HP: Hello. We’re here for ecancer.tv in Copenhagen for the Prostate Cancer Debate. I have three esteemed expert colleagues with me this afternoon and, in fact, between us we form a very nice multidisciplinary team. We’ve had some excellent discussion in the Prostate Cancer Debate over the last few days, I would like to ask Luis first of all what’s your take home messages on the use of docetaxel chemotherapy for hormone sensitive disease?
LC: I think everybody agrees among the experts and we’re now talking about the experts across the urologists, oncologists, the clinical oncologists, even maybe the people who are involved in the basic science, that chemotherapy has a new role in prostate cancer. What we learned is that chemotherapy, if you start chemotherapy in M1 patients at the earliest stage where it still is hormone sensitive we can get much more advantage for the patient. It means something in the range between 10-15 months of increase in median overall survival. So I wouldn’t say it’s a new idea but it is the confirmation of old ideas that we had. We knew that cancer is a heterogeneous disease, we knew that we have to attack different populations, we didn’t know if chemotherapy combined with hormone therapy could work in these patients, now we know it does work. This is the main message. Of course these are the main results but then we have to apply that in the early clinical practice. So I think in this meeting we also debated a lot which are the characteristics of the patients that make us feel comfortable with this decision or whether some patients we still have to think about other options besides chemotherapy at the beginning, particularly low volume disease and so on. So I think this is clear for me and I think it was very well accepted among the audience.
HP: I think it has provided quite a big debate, hasn’t it, with the three main studies and the CHAARTED study distinguishing between high volume and low volume metastasis with high volume having a survival advantage; STAMPEDE recently showing a survival advantage of up to 22 months for people with M1 disease. Has that changed your practice, Peter?
PM: Definitely. We were already changing the practice when we have these new hormonal therapies and also the discussion on chemotherapy later on towards a more multidisciplinary area. But still in the beginning we treated these patients by urologists, now with the implication of the results there which were convincing enough to offer even earlier docetaxel, that is a big change in the practice of urologists in treating advanced prostate cancer.
HP: And has it changed your practice, Luis? Which group of patients would you treat?
LC: Yes, I can tell you one thing, when the CHAARTED trial was presented at ASCO the first thing that we did in our department is to call our colleagues from urology and say, ‘Let’s go and have a meeting together to discuss this.’ So the urologists asked us, ‘Do you want to now receive all these patients to chemotherapy and all that stuff?’ So it was an alive discussion. Then we had the opportunity of having a live Chris Sweeney at our division also to discuss his results and out came STAMPEDE so there’s no doubt that we start to do that and we do that for most of the patients. I can accept that some patients with low volume, and if you look for the NCCN guidelines it’s clear there that maybe patients with low volume it’s not straightforward you should offer to them chemotherapy up front. I can accept that for patients with low volume that you can predict they have a very high response to hormone therapy, sometimes we are not quoted options for chemotherapy. But patients with high volume we cannot miss the opportunity and definitely we should offer them to those patients the chemotherapy. So we changed our practice, definitely.
HP: I think the STAMPEDE study initially when it was designed had six arms and obviously docetaxel was one of the arms, zoledronic acid and celecoxib individually were other arms and didn’t show any advantages over ADT alone. But at GU ASCO this year, or just this month, the biggest surprise to me was that the STAMPEDE trial has shown that zoledronic acid and celecoxib together given for hormone sensitive disease has a survival advantage. Now, Romano, could I ask why should that be?
RD: Well the choice of celecoxib and zoledronic acid was, I should say, laboratory driven because we know that COX-2 inhibitors like celecoxib are able to inhibit several cellular processes like angiogenesis, like proliferation. This happens through the inhibition of prostaglandin synthesis and other mediators of cellular proliferation. So their evidence is mainly coming from the laboratory on the inhibitory effect of celecoxib on cell proliferation and also COX-2 inhibitors have been used for the chemoprevention trials in colorectal cancer. So there is quite strong evidence of the role of the COX-2 inhibitors not only in the inflammation processes but also on some proliferation effects. So combining the celecoxib with the zoledronic acid which is known also for the inhibitory effect on bone resorption but not only because zoledronic acid is able to inhibit the which is a typical post-translational modification of proteins and through this effect it is able to inhibit the and the biological activation of many oncogenes of the RAS family. So combining together these two drugs we can obtain inhibitory proliferation of cancer cells. So I’m not surprised by this evidence, it comes from the clinic and it comes from the laboratory also.
HP: Thank you, thank you for that explanation, that’s brilliant. Luis, what do you think about the side effects?
LC: I knew about this lab work because we were interested a few years ago to test the effect of COX inhibitors in bone metastases. You have to think about most of these patients have bone metastases and there is also some evidence that COX inhibitors can help to inhibit bone resorption levels and so on. The question is on the practicality, are we going to use zoledronic acid in patients when in the STAMPEDE trial zoledronic acid did not add survival or even decrease SREs evidence in hormone sensitive. Of course there is a role for them in castrate resistant but not in hormone sensitive. So are we going to prescribe zoledronic acid plus celecoxib thinking that this will solve the problem of the advantage of survival in these patients? I think we still are not confident and we need to be more convinced maybe, I don’t know if other trials will bring this information or not or more data from the lab to tell us why this worked so well in STAMPEDE.
HP: Peter, will it change your practice or would you have concerns about toxicity that were voiced at GU ASCO?
