ASCO 2015
Enzalutamide preferable to bicalutamide plus LHRH analogue in prostate cancer
Dr Simon Chowdhury - Guy's Hospital, London, UK
Prostate cancer is always a big deal and here at ASCO there have been some ground-breaking studies. What do you think has been the big thrill for you in developments in prostate cancer?
There has been one very major breakthrough at this conference and it’s a UK based study, the STAMPEDE study, which is looking at newly diagnosed disease which hasn’t been a focus of research. So it’s newly diagnosed high risk or metastatic disease. A very large study, several thousand patients, on-going study and that has shown a very significant benefit for docetaxel in addition to androgen deprivation therapy.
That sounds simple, the way you said it, but it was a multi-arm study, wasn’t it, and there’s a bit of complexity there. Could you walk us through that quickly?
Yes, a very complex study, so designed predominantly by Max Parmar and Matt Sydes at the Medical Research Council. A very innovative design, it was actually applauded for its innovation by the ASCO committee. It’s a multi-arm, multi-stage design, so you have a comparator of androgen deprivation therapy and then several other arms which once completed they can drop out and then new arms come in. But this was a reporting of two of the initial arms compared to androgen deprivation therapy alone.
Using docetaxel early has been controversial, hasn’t it?
It’s very controversial, yes absolutely. There has been one positive study, the CHAARTED study, presented last year at ASCO by Christopher Sweeney and the GETUG-16 study which was negative, the Paris study. So, in some ways, as Ian Tannock said, in this dispute it was 1:1 France versus America and this was extra time and the British making the decision. So good to get a definitive result from that and STAMPEDE is a very positive study for docetaxel.
Indeed, many people were waiting with baited breath for the results of STAMPEDE. What, in terms of the numbers, did they get?
They got a very significant overall survival benefit, so from 43 months in your androgen deprivation therapy alone arm, which is important because it shows that men with metastatic prostate cancer have this lethal illness, and an improvement from 43 to 65 months. So a real game changer and something that will change practice.
There are, however, other studies here and you had the privilege, or the initiative, to have one where you were testing two new agents head to head against each other. Tell me about that.
Yes, that was a smaller study than STAMPEDE but I think an important study, the TERRAIN study, a randomised phase II study of 375 patients. So bicalutamide, one of the older anti-androgens, versus enzalutamide, one of the newer anti-androgens and a very significant benefit for the enzalutamide arm which was expected but enzalutamide had only ever been compared versus placebo. So a higher bar than before.
There is, presumably, a case to be made out for doing more head to head comparisons with some of these new agents?
Yes, I think there is. Partly head to head comparisons, partly also looking at how you… We’ve now got a group of patients who are on enzalutamide and abiraterone and becoming resistant and it’s what’s driving resistance, how can we overcome resistance? Is that by substitution or addition? So lots of interesting things about tumour biology there as well.
It seems you can actually push the androgen deprivation further and further.
To a degree. A really good question. Basically hard AR blockade certainly improves outcomes for men and abiraterone and enzalutamide have shown that. The concern is are you going to drive new phenotypes of disease.
And, of course, what could be the side effects?
Side effects, profile wise, both drugs have very good side effect profiles. They’re well tolerated, we use them a lot in clinical practice. I think you have to be careful with androgen deprivation therapy alone because of some of the metabolic and potential cardiovascular side effects, but abiraterone and enzalutamide are safe. One of the worries is what happens next, and that’s not a criticism of the drugs, because they’ve really changed what we can do, but we’re now seeing perhaps… there was a nice study by Eric Small from the West Coast Dream Team, which is a collaborative group looking and analysing the tumour biology. They showed that hard AR blockade with enzalutamide and abiraterone, in some cases, they’re getting a different phenotype of disease.
So you get evolution of the disease because of the treatment you’re using?
Yes, I believe so. We don’t know that definitively, we have to say it’s small numbers. But it makes sense from natural selection that if you block the androgen receptor, which is the dominant biological pathway, very hard, if you then have a cell that escapes through a different mechanism there’s going to be a huge selection pressure to take that forward. I think that’s what we’re seeing in clinical practice and Eric Small did a really nice job of explaining some of the work that they’ve done, which is a really impressive bit of work.
Looking at how some of these developments are going to affect practice and potentially could affect practice now, what should the cancer doctor take home? Let’s look first of all at STAMPEDE and then at your study, TERRAIN, and then something about the biology. So STAMPEDE first.
STAMPEDE is very much the take home one, two and three message from this conference for prostate cancer doctors. It shows that docetaxel significantly improves outcomes for men with metastatic disease and I would say you would have to have a very good reason not to be treating your patients with that. So I think it will move docetaxel completely up front for all men with metastatic disease.
And if they have high risk localised disease.
High risk localised disease is more controversial because there wasn’t an overall survival benefit as yet. There was a significant improvement in progression free survival and Ian Tannock, in his discussion, recommended against it. I would probably say it’s a discussion that you should have, bearing in mind other competing risks but for someone who is fit, well, who has got very advanced localised disease, you have to be potentially discussing that. I don’t think it’s changing practice yet in high risk localised disease yet, though.
And with the super-androgen deprivation agents, what’s the advice there?
Those drugs are already well established and the data on enzalutamide supported the previous studies, particularly the PREVAIL study. But it showed that there’s a significant benefit over what we were doing with bicalutamide. So I would question the role of bicalutamide going forward.
Pension it off?
I think so. I have to say, if I was a man with metastatic prostate cancer, which is a lethal illness, I would want to know I was on the best treatment. If you’re on a treatment that’s known to be inferior then you’re waiting for that to fail. Although drug costs are significantly different between an old drug and a new drug, you’ve got to look at the other costs that are involved with it – monitoring, increased scans and also the psychological morbidity for patients. As a patient and as a doctor looking after patients you want to be able to reassure them, reassurance for both of you, so I think enzalutamide does that.
And as far as the evolution of disease because of the therapy you’re using, how should cancer doctors be viewing that?
Again, as we touched on earlier, it’s very much we’re just learning about this area. So I would say the cell type that Eric Small talked about where you have this very hard AR blockade with enzalutamide and abiraterone and I think he called it an indeterminate atypical carcinoma, so a completely new category. It’s a disease that doesn’t tend to secrete PSA so if you’ve got a patient who isn’t so well on these drugs you need to think, OK, has it changed its spots, has it changed its phenotype, is it now being driven by non-AR pathways and do we now need to look at other drugs to challenge that? We need to be taking biopsies from these men, we need to be taking blood samples, and really rigorously interrogating them to try and find new targets for treatment. Because patients, once they hit that stage, tend to do very badly, very aggressive disease.
