ASCO 2016

ASCO 2016: Advances in Prostate Cancer

Prof Karim Fizazi – Cancer Medicine at the Institut Gustave Roussy, Villejuif, France
Prof Maria De Santis – Warwick Medical School Cancer Research, University of Warwick, UK
Prof Bertrand Tombal – Saint-Luc Hospital, Brussels, Belgium
Dr Mark Beresford – Royal United Hospitals Bath, Bath, UK

KF: Welcome everybody to this ecancer event. I’m Karim Fizazi, medical oncologist in Gustave Roussy, Villejuif, France and I’m here in Chicago during the ASCO meeting. This is the second day of ASCO, second big day of ASCO, so we’ve learnt already some news about prostate cancer. We will have a session today with my three colleagues: we have Dr Maria De Santis, Dr Mark Beresford, both from the UK, and Professor Bertrand Tombal from Brussels, Belgium. So I will start first with you Mark. We actually hear some good news in the last two years about the use of chemotherapy in this disease but this ASCO meeting so far has been more oriented towards biomarker analysis and how best to use the various compounds that we have. One striking thing that we’ve learned in the last two years or so is about the V7 variant of the androgen receptor and Emmanuel Antonarakis, who is really the guy who made the demonstration, updated his surveys. Can you describe what he reported?

MB: Yes, of course. I think you’re right, at the moment we have these options for treatment – we have chemotherapy, we have abiraterone, enzalutamide – and for the clinician the difficulty is knowing how best to sequence those, which patients to treat with which agent. We don’t really have any good guide at the moment. So it’s really interesting to see some studies presented that perhaps might help us choose our treatments more appropriately for patients. One of the problems in prostate cancer has been that we often don’t have good biopsy tissue of the metastatic setting, partly because many of the patients just have bone only metastases so they’re difficult to biopsy and often the primary tumour from biopsies or prostatectomy specimens may be from many, many years ago so it’s difficult to know how relevant that is to the current situation. So there’s lots of interest in so-called liquid biopsies and these might be circulating tumour cells or cell free DNA. The presentation that you referred to, he’s looking at circulating tumour cells and seeing whether this might predict for response to abiraterone or enzalutamide. So the AR-V7 variant is a variant of the androgen receptor which doesn’t have an androgen binding domain so the implication is that the receptor works independently of androgens so drugs like abiraterone and enzalutamide that work for that pathway may not be so effective. This study was a couple of hundred patients treated with abiraterone or enzalutamide and they were looked at for circulating tumour cells. It turns out that if there’s no circulating tumour cells present those patients do better with the drugs, if there are circulating tumour cells present they do less well and particularly badly if they are circulating tumour cells with the AR-V7 variant and that predicts for a very poor response to the treatment and really primary resistance to abiraterone. So for the first time now we maybe have a biomarker that we could do relatively easily in the clinic, not too invasive for patients because it’s just a blood test, that might then help us know whether we should be treating those patients with abiraterone or whether we should go straight to chemotherapy because it’s unlikely that the androgen drugs would work.

KF: Right, very nice data and it seems that we’re really entering an eve or an era of precision medicine for prostate cancer. Far after other cancers but finally we’re there with V7 variants for the DNA repair story. So that’s really beautiful. Bertrand, staying with predicting for efficacy of next generation androgen axis targeting drugs, abiraterone is a drug that was discovered a long, long time ago but obviously we are learning some new things about this compound. It seems that the metabolites are also important to consider, can you elaborate on that?

BT: Yes, so as you know it’s now one of the standards of care and unfortunately many people will progress after a certain time. So there is active work trying to prolong that period and here we show very interesting work on the activity on the different metabolites. One very nice observation is that abiraterone and D4A are metabolites by an enzyme we urologists know very well which is 5α-reductase, the enzyme that converts testosterone into dihydrotestosterone. What is very interesting is that the 5α reduced metabolite of abiraterone is no longer an agonist but may actually work as an agonist, so actually doing the opposite. Then comes that idea that if it is 5α reduced it opens the possibility of actually lowering down that 5α reduction process by using very common 5α-reductase inhibitors and in that paper they used dutasteride. Indeed they showed that they can block that transformation. So I would say that the beauty of that abstract is the simplicity of the observation, really showing that we finally know very little about the drug and about its metabolism, the way it is handled by the cell. So there is not yet clinical data with that although the triple combination, 5α dutasteride, abiraterone and ADT, was used in pre-prostatectomy models. I think that it opens a very nice perspective for the clinician because the combination will certainly add much toxicity to the drug.

KF: So it’s very fascinating because we’ve been using abiraterone in combination with prednisone then dexamethasone appeared to be interesting, perhaps to combine with abiraterone, perhaps finally dutasteride will be also combined with abiraterone. Coming to you, Maria, there’s also this very elegant paper that was reported some years ago indicating that the AR axis and the PI3 kinase/AKT axis are parallel and talking one to the other one. So based on this preclinical data a trial was conducted combining an AKT inhibitor together with abiraterone. It’s a randomised trial, can you elaborate on the data?

MDS: Yes, I think this is a very interesting and, as you said, very elegant trial. For prostate cancer it’s quite new to combine targeted therapy with androgen receptor targeted therapy. So, as you said, we know that the PI3K/AKT pathway is activated and becomes hypersensitive in metastatic castration resistant prostate cancer and it’s also activated with AR inhibition. So the idea is to combine an AKT inhibitor with an AR inhibitor and in this case it was abiraterone combined with ipatasertib. It was a randomised controlled trial, one by one by one, a three arm trial, testing out two different doses of the AKT inhibitor together with abiraterone. The preliminary data, interestingly, show that the radiographic progression free survival actually was better with combining abiraterone with the higher dose of the AKT inhibitor. So the first sign that this model might work and might work better than what we do in daily clinical practice.

