC: Welcome to San Francisco. We’re here at the GU ASCO conference for 2016 and I’m joined by two old friends who are experts in the field of urological oncology, Peter Iverson from Copenhagen in Denmark and Heather Payne, radiation oncologist, or clinical oncologist as we call them in the UK, in London. I’m Noel Clarke, I’m a urological oncologist from Manchester. We’ve had some fascinating insights into new developments and some remarkably good data from trials from Europe, from the USA and other parts of the world and we’re going to share those with you this evening. Now, Heather, I’m going to come to you first because we’ve had a couple of major studies which have been reported on radiotherapy: RTOG-0415 which was a randomised phase III non-inferiority study comparing fractionation schedules in low risk prostate cancer. And then secondly the CHHiP study, a very large scale study which has been looking at hypofractionation schedules in intermediate risk. So just give me your thoughts on RTOG-0415.
HP: Just as background, hypofractionation for prostate cancer was thought possibly to be beneficial because prostate cancer cells are likely to respond to a smaller number of big doses of radiotherapy as a result of something called the alpha-beta ratio. Now the first study, and it’s great to see radiotherapy studies in prostate cancer, there’s a lot of it in this meeting which has been fantastic. The first study showed non-inferiority between the standard and a hypofractionated regime but my only thoughts on that study were that these were men with really low risk disease and certainly in our practice they would probably have active surveillance. So although it was non-inferior and it’s great to see hypofractionation being investigated, I don’t know if I… I wouldn’t treat somebody with low risk disease.
NC: I think it was a study of its time, wasn’t it? And in planning all of these studies one starts off with an intention and the world moves on. And the world had clearly moved on but the results were, nevertheless valid. Probably more relevant were the CHHiP results because intermediate risk prostate cancer, Peter if I can come to you on this, is a disease which we would treat actively. Now the results were really very good, I thought.
PI: Yes, it’s a huge study, recruiting more than 3,000 patients actually, and it’s a three arm study having a standard arm of 74Gy and then comparing it to two hypofractionated dosages of 3Gy per day for 20 days versus, if I remember correctly, 19 days.
HP: Yes.
PI: And even though the study was not powered for statistically comparing the two hypofractionated dose schedules an interesting difference appeared between the 19 day schedule and the 20 day schedule which was fascinating to me, that a difference actually might appear with only one day’s difference. What I’m thinking, there was no inferiority between the conventional dosage of 74Gy and the 60Gy hypofractionation dosage schedule which, of course, is interesting. What I’m a bit concerned about is the follow-up because it was actually suggested by Dr Dearnaley, who presented the study, that this was enough now to change our standard of care when it comes to radiotherapy. I’m only a urologist but I’m wondering if five years of median follow-up, which was the case here, is enough really to conclude that you can change the standard of care in this.
NC: Yes, and it was interesting because the toxicity data was quite encouraging and there was a specific question which was put to David Dearnaley from the audience by a senior member to the effect that five years wasn’t long enough to assess the side effects. I don’t know, Heather, if you have a view about that.
HP: It was a median, wasn’t it, and I think there’s a lot of experience in the UK of using hypofractionated regimes and following patients up for longer. The majority of late side effects you’re probably going to see between 2-5 years and there’s going to be a small number of very late ones. But I think the data is sufficient to change practice for intermediate risk disease.
NC: And David Dearnaley made the very valid point that if you’re going to get serious late side effects you will often get quite pronounced early side effects. Clearly they weren’t seen in the CHHiP trial which was really quite encouraging I thought. So as a serious prostatectomist, Peter, should we give up? Should we hand all the patients over to the radiation oncologists?
PI:  I don’t think we can conclude, based on this study, that we should give up surgery. This was a comparison of two radiotherapy schedules, or three schedules actually. So no, you’re not going to hear me say that we should give up radical prostatectomy, not based on this at least, there might be other reasons.
NC: Now, there is another study which was read at this meeting by Bill Shipley, a subject quite close to your heart which is the use of bicalutamide and some quite interesting results, I thought.
PI: Yes, we have been waiting for these results for some time actually. The study was a two arm study including I think it was 760 men with rising PSA following radical prostatectomy between salvage radiotherapy without endocrine therapy versus salvage radiotherapy plus 24 months of bicalutamide 150mg daily. I have seen data before showing a difference in time to metastasis and in cancer specific survival but now there is a difference, actually, in overall survival with approximately 13 years of median follow-up. So that’s a very mature study.
