Dr Neal Shore - Carolina Urologic Research Center, Myrtle Beach, South Carolina, USA
Prof Nicholas James - Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
NS: Hello everyone, it’s a pleasure to speak with you today from ASCO in Chicago 2017. My name is Neal Shore, I’m the Medical Director of Carolina Urologic Research Center in South Carolina here in the United States. It’s a great pleasure for me to speak with my colleague and good friend Nick James who is the Professor of Medical Oncology at University of Birmingham in the UK. Nick has been really one of the all-time champions in prostate cancer research, has just been a paragon of excellence in research and clinical excellence for not only clinicians in urology, medical oncology, radiation oncology but, quite frankly, in training programmes around the world and so much so based upon the data that you just keep churning out thanks to the brilliance of the STAMPEDE collaborators. So here at ASCO today we talked about your presentation on the STAMPEDE arm for combining abiraterone acetate and prednisone. Maybe you want to just recap the essential key findings? We’ve talked about this and there is archived information on ecancer.org. But after you do that I’d love for you to talk about the implications of the findings and how it’s going to relate to future STAMPEDE trial arms.
NJ: Firstly thank you for the introduction. The data we presented was for men starting long-term hormone therapy for the first time. This is, if you like, the core entry to the STAMPEDE trial. We’ve had what you might call the Frank Sinatra approach to trial inclusion which is people do it their way, they decide that if this person is going to get long-term hormone therapy they can go in the trial. We have, of course, formalised that into T stage blah but that’s fundamentally what we’re looking at. The hypothesis we’re testing is that if something works later it will work better earlier and in this case it’s abiraterone that we’re testing. We’ve previously reported results on docetaxel, zoledronic acid and celecoxib. What we saw was that shifting abiraterone into the newly diagnosed setting starting long-term hormone therapy has what I can only describe as spectacular impact on outcomes.
When we set the trial up we were targeting a 25% survival improvement, which we thought was reasonable and would certainly have been worth having. But what we saw was a nearly 40% improvement and because there was the LATITUDE trial presented at the same time at the same meeting showing an almost identical result we can be very sure this is not a fluke. The trials were both consistent in terms of their effect on overall survival, failure free survival, skeletal related events and so on, so big improvements in all of these things.
What surprised us was the magnitude of the change. The hazard ratio for failure free survival in STAMPEDE was 0.3, so a 70% improvement and that was consistent between the M0, 50% of the patient population, and the M1s. In fact, in the M0s the hazard ratio for failure was 0.2, so an 80% reduction in failure at three years which is just huge. It meant that, for example, for patients having ADT plus radiotherapy in the M0 population 25% of them had relapsed at three years, under 5% had relapsed and these are patients with things like enlarged pelvic lymph nodes, high PSA, high Gleason. So that’s all very interesting and, of course, the metastatic results pretty much exactly mirror what Karim presented in LATITUDE.
So we think this should be practice changing and we think it should change practice for M0 as well as M1. Obviously it does raise all sorts of issues about funding and access and so on but we think a change of that magnitude… if you relapse you’re going to die of prostate cancer, if you haven’t relapsed you may well not die of prostate cancer.
NS: That’s a fantastic summary of a lot of data. It’s clearly going to be practice changing, the results are exceptionally profound. The tolerability and safety there were no new signals, in fact it was remarkably well tolerated for a very long period of time taking prednisolone 5mg daily in addition to having the T levels lowered so significantly. I’m sure you’ll have so much more data to go through later on, trial which you’ve accomplished always have so many more interesting things later on – quality of life, health economic outcome reported data, you and I have talked about that. Many have asked how do we balance some of these different therapies and their implications but you had mentioned to me earlier how the reduction in skeletal related events was so profound and that’s a big economic generator when you can drop that. So maybe that balances off some of the cost as well.
