Prof Eleni Efstathiou – MD Anderson Cancer Center, Houston, USA

Prof Gordon McVie - European Institute of Oncology, Milan, Italy

GM: Thank you for joining us to discuss what’s been happening in prostate cancer at this meeting. It’s been a very busy meeting for the urology oncologists. Today’s plenary session was discussing common or garden patients with prostate cancer, my age or older, who at the moment would get ADT, androgen deprivation therapy. The trial that’s caused some discussion is docetaxel plus ADT versus ADT, what’s your take on it, Eleni?

EE: First of all, thank you for having me again. It’s always a wonderful pleasure.

GM: That’s very kind, my pleasure.

EE: I think this has been a tremendously interesting day at ASCO with regards, I would argue, for me the CHAARTED trial, the one you’re referring to, has been the most important data presented at this ASCO for me.

GM: Definitely.

EE: Again, it can be argued, however, we saw a clear survival benefit of a year in those patients who come in the door in our clinic, in our practice, and have what we call de novo metastatic disease. Then comes the question, we had a previous trial run by experts in the field, supported heavily on the European end - J'etuve trial - that was presented three years back, or two, at ESMO and I was the Chair of that session and I remember the presentation being disappointing in the sense that it was a negative trial. My question was how did you enrich for high risk disease in that trial?

GM: Bulky disease.

EE: Bulky disease.

GM: That’s where it is.

EE: That is the big difference between the two trials. In that specific trial, run by Dr Fizazi who is undoubtedly a leader in the field, we had 20% of patients with high risk features, in this one it is 70%. The difference is astounding. We can debate how to define those high risk patients but essentially the high risk patients, I would argue, would be the man who would walk in the door and have clean symptoms for this disease and is diagnosed through those symptoms because he has extensive bone metastases and maybe even visceral metastases.

GM: And lymph nodes.

EE: And lymph nodes that are bulky, another issue that’s very important to address. These are the patients that today were identified as the candidates for that type of treatment, meaning docetaxel up front. Now, having said that, we need to look at the control arm that was ADT alone. Unfortunately, even though it was again enriched for high risk, the patients following progression did not receive chemotherapy docetaxel as often as you would have expected, it was only, if I understood the data correctly and looked at it very carefully, it was only 30% of those patients that received chemotherapy. In the Western world, at least, we’re used tonumbers of around 60-70% so that is something that will be discussed in the forthcoming meetings, I’m sure, and addressed but there is obviously some great answers to some big questions that we’ve had coming through today.

GM: So you’re saying that if it had been docetaxel up front with ADT versus ADT and, on progression, docetaxel it might have been a different answer?

EE: It might have been a different answer. It might have been a different answer but, still, the high risk would have been identified. Here’s the final point that I would like to make, we can go on talking about this for ever, but the great point is the perseverance of the investigators because some of those docetaxel trials were dropped after J'etuve was negative and I would really like to commend the investigators for their effort.

GM: For patients.

EE: And patients in waiting.

GM: And believing in the data.

EE: Exactly. That is wonderful.

GM: So, bulky disease, the de novo prostate cancer patient comes in because they’ve got symptoms of bone or whatever. You’re now verging to saying, ‘Hi guys, docetaxel up front and ADT.’

EE: I will tell you that on Wednesday when I see patients in the clinic and somebody will walk in, I will put it on the table and discuss it with the patient. And even though the patient will be reluctant because it is chemotherapy and the paradigm has shifted away, and I’ve been a huge advocate, as you know, of the new androgen signalling inhibitors, I will bring up the data and I will prompt the patient to consider getting chemotherapy if he has those features. If he has multiple bone lesions, if he’s having symptoms from them and if he’s actually meaning in the sense that he’s becoming a symptomatic patient or he has visceral disease.

GM: It’s not so straightforward, of course, is it, especially for the older prostate cancer patient. They’ve got comorbidities, they handle neurotoxicity not so well, it’s important that they be able to self-care and maybe it’s that we will see this time next year a dialogue between the geriatricians for, let’s say, the over 75s or the over 80s how to assess a man to get docetaxel. Because it’s so easy just to do the ADT.

