Treatment strategies and options in castration-resistant and advanced prostate cancer
Prof Peter Mulders – Mount Vernon Cancer Centre, London, UK
Prof Luis Costa – Hospital de Santa Maria, Lisbon, Portugal
Prof Antonio Alcaraz – Medical Advantage Barcelona, Barcelona, Spain
Prof Anwar Padhani – Institute of Cancer Research London, UK
PM: Welcome to ecancer.tv. We are here in Lisbon in 2015 at the Prostate Debate meeting. We have several experts here and we would like to address some of the points discussed in this meeting. First, my question is actually on the imaging possibility and imaging in prostate cancer has two key issues. One is the diagnosis of M and M0 disease in castration resistant prostate cancer but we also had many questions from the audience on how to follow up these patients radiographically. What is the update on that?
AP: Traditionally we’ve done bone scans for this. The question that always comes up is how confident can we be that what is oligometastatic disease is not polymetastatic disease and what is M0. Now we know, and several meta-analyses actually show this, that bone scans are really not fit for purpose in 2015 and if it’s a critical decision point, and it is in many instances, then we should be using more sophisticated techniques or more sensitive techniques. In 2015 that’s probably a PET scan, something like fluorocholine, or something that could be more affordable, something like a whole body MRI scan. In my institution we would use whole body MRI first; if that’s negative, say we’re looking for M disease, then we might then go to choline as a second scan. So that’s how we would look at it?
PM: So how is the follow-up of these patients? Because traditionally, and even in the latest trials, the follow-up is with bone scan and CT scans.
AP: Yes.
PM: So how is the follow-up of these patients anticipated in 2015?
AP: That is also changing in our institutions, in fact, in the last three or four years it has completely changed. Traditionally, as you say, it was CT scans and bone scans and now we follow with MRI scans on a regular basis. This we do on a routine basis. This is to see in non-metastatic disease if we are looking for metastases, for example patients coming up to salvage therapy, perhaps, for biochemical recurrence in a non-metastatic CRPC setting then we will follow with regular whole body MRI scans. And if the patients have M disease and we’re following chemotherapy or abiraterone or radium we will often use whole body MRI scans to follow when they are responding and when they are relapsing.
PM: With the availability of these techniques also in my centre this is really a conversion that we made. What happens in Barcelona or in Lisbon on this aspect? Are you also changing that or do you still use bone scan and CT scan, because in the trials you have to?
AA: I think you point to the real problem. We still maintain bone scan and CT scan and the main reason, probably, is that the approval of the different drugs are based on clinical trials using bone scan and CT scan. So we adopt this classical way to follow our patients and we do, mainly depending on PSA doubling time, we pace the whole. We scan our patients every three months, every six months depending on PSA doubling time. But I’m fully aware that the future will not be bone scan and CT scan and probably I think whole body MRI could be even more practical. In our institution it will be totally impossible nowadays because of the availability of MRI but we plan in the near future, yes, to be adopting some of this.
PM: But in most of the centres still in Europe it’s still the case I think.
AA: Exactly.
PM: But just to go to the next question, Antonio. We’ve seen these trials in metastatic castration resistant prostate cancer, now we have run the trials in M0 castration resistant prostate cancer where diagnosis is important. But now also we have data that chemotherapy, even in the hormone sensitive, is important and has an effect. So chemotherapy is moving to the hormone sensitive but also these novel therapies are moving to an earlier phase in the latest trials initiated in hormone sensitive. How will that impact in the near future and how long will it take that it has its place now?
AA: That trial started showing us that we are in a very unstable landscape that is really changing year by year but definitely it will change our practice. You have already mentioned… let me start with hormone sensitive disease. We thought that taxanes were only for castration resistant and now we know that this is active, these are active drugs, on hormone sensitive. Now the point is selection of patients. I think that the three clinical trials, GETUG, CHAARTED and STAMPEDE give us enough evidence that hormone sensitive disease is sensitive to chemo but I would say that not for every single patient. Nowadays I will adhere to the idea of a high poor prognosis or high burden of disease.
PM: What’s the percentage of those patients do you think?
AA: Well I have good data because in Spain we have data on that and there are 5% metastatic disease at diagnosis; of those around 50-60% will be high burden. I mean that for the full diagnosis patient with prostate cancer, this is around 3% of the total, that in my opinion should go for hormone treatment plus docetaxel, that is the number at this point and I think they deserve that treatment. You have also mentioned M0 patients and just before entering on M0, maybe for next year, ’16 or probably ’17, we will have very similar on STAMPEDE, there is one more branch similar to the one comparing ABP to docetaxel plus ABP and this is using abiraterone or abiraterone in combination with enzalutamide. That will give more information about how to treat this.
PM: How many patients are already in that? It has now accrued a lot of patients, I think more than a thousand patients already.
AA: That’s it, it’s a very important branch of the study with more than a thousand patients and is supposed to be for next year, in one year from now we should have the data and that will give even more information for those patients. Now, going to M0, we have three clinical trials, two of them I would say very important, using enzalutamide or using ARN-509 in which this antagonist of the androgen receptor and we will see. I am quite sure that we will get an improved delay on progression.
PM: So when is that expected?
