Dr Jan Oldenburg - University of Oslo, Oslo, Norway
Mr Simon Brewster - Oxford University Hospitals, Oxford, UK

JO: Hi, my name is Jan Oldenburg, I’m a clinical oncologist from Norway and I’m here at the EMUC and I’m happy to meet Simon Brewster from Oxford. We are going to discuss prostate cancer which was presented here at EMUC but also other findings from 2017 which we think are interesting. There was a poster award this morning for the Norwegian poster on non-metastatic prostate cancer, how they were managed, and I found it interesting. It was a huge number of patients reported, they were prospectively assessed by the Norwegian Cancer Registry and then they were looking at the outcomes. There were three different treatment groups: you could say that one had radiotherapy the other had radical prostatectomy and the other something like active monitoring.

SB: Yes, there were about 4,500 patients aged roughly between 60-75. 900 had radical prostatectomy, 1,300 had radiotherapy and about 1,200, the other 1,200, had no local treatment. Presumably they had various treatments but nothing like a radical treatment.

JO: That’s right. And the beauty of it is that it is not a selection at all, it’s from the whole population of Norway. What we can learn from this, it’s a question. Radical prostatectomy came best out but I talked to the first author and she said patients who had radiotherapy they had poor prognostic features.

SB: Sure, a non-randomised trial so you cannot draw conclusions. But it was interesting that prostate cancer related death occurred approximately six times as often in the not locally treated group compared to the local treatment groups where there was much less difference between the surgery and the radiotherapy groups.

JO: That’s true. And also they had used the new Gleason grading with the five different groups and they were able to show the impact of each Gleason group on survival, which I found was interesting.

SB: Yes, and also interesting the finding that patients with an ECOG performance status of 0 did much better in terms of prostate cancer death than all the other groups that had a worse performance status, ranging from 1 to 4, but still didn’t do well on either overall mortality or prostate cancer mortality. I don’t think I’ve ever seen anything like that published before. Then, of course, they found quite a lot of patients, 8.5% overall, dying of prostate cancer but three times that number, 25.5%, dying of other causes over that ten year period. So an awful lot of men dying of other causes, having either been treated or not treated for the prostate cancer.

JO: That’s true, it was higher figures than I would have expected when looking at the ProtecT data, for example. There was hardly anybody dying of prostate cancer.

SB: Yes, just 1% in each group, wasn’t it?

JO: Yes, and they exactly had the same survival. So that gives us a lesson about randomisation before you can compare groups but on the other hand this is population-based data, they’re very valuable but these findings you should discuss with your patients very carefully because otherwise everybody will jump onto the conclusion that radical prostatectomy is the solution. It is not, it is careful selection of patients, that is the job of a urologist, of course, so they were selecting the patients very carefully. That’s good, but for selecting patients for treatment we have to rely on randomised trials.

SB: Definitely.

JO: We don’t have enough of them comparing different treatment modalities, that’s really a problem.

SB: No, that’s true. There was an interesting further conclusion with these data, particularly about high risk disease. Because what they found was that the risk of prostate cancer death went from 1.7% for low risk disease, whatever way it was managed, up to 17% for high risk disease. And, astoundingly, overall mortality from any cause went from 14% with low risk disease to 38% with high risk disease. So having high risk disease gave these men, regardless of treatment, a higher chance of dying from their disease and a much higher chance of dying from another cause which I found very interesting.

JO: This is peculiar.

SB: Yes, it supports the idea that high risk disease in non-metastatic patients should be tackled aggressively, I think, with either surgery or radiotherapy.

JO: I agree. What is important for this data is that the Norwegian authorities do not advise for PSA screening. Probably there is a lot of PSA screening going on by general physicians and we don’t know the impact of that. I’m actually planning a study where we look into PSA which was taken by GPs and we might be able to collect as many as 2,000 PSA samples and these will be matched with data from the cancer registry. So hopefully at some EMUC I will be able to have data on this. But until then it’s important to remember we don’t know how these patients were diagnosed. Probably some of them due to elevated PSA, some might have been symptomatic. I don’t think they had that information.