EE: In fact, there’s a wonderful paper that Jean Pierre-Droz initiated with the collaborative efforts in the geriatric group, and he was very kind to invite me to participate, where he’s really showing, because he actually studied it prospectively that frailty is the only parameter that needs to be taken into consideration, not so much age as comorbidities linked to age.

GM: I totally agree with him.

EE: And that is coming out very soon.

GM: But oncologists are not so hot at judging or measuring or rating frailty and we need to learn that, I don’t think there’s any doubt about that.

EE: Absolutely.

GM: So let’s go on to castration resistant prostate cancer. This is very familiar territory for you, you’re one of the reigning queens of the topic. Let’s deal first of all with abiraterone, where are we today post the ASCO urology meeting?

EE: With regards to abiraterone data what we now know is consolidated, that we have a benefit from treatment in the metastatic CRPC whether it’s asymptomatic or even symptomatic post-chemotherapy. With regards to enzalutamide we also have conclusive data. Today, in fact, it was published on-line at The New England, 1st metastatic CRPC asymptomatic symptomatic chemo-naïve patients. The indications have moved forward in most countries of the world that I’ve been and addressed June that we are, that it is of value in the the issues with urologists and medical oncologists. The question that arises is that however forward we have moved with current drug development we have not gone above an overall survival prolongation of more than 3 months, or 3.5 on the median, with the exception of the trial we just discussed, but we’re talking about CRPC. As we need to do better we need to identify... we’ve made a wonderful work, and I have participated very little, but others have made enormous advances in drug development, the question is therapy development.

GM: And management.

EE: And management. And we’ve done well; we’re having greater improvement in survival and you saw the data from both the enzalutamide and the abiraterone trial - the metastatic CRPC patient right now survives on a median of 36 months from that point of castration resistance, which is much better than it was before in 2004. So the questions that, in my mind, come are why are we treating all patients the same regardless of what is obvious, probably, as an indicator of primary resistance to androgen signalling inhibition? A lot of investigators have published even retrospective analyses looking at those prognosticators and likely predictors of outcome. Why don’t we take the risk to run trials that are based on these risk categories as we saw today? In that sense we have not been moving forward.

GM: You’re ten years behind breast cancer, without a shadow of a doubt.

EE: Definitely, if not more. So we have been making attempts to combine drugs, for instance docetaxel with different reagents. All failures. And I’m actually right now criticising my own work, we’re now starting to combine androgen signalling inhibitors together. So we... and I’m coming to what we’ve been doing, we actually combined abiraterone and enzalutamide in a phase I/II trial. Why though? Our hypothesis was biology driven. What we’ve established with our prior reports on bone biopsy trials is that essentially following abiraterone or enzalutamide independently as individual agents, what we see is that there are some feedback mechanisms that arise that may be implicated in ensuing resistance to those drugs.

GM: To the second drug particularly because there doesn’t seem to be any advantage of which one goes first in the sequence.

EE: Correct, when you sequence them. Essentially what we saw is that following abiraterone there is an increase of the androgen receptor and following enzalutamide there is an increase in testosterone as feedback, even though they hit their targets with regards to androgen biosynthesis and nuclear androgen receptor respectively. So we said if we combine them we may be able to inhibit the feedback mechanisms and augment efficacy,not effectiveness, at least efficacy with some measures of efficacy that we would use. That’s our work and to assess the safety of the combination, this is the first time we’ve combined these two drugs. Even though that may seem obvious there are some on-target effects that need to be considered, especially in long-term treatment. Then the pharmaco-kinetics because enzalutamide induces CYP3A4 and that’s the enzyme that metabolises abiraterone so we might be inhibiting the concentration of abiraterone. Then we wanted to assess measures of efficacy but mainly study the pharmaco-dynamic effects of the drugs on the tumour microenvironment and look again for predictors, as you insinuated, of resistance to those treatments because we’ve alreadypublished some data to support that the presence of the variants, and it’s a paper that’s coming out...

GM: This is the splice variant.

EE: The splice variant is very associated with resistance.

GM: To both drugs?