NC: One comment which Bill made which was that this was old style prostate cancer, that there were much more advanced cases. Sitting and listening to that and knowing the data from the RADICALS study which was mentioned, I didn’t agree with him. What I know is from the recruitment to the RADICALS study is that 60% of the patients going into that study are actually T3. So when we’re looking at hormonal schedules, which we will ultimately do with a modern trial which you’re closely involved with, the RADICALS study, we may well see a confirmation of what Bill Shipley and the Boston team have started to show us with this early study. It really is quite promising I think.
PI: Right. I think I’ve always been biased by the fact that in high risk and locally advanced disease where the prostate is still in place we have shown very convincingly that the addition of endocrine therapy as adjuvant endocrine therapy has made a tremendous difference. So I’ve always suspected that that would be the case also in the salvage situation albeit the prostate is not there anymore.
HP: It makes complete sense, doesn’t it?
PI: It makes sense. It makes sense.
HP: Because it’s such well-established data.
PI: But it leaves us with a couple of problems, I would say. What is the optimal schedule? Is it really 24 months and are we going to use bicalutamide today with all the new modalities we have in hand? I think that’s going to be an issue for debate really.
HP: I must admit, for my salvage patients I would choose bicalutamide.
NC: That’s interesting.
HP: Quite often I give patients a choice but I think bicalutamide has advantages with no risk of osteoporosis that more men were saying libido energy levels obviously at the cost of gynecomastia. But I think for some men it’s a better tolerated drug when you weight up the differences.
PI: In terms of quality of life maybe but if we talk efficacy we don’t have any head to head comparisons between an antiandrogen and an LHRH agonist for instance.
NC: We will perhaps be able to compare the various studies. RADICALS in its hormonal element has recruited 2800 patients, there’s a GETUG study as well which is similar in its design. So hopefully we’ll be able to answer that question.
HP: But also the EPC showed a survival benefit, didn’t it, for locally advanced with adjuvant bicalutamide.
PI: The EPC…
NC: The Early Prostate Cancer trial.
PI: Yes, that was the Early Prostate Cancer trial with bicalutamide, there was a difference between bicalutamide as adjuvant therapy compared to placebo. The difference was very similar to what we have seen with LHRH agonists but it was not a direct comparison.
HP: Yes, but extrapolating that you would think that there is a role for bicalutamide in adjuvant therapy.
PI: Yes.
NC: So, sticking with the hormonal theme and combined therapies, STAMPEDE, which is a remarkable study, which you and I…
PI: Becoming more and more remarkable.
NC: We’ve been very closely involved with it so we’re very proud of it so we talk about it all the time, even in our spare time. But some interesting data from STAMPEDE emerging in a rather unexpected way, Heather.
HP: I don’t think anybody really saw that one coming, did they?
NC: Well…
HP: Well I didn’t. But looking at the combination of zoledronic acid and celecoxib showing a survival advantage. And whether that’s an additive effect or whether it’s synergistic I don’t think we quite know yet, do we?
NC: Well, the interesting thing, having been very close to this as part of the trial management group, the celecoxib and zoledronic acid part was stopped because of failure free survival issues and 80% of that was PSA based. Now what we know from pathophysiology is that celecoxib and zoledronic acid would work in a different way, likely to be in the bone, and the year improvement in patient survival was only in those patients with metastatic disease, no effect on the primary. Fascinating physiologically and I think a lot of work to do; there are a number of reasons why. But the difference is so big it seems to be unlikely to be due to chance to me. Peter, you had a quick look at that data, you’ve not had a chance to scrutinise it but it is very different, isn’t it?
PI: No, I’m surprised and trying to think of some kind of explanation. Celecoxib, there is a rationale for slowing down tumour progression and when you go to the old papers on zoledronic acid, if you go to the first study reported by Fred Saad there was actually a difference in survival, it was not statistically significant but it was there and if I remember correctly the hazard ratio was in the range of 1.20. So I don’t know if we already saw this trend at that time and now it’s becoming more clear in a larger group. If there is a synergy or added effect with celecoxib, I don’t know.
NC: Well, it’s a fascinating story.
PI: But it was interesting to hear the American remarks to the results.
HP: That toxicity.
PI: Actually stating that this probably would never fly because of the cardiovascular problems with celecoxib.
NC: Now I found that an absolutely fascinating statement because the hazard ratio for the STAMPEDE celecoxib and zoledronic acid is very large and the survival in metastatic and improvement in survival of one year, well if that had been CHAARTED in ASCO in 2014 that would have made big, big headlines. So I think that story is going to run and run. So we’ve had a fascinating time here at GU ASCO in San Francisco. There is more to come. I hope our discussions have been informative and helpful, it has certainly been food for thought listening to the opinions of my friends and colleagues and it’s been food for thought listening to the data coming out of the meeting. Thanks very much for listening.