SB: It didn’t say, actually. It didn’t say but we do know from the Swedish neighbours that screening does result in quite a high amount of over-diagnosis and over-treatment of insignificant disease. So there’s nowhere in the world that does population based screening at the moment.

JO: No, do you know the Stockholm 3 study? They used SNPs in addition to family history and PSA and they are able to detect cancers which are clinically significant in a more reliable way and do not have to biopsy these Gleason 6 where we don’t know what to do, which is really interesting. There is a study going on in an area in Norway around Stavanger where all patients going to the GP instead of having a simple PSA they will have a Stockholm 3 panel and then we will see what might come out of it in a population based manner. This could be really interesting.

SB: This Stockholm 3 was also presented as a poster which won a prize today but when asked by the panel how doctors can send their patients to get a Stockholm 3 test he was a bit evasive. He just said it was not really available to all comers, it’s a mixture of demographic details, various blood tests, a genomic test as well. It’s not straightforward and he didn’t say how much it cost. Talking of other potential diagnostic markers, we had big hopes for a marker called Engrailed-2 which was being publicised and there were a few papers came out back in 2012 from a UK group. It’s a urinary marker for a HOX gene transcription factor and supposed to really going to be helpful in finding out which patients with an elevated PSA had prostate cancer. But I saw a poster today from the Czech Republic where they’d used 90 patients with prostate cancer and 50 controls and they found that En-2, as it’s called, was slightly less useful than PSA itself in doing this. So this was an important negative finding because we haven’t heard very much about En-2 for a few years and clearly it is not living up to the hopes of initial studies.

JO: No, that is a theme which we are getting kind of used to in biomarkers. I was at a session for pathologists on Thursday which I found really interesting but the marker they considered most interesting for clinical use was AR-V7. I don’t know if you have been at the APCC meeting in St Gallen this year, there was a voting about the usefulness of AR-V7, this splice variant of the androgen receptor. When you have this splice variant enzalutamide or abiraterone are not supposed to work so it’s clinically meaningful but essentially nobody in the auditorium did use this test.

SB: Right, is it difficult to access?

JO: It is a bit difficult. We don’t have it in our clinic, at least in Norway. I’m not aware of anybody using this test in Norway. There was at this consensus conference in St Gallen where you have discussions about areas where you don’t have high level evidence but where you think this is important you should discuss the pros and cons and then probably reach a consensus. It was a really strong consensus that this is not a useful marker. But for the researchers, they felt, wow, this is the thing we have to do. I find these meetings where you have interaction between researchers and urologists, medical oncologists or clinical oncologists like me, really, really important because you get on a similar level at least once per year.

SB: That’s absolutely right, yes. Of course we urologists manage castrate resistant prostate cancer less and less because there are more and more drugs coming through that are potentially cytotoxic and really there has been an expansion, a massive expansion, of the medical oncology community and clinical oncology community to handle these agents. I was reading an interesting poster about this new class of drug called PARP inhibitors. About 25% of castrate resistant prostate cancer patients have a mutation in the homologous recombination DNA repair gene group which includes BRCA2 and BRCA1, the breast cancer genes. There has been a small study of a drug called olaparib which was published last year which apparently induces a response in about a third of patients.

JO: This was tremendous, a tremendous result.

SB: On the back of that a different company, I don’t know quite who it is but they’re setting up two big international studies called TRITON-1 and TRITON-2 where they are going to use a new PARP inhibitor called rucaparib in phase II and phase III randomisation studies for chemo naïve CRPC which sounds very interesting. It’s just recruiting at the moment in 25 centres around the world, so really exciting.

JO: That is really important because probably you will have really effective treatment for those who have these mutations at the cost of very little side effects.