EE: To both drugs and, for us, it has been reported in enzalutamide. We’re going to come to both drugs because Dr Antonarakis from the Hopkins group presented some very elegant work today on that and actually he’s transitioning into liquid biopsies which are the circulating tumour cells. Even biopsies are difficult to perform in this setting, we need to persevere, they’re not as expensive, granted. We need to involve pathologists more in that work, in molecularly characterising, because what we did in our work was actually use very simple approaches to immunohistochemistry and assess in a similar fashion that breast does the level of the androgen receptor.

GM: I have to say that your phase I/II study is much richer in terms of supportive investigation than any of the breast cancer phase I trials of a decade ago so actually you’re learning from that.

EE: Correct. We’re inspired by them.

GM: And this is a very, very rich study which is why people are looking at it with awe. Tell us about what the data looks like.

EE: Well thank you very much. The data is interesting in the sense that there was no new safety concern but, as a discussant picked up and pointed out, we need to take care to point out some fatigue that ensues in these patients. You’re combining two agents that incur fatigue, take into consideration prednisone as well, so you need to be careful even if that grade 1 fatigue is there because we should not any more take for granted that patients should pay with toxicity, with quality of life, the effectiveness of an agent. That effectiveness to cost ratio should be considered. So that’s one. The other part is there were no PK issues that came about.

GM: Yes, and that’s a great relief.

EE: That’s a great relief.

GM: No interactions.

EE: Because there are two phase III studies that are currently on-going so they’re informed by that. The pharmaco-dynamic effects were reached in the sense that we actually were able to see that there was an inhibition of feedbacks. So one drug is not blocking the other at the tumour microenvironment level, which is great. Efficacy – too early to judge but I can tell you what was very good in this study was that we could already identify that even when you combine the two drugs there is a 20% of patients who are primarily resistant to the combination. So you cannot overcome primary resistance, it’s there. These are your candidates for a more aggressive therapy, we’re going to come to the chemotherapeutic question.

GM: And did you have splicing data on that?

EE: Correct. So we looked at splicing data, as we had before, and we were able to identify that one third of the primary resistant had the splice variant V7. What we know already from the literature is there are twenty splice variants, arguably V7 may be the most important. So that’s why we coined this ratio of determining the C terminal of the receptor that is translocated in the splice variant and the end terminal of the receptor. Adding that ratio to our already established signature for androgen signalling, which is presence of CYP17 and end terminal over-expression of AR, with that we are now able to distinguish, we’re enhancing our predictive performance and we can distinguish from baseline who may be primarily resistant.

GM: So who doesn’t get the fatigue from the drugs or nothing.

EE: Right, and also we actually saw that these patients have a much worse prognosis.

GM: Sixty something patients?

EE: There were sixty patients, eleven were primarily resistant. Of those, in sixteen months five have died. They received subsequent chemotherapies, that’s not the question. It brings me to the concern about chemotherapy as we know it, taxanes used with splice variants. There is some investigational data that supports that as the microtubules are responsible for the translocation of the receptor to the nucleus and splice variants may not be employing the microtubules to get to the nucleus then the use of taxanes to block the nuclear translocation may not work for splice variants and that needs to be studied as well. Because then we may need to look into combination chemotherapy or novel agents. It’s actually very interesting how the research at the basic level is coming together with the correlative science that we’re looking at.

GM: You’re a bit modest about the response data. Do you think it’s a bit early and all the rest of it? But these are patients with bulky disease by anybody’s definition and you’ve got some pretty spectacular PSA surrogate markers.

EE: Declines. It is true that 80% of the patients had a decline of more than 50% of the PSA and importantly it was sustained. But that’s close to the other two trials and they were big phase III trials. What was nice is that we could see that 15% of patients, again small numbers, but they remained with an undetectable PSA for protracted periods of time.

GM: That was impressive. It’s persuasive.

EE: That is very persuasive but we’ll have to wait because I have to tell you that 25 patients are still on trial with 16 months out so I think that the time on treatment is going to give us a lot of information because, unfortunately the way our clinical research is going, we’re not going to be getting a lot of information from overall survival anymore. We’re dangerously close tokidney cancer drug development. Our PFS is going to be a good marker to use, probably, moving forward for the time being since we don’t have other biomarkers.