KF: Right, and I think we should learn perhaps even more in the future and some data will be reported at ESMO regarding whether the drug works the same depending on the gene signature of the AKT axis being at work. So we should follow this data very closely. Mark, we’re now using very often all these compounds sequentially – abiraterone, enzalutamide, docetaxel, cabazitaxel, radium etc. I saw this abstract from the Spanish group, the SOGUG, about docetaxel safety depending on whether the patient had received or not previous abiraterone. Can you tell more about it?
MB: That’s right, yes. So this is part of a randomised phase II trial that was really just reporting the toxicity data not the efficacy but it was looking at patients who progressed on abiraterone and then were moved on to chemotherapy. Some of the patients were randomised to continue with their abiraterone alongside the docetaxel and other patients just had docetaxel alone, which would be our standard treatment. So this first analysis really was just to look at the tolerability of that and, somewhat surprisingly, those patients who had continued with abiraterone had more in the way of side effects and particularly pronounced was the neutropenia. So the neutropenia rate for the chemotherapy alone was around 30% and it was doubled to over 60% with the continued abiraterone; the febrile neutropenia rates similarly were doubled from about 11% to 22%. So an odd observation in that the abiraterone itself doesn’t seem to cause neutropenia but when combined with chemotherapy it seems to potentiate the effects of the chemotherapy. So there is a bit of a concern if we start to combine these treatments that we might see more toxicities coming through.

KF: That’s very thought-provoking because the phase I trial was done with abiraterone and docetaxel and didn’t really report any increased toxicity for either of these drugs. It may have some important consequences for trials we’re currently conducting where abiraterone and docetaxel are being combined up front for metastatic disease. So we should look at this data very closely as well. Bertrand, staying with the issues regarding toxicities, generally speaking and more specifically for these drugs, abiraterone and enzalutamide don’t really do the same, not the same target, not exactly the same toxicity, what about cognitive impairment with these two drugs.

BT: First of all these drugs were, as you know, validated on a very standard approach, FDA, that use NCIC toxicity which is basically patient reported toxicity. There are many toxicities which are not well captured by this clinical trial. Just to take the example of androgen deprivation therapy, it is until maybe five years that we have recognised that it causes a cardiovascular side effect and also that it has a profound impact on cognitive function, depression even leading to suicide in some people. So it makes sense to believe that if you make deeper blockage of the AR axis, whatever the mechanism is, you may actually increase the side effects and depression and cognitive changes are two of these. On top of that, as you know, enzalutamide has a GABA-A activity, it crosses the blood barrier, and some say it may, although we don’t have rigid data, explain some of the excess of fatigue. So that study conducted by the Canadian group of Vancouver was extremely interesting because they assessed with specific tools cognitive function and depression and they tried to see what were the changes over time. The first, quite reassuring, observation is that there are changes but not major so we don’t see dramatic changes that would lead to what the specialists in the field would recognise as clinical implications. So the first observation – there are changes but mild changes. Then, once again, we find that difference that many clinicians would report, once again without having head to head comparison, that this seems to have a little bit more patients with more cognitive impairment, more depression, when they receive enza. When you speak to people we know about that, we know it’s minor, we know there is a difference but once again the working hypothesis is that AR is extremely ubiquitous and that these molecules have multiple effects will translate in these patients. I don’t think it’s a problem right now, my concern is that if we move into the M0 setting, if we move into the adjuvant setting where we’re going to treat these patients for two, three or four years, then we might see clinical consequences. So that paper is very good and basically what it is is really a plea for the company and the groups who investigate to think about moving away from traditional tools to assess toxicity and take into account assessing this toxicity as well.

KF: Absolutely. Maria, I guess one of the major achievements that we’ve made in the last 2-3 years for advanced prostate cancer was really the demonstration of the overall survival impact of docetaxel when used up front, together with castration for metastatic disease. I guess most of us are now using this as a routine treatment for many patients and the question is what should we do when these patients progress with CRPC. Until this ASCO 2016 we had really no data out to help us. We’ve just reported the data, retrospective data, from the GETUG-15 French trial, can you tell us what you think about this data?

MDS: Sure. The docetaxel use in the hormone naïve setting has become standard of care. This is very true and we are happy with this new treatment paradigm. However, there is considerable uncertainty about the follow-up treatment, as you said. Follow-up treatment for patients progressing and becoming castration resistant after early use of docetaxel in the hormone naïve setting are docetaxel again but also abiraterone and enzalutamide and other treatments like radium-223. But this is a new patient group and we do not have experience with those patients, we don’t know how good the other treatments are in this setting and how to proceed. So what we saw now with new data of GETUG-15 is that docetaxel used as a re-challenge when patients are castration resistant seems to be less active than other treatments and less active than we would expect from the data we have from the TAX-327 study, for example. So PSA responses are much less than we would expect. However, the abiraterone enzalutamide, for example, seem to be as active as we would expect. So these are the first hints that it is safe and abiraterone and enzalutamide are effective to use in that setting. Maybe we would not use docetaxel at this point but to use second line chemotherapy, for example.

KF: Right. Again, many, many insightful data were reported at this ASCO 2016. We are really making progress year after year and biomarkers are coming and they should help us. We have many, many drugs that we should learn more and more to know how to best combine them or not. So that’s really a good time to do GU medical oncology, I guess. With that I would like to thank you and I would like to thank ecancer. This was again ASCO 2016 here in Chicago in June 2016. Thank you very much.