SB: Cost of little side effects. Presumably they’ve all got to be tested for the gene mutations.

JO: Yes, absolutely.

SB: I don’t know, do you know how much that costs? Is that going to cost a lot of money to do?

JO: That will cost some money but for the studies it’s included, it’s reimbursed.

SB: Of course, yes.

JO: That is always a nice window to see how many patients are we dealing with really. Because often these patients are selected in very specialised cancer centres like the Royal Marsden where Johann de Bono is. I think it’s good to have it population-wide and see what we are getting. There might be differences between the populations as well.

SB: Indeed.

JO: Just let me ask you, because you said the castration resistant, you give the ADT treatment to prostate cancer patients, metastatic ones, then their oncologist takes over? That’s the way we have it in Norway.

SB: That’s exactly what, yes. We usually initiate the ADT and provide advice about exercise, diet, bone strengthening, this kind of thing, and then we refer the patients on via the multidisciplinary meeting to the medical and clinical oncologists for further care. Of course we do have to get involved if they obstruct their ureters or their urethras or have haematuria but other than that.

JO: It’s very similar to our practice. But let me ask you, orchiectomy, how often is that performed - instead of medical castration you have a surgical castration?

SB: Very rare nowadays actually. Before we had degarelix, and if you wanted rapid testosterone castration level, then orchiectomy was probably the best way to do it rather than giving an analogue. But now we have degarelix it works virtually as quickly as an orchiectomy and so patients will, of course, prefer that option.

JO: I have talked to most of my patients who have to rely on lifelong ADT treatment and I advise them to consider orchiectomy. Some have agreed to it and nobody has yet regretted the simplicity that you don’t have to think of these applications every three months or in degarelix every four weeks. I think for lifelong treatment it’s considerable and also it’s very cost effective, of course.

SB: That’s absolutely true, you will save your health service money, there’s no doubt about that. I think there have been a couple of studies where patients have reported preference in having injections rather than being castrated.

JO: I think that is the initial reaction of almost everybody but sometimes, yes, it’s worth to have a discussion about it.

SB: There was a study from Belgium – it’s becoming quite popular, certainly in trials, to do primary treatment for patients with oligometastatic disease, so either a radical prostatectomy in addition to androgen deprivation or radiotherapy in addition to androgen deprivation for men with less than three metastases. There was a small poster from a Belgian group who were recruiting to a trial reporting that local events occurred nine times as often in the patients who did not have a radical prostatectomy compared to those who did have. So most of these were urinary retentions, one or two ureteric obstructions, but they were arguing obviously in favour of the surgical arm of the trial, saying that even before the long-term outcomes were known.

JO: Which is really interesting and that makes perfect sense because we know from all the groin lines of treatment, of metastatic castration resistant prostate cancer, survival is prolonged massively and the risk of developing local problems if you have prostate cancer in place, it’s much more important nowadays than for five or even ten years ago. So it’s interesting and also the concept of radical radiation therapy to oligometastatic prostate cancer is really appealing but I would like to see the results of these studies and ideally it would be a comparison between no intervention, surgery and radiotherapy.

SB: Yes, ideally, but we’d also really want to see a distinct survival advantage in the group that underwent the radical treatment plus the hormone. If there wasn’t a distinct survival advantage the argument for doing the treatment and the cost of it and so on would be somewhat dampened down.

JO: I agree but it’s all about selection and you would select the young and healthy males for a prostatectomy and the obese, older, a bit frail man you would say, ‘OK, hormonal.’ Then you create a self-fulfilling prophecy. But I am curious about the STAMPEDE trial, I think there is an arm where there is prostate radiation, despite metastatic disease, and these are so many patients. I think the STAMPEDE forum is just great, I would like to participate from Norway. I’m really looking forward to these results, I must say, it’s such a great study. So thank you, Simon, it was a pleasure talking to you, discussing these findings.

SB: Likewise.

JO: And thank you to the organisers for having us here. Thank you.