NJ: Absolutely. We’ve just done the health economic analysis for the docetaxel data we presented here two years ago and the striking thing about that was that we worked with NICE, which is the UK body that looks at these things, and they got moderately excited about the survival benefit but it was, ‘So we have to pay for something extra to make people live a bit longer with advanced cancer,’ and this is a recurring theme and it’s a problem. The thing they got really excited about with the docetaxel data was the 40% SRE reduction because they were saying, ‘This is money we never have to spend. This isn’t extra money, this is money saved.’ It turned out that that wiped out almost all the costs of giving docetaxel; we’ve just done the analysis, we haven’t published it yet. So we’re seeing a bigger effect on skeletal related effects with abiraterone so although the drug is more expensive the savings look like they might be bigger. The health economics is going to be more challenging I’m sure, it’s a more expensive agent than docetaxel and you’ve got more clinic visits and so on but the benefits are very large. So I think it will turn out to be cost effective.
NS: I think you’re spot on. These are really important ways that we, as cancer researchers, are understanding what our health policy people want to see. To your point, if you can cut down on orthopaedic surgical interventions, cord compression, the need for more palliative radiation for pain, visits to the emergency department, hospitalisation, these are massive cost reductions to any healthcare system.
But let’s move on now, Nick. Again, I can’t compliment you enough, what you’re doing in the collaboration which is STAMPEDE and all the folks within the UK and in Switzerland who have given the world this incredible amount of data to help change practice. So now with the learnings of this most recent arm, how is that going to inform you and your committee that is overseeing future trials?
NJ: What we did with docetaxel two years ago was that we amended the protocol to permit up front docetaxel as part of the backbone of care that we were then adding to. Then we just stratified the randomisation so that we have equal numbers of docetaxel patients across whatever arms are recruiting. So we will do exactly the same with abiraterone, we will amend the protocol to permit up front use of abiraterone or docetaxel, not both and stratify the randomisation. So in the immediate future we don’t envisage much switching from docetaxel to abiraterone because of the reimbursement and the licence. With docetaxel that took about six months to get it into the NHS England commissioning guidance. So we expect, given the magnitude of effect, that we may well be able to nail this down in about six months. So from that point onwards what I suspect we’ll see is largely a switch towards abiraterone over docetaxel if people have the choice. It is possible, because docetaxel is cheaper, that we will be pushed down the route of carrying on using docetaxel because probably the survival benefit is of a similar order of magnitude. But whatever happens the trial design incorporates this in the stratified randomisation.
So that’s in principle how we’ll deal with it and it’s worked very well with docetaxel. It’s also worked very well with radiotherapy because for node positive patients some patients do, and sometimes they don’t, get radical radiotherapy to their pelvic nodes. Again we stratify by it and we’ll be presenting more data on the interaction between radiotherapy, abiraterone and docetaxel at future meetings.
In terms of future and current arms, we have two more sets of results due to come out. We have already recruited out over 2,000 men to a randomisation for metastatic disease to radical radiotherapy to the prostate. A lot of those patients were getting docetaxel as well so that will be very interesting. We hope that that will be mature next year. The year after we’ve also recruited out a further 2,000 men to a randomisation to abiraterone plus enzalutamide together, a combination therapy, and again we have some docetaxel use in that arm as well. We anticipate that we should have mature results for survival results in two years’ time for that.
We’ve just added to the trial the diabetes drug metformin for the non-diabetic patients going in. This is potentially very interesting. We have two sets of things we’re interested in with that. Because there’s a lot of epidemiological data suggesting metformin gives diabetics a better outcome than other anti-diabetic therapies we thought it was worth testing in a non-diabetic population. The second thing we tested is that hormone therapy has all sorts of adverse effects on bone, diabetes risk, fat accumulation and so on. We hypothesised that metformin may actually ameliorate some of the toxicity of ADT. So even if we don’t affect survival we think we might actually affect things like weight gain which is a big problem for a lot of men on ADT. So we will see.