GM: But in kidney cancer sequential use of TKI inhibitors, for instance, has worked and we’re pushing out to five years, six years, seven years. So far sequential use of the two drugs we’ve got, we’ll talk about the third one in a minute, has not delivered so the combination is the obviously logical way to go. So you’re halfway to the median of your 30 months with these patients, aren’t you?

EE: Right.

GM: So that’s quite encouraging.

EE: I like to always be reserved because you can be biased if you’re running the trial but I’m glad to hear other investigators be supportive.

GM: Yes, I think it’s looking extremely encouraging but, as you say, the data you’re getting out of the pathobiology of the process and the interference of these investigative agents, they’re investigative because they’re used together, I think that’s very rich and that’s going to inform your next series of trials.

EE: There are two trials and actually STAMPEDE has an arm addressing that question as well. What was important also, and I wanted to bring it up, is you’re probably very familiar with Dr Hussain’s work who actually found that that short time of response on androgen deprivation in hormone sensitive is a prognosticator of a very bad outcome. It seems that there may be a link, even in these new-found agents that we have, in castrate resistance and they think that 20-25% primary resistance is a very important link to that resistance to the novel drugs.

GM: Just to wind up, drug number three, did it miss the bus?

EE: This is a disappointment.

GM: It was not the greatest result we had hoped for. Tell us about the trial, you were involved in this trial.

EE: I was very heavily involved in that trial and vested in the sense that we all believed that there is a need for a third drug out there that’s also an androgen biosynthesis inhibitor that had the most wonderful phase I/II data and we actually could see in the clinic, we could already tell without even knowing who was on active drug and who on prednisone alone. And I will again refer to Dr Fizazi who had forewarned that this may happen given the event of the other reagents in the market. So undoubtedly any patient who failed the trial and progressed had to receive at some point in time either abiraterone or enzalutamide. It was approved in North America and in Europe. I had a lot of patients, you could not refuse a patient to receive that, it’s unethical, of course, and I think that that has influenced the outcome because we all saw today that the RPFS data is there, the progression free survival was positive, the overall survival benefit was not met. It is unfortunate and I hope again that the company will persevere and continue running other trials with orteronel that are on-going right now.

GM: So which would be your preferred partner to orteronel?

EE: To orteronel? That is a good question. There are some drugs, actually, that are currently in development and that are actually targeting the end terminal of the AR. So the question is would you couple it or run alone that type of drug? Or there’s another option that I just was thinking about – orteronel had the opportunity to be run without prednisone and they never really pursued it because the big asset for that drug, and it showed some fabulous mass-spec data on the depletion of testosterone today, the big asset was that it does not inhibit the CYP17 hydroxylase so it could be used alone and they never took advantage of that in their phase III.

GM: So there’s still life in orteronel?

EE: In my mind there is but it’s not up to me, of course.

GM: OK. Highly illuminating discussion, thank you for that. The take home message for urologists who are not able to come to Chicago? We’ve dealt with docetaxel and I think we’re happy with that in bulky disease and symptomatic disease. What about the castration resistant prostate cancer patients?

EE: There are strides that are being made currently. I have a couple of messages. The first one is very obvious: we are in desperate need of biomarkers that will guide the application. Just really performing phase III trials that are uninformed is not going to get us anywhere. You would expect we would learn from prior errors and correct them and we would be more inspired from breast cancer. The other thing is a positive message and it’s a little bit of an inside joke in the prostate field: ten years ago there wasn’t as much enthusiasm; two year ago the presentations still were happening in small rooms. Today presentations were in a large hall that was full of people so this means that there are so many people with intellect, with high intellect, working in the field right now that it is bound to succeed and we will reach if not a cure at least secondary prevention for this disease.

GM: When you’re doing these phase III trials I hope you’re taking some tissue and some serum and banking them because these biomarkers are going to come from somewhere in the next two or three years and if you haven’t stored that tissue in patients in the context of a phase III trial...

EE: You won’t be able to look back.

GM: You’re going to miss a trick.

EE: Absolutely. I think we’ve figured that out.

GM: Eleni, thank you so much. I really appreciate you giving us your time and your wisdom. I appreciate it very much indeed.

EE: Thank you very much. Thank you very much for having me.