PM: No, not too much. I think the design of the STAMPEDE study is such that you have combinations and one combination we don’t have to forget is hormonal therapy. So the effect apparently of hormonal therapy in combinations with these agents or with chemotherapy, there is a kind of synergistic effect apart from the selection of cells that have hormone responsiveness and the unresponsive cells de novo. I think this synergistic effect also with the opportunity within STAMPEDE to combine it, for instance, with radiotherapy, you see that there is something ongoing and hormonal therapy, standard hormonal therapy, is still a big option there. So the combination of treatment to offer, apart from the toxicity, will be shown there and in STAMPEDE also.
LC: If you allow me, I think we have also to think about there are some cardiac events with the COX inhibitors that we know. We know that cardiac problems and there due to the cardiac problems is one of the competing factors for death in these patients, even with advanced stage. So I think we have to be careful not to just adopt this fantasy of putting all patients on celecoxib and because we don’t know yet what is going to happen really for the safety on the cardiovascular side and if you can do that long term for those patients. I think so, that’s my opinion.
HP: Thank you. I mean, it certainly provoked a lot of discussion at the meeting and indeed here between the four of us. I’m sure this is going to continue to be discussed and there’s obviously further factors that we will need to consider. But moving on a little bit, there has been discussion today about M0 disease. Peter, do you think M0 disease exists?
PM: So M0 is apparently radiographic evaluation standard with bone scan and CT scan and it’s clear and it’s the conclusion that it is sub-optimal, definitely sub-optimal. So with the new PET scanning or MRI there’s a better imaging. Then we become aware of the fact that although these patients were on traditional CT scan and bone scan negative about 30-40% of these patients have these minimal metastases when you detect them on the other measures like the new PSMA scanning, for instance. So it’s more that M0 should be considered as minimal metastatic advanced prostate cancer than it is really the M0. The trials there are ongoing and I think finally we will consider them as an earlier phase of the treatment of castration resistant prostate cancer and not mentioning the M0 indication. So that will be a change here but definitely these trials should be done to see if that minimal metastatic patient population of castration resistant prostate cancer it has an effect. I’m confident that it will show an effect.
HP: Because they become low, low volume, don’t they, really, as to the low volume.
PM: With the technology.
HP: We’ve also heard, Luis, that the FDA is accepting metastasis free survival in this group of patients. Do you think that’s a valid endpoint for some of these studies?
LC: I think so. I mean, we are clinicians we have to tell the hospital administrations and the regulatory issues and so on. But if I was a patient and someone asked me, ‘Do you think that the time until metastasis appears to you is important?’ I know I would say definitely yes. Because if you live with the knowledge that you have a metastatic disease it’s totally different to your life, I think so, it changed a lot. So even from, let’s go and say, a quality of life respect it is so important. So I think we should accept that, that this will be an important endpoint in the future. If that will be translated on survival or not, I don’t know yet, but I think it will be an important point. Everything that we can do in our hands as clinicians to participate in clinical trials that can provide prolongation of time without metastases, I think will be important, definitely.
HP: Thank you. So I think we await the results of those studies with huge interest and they could make quite significant differences to the way that we’re managing men with prostate cancer at the moment. One of the other areas of great interest has been biomarkers and the term a liquid biopsy. Now, Romano, could you explain that to us a little bit more? There was a study presented by Howard Scher at GU ASCO again; would you be able to enlighten us a little about that?
RD: Sure. We can call them, those approaches, instead of liquid biopsy we can also say just blood-based biomarkers.
HP: Liquid biopsy sounds so nice, though, doesn’t it?
RD: It’s nice anyway, of course. There is a strong interest on the application of less invasive diagnostic procedures. Those are important not only to make a diagnosis but also, even more important, to monitor the progression of the disease. We use this approach, for instance, in non-small cell lung cancer; it is quite established because there are secondary mutations in the target that are associated with drug resistance. So it’s very important to monitor the occurrence of these mutations in the blood and the liquid biopsy approach because we can change treatment because we have more specific drugs for mutated targets so this makes all the whole approach more rational. We can probably do the same in prostate cancer because we have strong evidence that there is a family of splice variants of the androgen receptor, the most popular is ARV-7 but this is not the only one. Because ARV-7 is probably 50% of all splice variants, the other variants are also associated with resistance to hormonal treatment. For this reason we should be able to monitor all the variants before saying this patient is resistant due to this reason, this specific reason. The laboratory approach is feasible, we are trying to make the laboratory approach to the screening of this variant more reliable in terms of technical platforms and also less expensive because, of course, there is the cost that should be considered. The splice variants are not the only reason for resistance, there are additional reasons for resistance also, the androgen receptor can change due to mutations of the receptor itself, not just for a splice variant but for mutation, polymorphisms, in the gene sequence that can change the structure, the organisation of the target itself. So if we put together this knowledge we should be able in the next years to have reliable tests to screen for the occurrence of the secondary mutations associated with resistance. The second problem will be the standardisation of the clinical condition because we know that the volume of the disease, the kind of treatment the patient receives, can affect the amount of the mutated alleles in the blood. So there is not only a technical problem but there is also a clinical problem of when and which condition to apply this kind of approach which is very promising again, it should be explored in the next years.
HP: Thank you. Sadly I think we’re going to have to end here as we’re out of time but I’d like to say an enormous thank you to my colleagues for a very interesting discussion that I’m sure will continue when the cameras stop rolling. Hopefully this has provoked some questions to all of our audience who I would also like to thank immensely for joining us this afternoon. Thank you so much.