Then we’ve got two further interesting methodological things lining up as well. In the UK there has been a second trial recruiting in the same population as STAMPEDE looking at oestrogen patches as an alternative way of ADT. The hypothesis being that a lot of the toxicity of ADT is actually oestrogen deprivation. So that trial has been recruiting well and it has met a lot of its endpoints so far. We want to expand it to a phase III trial but it suffers by competing with STAMPEDE so it’s taking a long time to recruit. So we’re going to add an oestrogen patch arm to STAMPEDE knowing that we will never power the analysis within STAMPEDE but the intention is that we will be able to do a pooled meta-analysis with the PATCH trial oestrogen patch patients and the STAMPEDE oestrogen patch patients. The result of that is that instead of PATCH reporting in 2023 it will report in 2021, so it will bring forward the reporting time at virtually no cost because the trial already had ethics approval, it’s all running and so on. So that seemed to be a win all round.
So that’s, if you like, a statistical development but it sets a model for how you could do international collaborations in the future. Instead of setting up a trial in multiple countries you set up multiple trials in multiple countries and pool the data. You avoid a whole load of cross-border regulatory issues by doing that.
The second thing we’re about to add is a PARP inhibitor. There’s obviously a lot of data emerging around DNA repair deficits predisposing to a good response to PARP inhibition. We’ve pulled out a proportion of our blocks and the core abnormalities, the BRCA ones, are present in about 5%, maybe slightly fewer patients. There’s then a hinterland of BRCA-like related things that also appear to give you sufficient sensitivity to PARP inhibitors that we maybe can bump the eligible proportion up somewhere between 15-20%, it depends where we want to draw the boundary. So we’re just setting up the infrastructure to do up front sequencing of newly diagnosed patients with metastatic disease, this is tumour sequencing, and we’ll randomise eligible patients between standard of care, whatever that happens to be, docetaxel, abiraterone, ADT, and the same care plus the PARP inhibitor. So we hope to go live with the randomisation to that in the autumn, we’re just battling our way through some of the logistic issues around how we get the sequencing done in a timely fashion.
NS: That’s fantastic. The metformin trial which potentially would improve quality of life parameters, the transdermal oestrogen which, because it’s transdermal and not given in the previous historic oral form, potentially cuts down on VTE, thromboembolism, cardiovascular toxicity.
NJ: Yes, it does.
NS: And again improves quality of life, I think that’s fantastic. Then, of course, the PARPs as you’re alluding to, an explosion of different PARP trials out there. I can’t think of a better organisation of collaborators to get this done in a timely way for the benefit of patient care. I love your idea and your notion about international cooperative groups; we need to do so much more of that. We talk about siloing governments, universities, communities, specialties but countries and trialists we can do better. No-one better than you to lead that charge, no pressure though.
NJ: Thank you very much.
NS: That’s great. Any other thoughts regarding your experience here at ASCO this year?
NJ: There’s a couple of other things that we’re doing within STAMPEDE which are obviously emerging themes more generally. So circulating tumour DNA is obviously a very hot topic, not just in prostate but everywhere. We have a circulating tumour DNA collection going on within the abiraterone enzalutamide and parallel control patients so we’re taking sequential samples. One of the things we’re going to be looking at is if, for example, can we see AR mutation transcripts rising as abiraterone enzalutamide resistance kicks in and how do changes in that correlate with response? Gerhardt Attard is leading both the abi-enza arm and that sub-study. We have a second linked translational programme which we’ve called STRATOSPHERE and we’ve just got a large sum of funding from Prostate Cancer UK so we’re going to start pulling out on a large scale, we’ve just pulled out 500 blocks, we’ve got potentially 9,000 we can get our hands on, with a view to doing DNA, RNA and protein analysis on the blocks. So we’ve got a very exciting resource to deal with.
NS: That’s outstanding and Gerhardt is just exceptional in his ability to sort through all this. He’s done incredible contributions. Thank you so much and thanks for everything you’ve done. I look forward to seeing you at future meeting