AA: Based on the phase II clinical trial we should expect that delay around one year on the development of metastasis. I have no clear idea whether that will impact on overall survival, mainly because of the different lines of treatment that we will get afterwards. But that will be a very important issue also in how to treat our patients.
PM: So, Luis, we had vigorous discussion here at the Prostate Cancer Debate on what treatment to give on the patient we presented. We have several options for castration resistant prostate cancer and we still have options after each other like the sequencing, there’s a lot of discussion there. What is your main message from that discussion on castration resistant prostate cancer?
LC: Yes, I think what really we can understand nowadays is that we have new information about how to treat prostate cancer and we have new options that we didn’t have before, five years ago. All these new options are valid and the patient is just one and is not going to use just one of the options. So I think it’s important that we do the exercise every time that you’re going to decide for a patient, OK, what is my best first option and what will be the following one? So we have to look for the full package, not only for the first decision. That, I think, will be more and more relevant for the future. The full package can change with the advent of new trials with new results, so most probably one year from now you may be thinking about providing new options for the patient as Antonio just said to us. Now we have to combine that which is coming from the clinical trials which is the aim of every oncologist that is precision medicine. We would like to know what is the best treatment for the patient right now. So we need to have more information from the basic science, from the translational science, to bring us more information regarding tumour characteristics and patient characteristics, then we can decide better which will be the option.
PM: So apart from the fact that visceral mets is an exclusion criteria for, for instance, radium-223, what is influencing the decision on chemotherapy or abiraterone or enzalutamide because they are all recognised to be effective?
LC: Yes, you’re right. Either chemo, either abiraterone, either enzalutamide can be very effective in the metastatic prostate cancer castration resistant setting. The question is if this patient will need chemotherapy at any point, what is the right window to do it? Is it right at the beginning or should we move that forward after abiraterone. I think we don’t have the right answer for that. We can try to dig a little bit on the clinical trials, look for the characteristics of the patients. Until now I will say that for those patients that have a short period of response to hormone deprivation, those patients that have extensive disease and symptoms, those are the patients that we must think up front if we are not going to lose the window for giving them chemotherapy. Besides that I cannot go further until we have more precision medicine.
PM: You think in 2017 or ’18 we will have different opinions, Antonio?
AA: I’m totally sure that this is moving very fast and when receiving the new data we are changing our practice. I think the data from CHAARTED and STAMPEDE is a clear example of that. But definitely the new drugs like abiraterone, enzalutamide or new anti-androgens like ARN-509 will move earlier on M0 disease probably. So this is a very changing landscape.
AP: Peter, doesn’t this bring out this whole issue of timely readouts? Because if we’re going to base these decisions on volume of disease or the duration of response then we’re going to need better ways of monitoring disease and PSA is not going to cut this and that’s why we’re going to need imaging.
LC: That is key. I would like to have metabolic evaluation of the tumours.
PM: Do you think it’s possible to have metabolic or molecular imaging in the future? We know about PET scanning, the possibilities there.
AP: Well exactly. So we’ve already got metabolic imaging with a non-specific tracer like fluorocholine, that’s a plain metabolic tracer, nothing more than that. And it’s not very specific but actually in terms of the total burden of disease and how it’s doing it’s actually quite a good readout. But we will have more specific tracers as well. So, for example, we can anticipate FDHT, fluorodihydrotestosterone which is an AR receptor marker, to be able to inform on the total burden of disease that expresses androgen receptor compared to the total burden of disease in the body.
LC: The heterogeneity.
AP: Correct, and that tells you the heterogeneity. And that sort of thing will be able to inform on whether… do you go for an AR axis inhibitor or do you go for a more non-specific chemotherapy type treatment as well.
PM: So the imaging as a follow-up, once again, there is also a necessity and we have seen that, that you can see what is the prognosis of an early response measurement apart from PSA or apart from other traditional imaging. Is that something feasible? Are there investigations in that direction?
AP: Yes, so these investigations are just starting. What we’ve been doing is we’ve been working towards up until now development of technique. So for the last five years we’ve been developing techniques until they’re optimised and we think are now ready to be now used in the manner that you just described. So we’re at the moment working on an MRI document which will come out the middle of next year, or the early part of next year, which is a recipe. This is why we should be doing imaging and you’ve just said it – we want early readouts, we want more timely readouts, we want disease burden assessments because this is all prognostic, but if you’re going to use this technique this is how you should do it. This is the technique, this is how you report it, this is how you communicate. So these standards are now going to come up very shortly.
PM: Apart from the imaging, Antonio, is there something from the molecular field that we can fine tune the expectation for response of abiraterone or enzalutamide?
AA: Well, I think the imaging is going to be very important, probably whole body MRI can give us a very good idea about response, even in the size of the metastases, for reduction of size. But definitely I think the biology will get a very, very important role in the near future in order to select which treatment for which patient. CTCs, there is a lot of work on CTCs and I think molecular profiling of CTCs can give us a very good clue about, for instance, AR expression and whether this is more successful to respond to immune drugs, hormone therapies, or whether we should escape from those and go directly to cytotoxic drugs.
PM: OK, thank you for your information on this exciting topic, actually. A lot of things are happening, a lot of data are gathering and we will definitely have a different view next year.
