Treatment options in castration-resistant prostate cancer: Expert discussion

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Published: 29 Sep 2014
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Prof Karim Fizazi, Prof Eleni Efstathiou, Dr Bertrand Tombal and Prof Stephane Oudard

Prof Karim Fizazi chairs a discussion with Prof Eleni Efstathiou, Dr Bertrand Tombal and Prof Stephane Oudard about the latest in prostate cancer treatment for ecancertv at ESMO 2014.

They discuss the treatment paradigms, novel drugs and new, verified treatment regimens and advances announced at the ESMO Congress.

Specifically, they look at what's new in castration-resistant prostate cancer, clarify the use of combination and sequential therapies, and debate the hot topics coming out of ESMO 2014.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

KF: Hello, I’m Dr Karim Fizazi, a medical oncologist from Gustave Roussy in France and I’m here in Madrid at the ESMO meeting sitting together with very important faculties in GU oncologies and good friends, namely Dr and Professor Eleni Efstathiou from both MD Anderson and Athens in Greece, medical oncologist. I have also Professor Bertrand Tombal from Brussels who is a urologist and we have also Professor Stephane Oudard from Paris Georges Pompidou who is a medical oncologist. So we’re all here at the ESMO meeting and our goal is really to try to explain to you what, in our opinion, has been the most important part of the GU sessions, specifically prostate cancer. So first of all we just had some new data about the CHAARTED trial which was looking at patients with pretty much de novo metastatic prostate cancer. Stephane, can you please remind us what have been the results presented today?

SO: Yes.  Chris Sweeney presented his phase III study which was already presented at the ASCO meeting. At the ASCO meeting he took all the patients with either high tumour burden or low tumour burden and today he just presented patients having metastatic disease, hormone naïve, with high tumour burden. And the results are outstanding so far because we have a gain in time of 17 months interval of ADT plus docetaxel compared to ADT alone. This is just amazing because the difference is huge, again 17 months. It means that in fact if you have a patient in your daily practice at your hospital tomorrow or on Monday coming with metastases everywhere, either at the liver, liver mets, bone mets and so on, in a good shape who has no comorbidity, we should recommend to this patient to have ADT and docetaxel.

KF: Well this is quite a strong statement. Bertrand, is that also your take home message for the practice as a urologist? You do see these patients?

BT: We see these patients a lot because usually they will come to the urologist to start with. The reaction of the urology community has been quite good as well although it challenges the way we’ve been treating these patients for sixty years. So it may take time before everybody is aware. There are still some people reluctant in believing, especially the amplitude of the benefit, but overall, at least in the country I know where we work in a multidisciplinary setting, clearly it’s going fast. The problem of urology, as you may know, is that the level of awareness and multidisciplinarity is extremely heterogeneous across Europe so as faculty urologists we’re going to have now to travel to explain that to our colleagues. Because really we’ve been using ADT for sixty years, basically we know it doesn’t work in these patients so it doesn’t come as a surprise, we were expecting that for many years. So now it’s up to us to behave responsibly and try to educate our colleagues about that. But, honestly, as a urologist, the data are outstanding and yes we should do something different for these patients.

KF: OK, I guess you both are very convinced. Eleni, let me ask you, do you see any main issue with this trial or these findings? Are you totally convinced? Do you see any limitations for tomorrow’s practice?

EE: Well, the limitation comes with regard to what exactly are we looking at, how it translates into daily clinical practice. If we look at the countries where we come from or where we practice I think the de novo metastatic cases are limited. So where it may have an impact as a practice change would be in countries where PSA screening has not infiltrated as much and you get more of that de novo metastatic disease, namely one of the growing areas is China, for instance, in Asia, in some parts of South America. There the discussions regarding the matter will be more important and how it will impact their clinical practice.

Because we have to look at it with a perspective; we have to look at exactly what it means to define as a high volume of disease. We have to take into account the previous trial, your trial, GETUG 15, where you actually had enriched it more for the lower volume disease and understand the differences between the two. Chris really presented today some of the data but he didn’t go into as much depth as I would have liked with regard to, let’s say for example, visceral metastases. We know there’s a difference, even looking at other people’s work, between liver and lung metastases, bulk of lymph node metastases. So there’s a lot of discussions ahead of us before we actually change completely our practice, especially in countries like ours – North America, Western Europe, most parts of Europe, I would say.

KF: So basically I guess the three of you are quite convinced by the data, strong data from a large trial, and probably the standard is now switching for patients with large volume disease, whatever way you define that. What about low volume disease? Because here we have a problem, at least with the data that we have, with GETUG 15, that doesn’t support overall survival at the moment with the follow-up that we have and CHAARTED for these patients also shows a trend. So if tomorrow, Stephane, you will see a patient with low volume metastatic disease, let’s say retroperitoneal lymph nodes or just one or two bony metastases, will you use docetaxel as your up-front treatment on top of ADT?

SO: I think no, because we don’t have enough mature data so far, especially in the CHAARTED trial. I think we need more data to be convinced that it’s working both, in both high volume and low volume. So far I will continue to go for hormonal therapy, especially for clinical trials so far, because we have a lot of new clinical trials which could be addressed to these kinds of patients so far. So I recommend not to put those patients so far in with docetaxel.

KF: OK, let me switch to something else now – castrate resistant disease, which we all know quite well I guess. Abiraterone was probably the first next generation hormonal therapy to demonstrate that it can significantly postpone progression in the pre-docetaxel setting. So patients who are asymptomatic can probably remain asymptomatic for quite long term and that includes symptoms, obviously, but also PSA and also radiographic progression. Now one thing we didn’t know until today, basically, was whether we were also postponing death by using abiraterone in this setting. Can you comment on that, Eleni?

EE: Today we had the opportunity to listen to Chuck Ryan present the fourth interim analysis after a four year survival follow-up. I think we got a glimpse of what we expected. Let’s not forget the history behind this. During the second interim analysis when the benefit was shown in the radiographic progression free survival it was decided and it was considered ethical that the patients even in prednisone alone should cross over. So back then I remember you and I had discussions where I said, “Well, we’ll never be able to see the results now because we have to stop and interrupt.” And you said no, you actually told me that, I remember, “No, maybe there’s a chance we’ll see a difference,” and it turns out you were right. This is where it brings to the point that actually Bertrand discussed, well, you’re usually right, I know, but regardless this brings us to the point that Bertrand brought up during the discussion. Today is indeed a confirmation that this drug does work statistically as well as we knew in the backbone of chemo-treated and chemo-naïve disease. We were all convinced; we were using it in practice. Practically it means that patients may have more access to it in more countries than some of where we’re practising because even regulatory… it may convince the authorities that they can reimburse this agent easier. However, for our practice it doesn’t change anything; we’ve already been using it. But it brings the point of timing of abiraterone acetate and, in general, androgen signalling inhibition because it’s exactly what you had predicted, that even if you put it later in the treatment you won’t get as much benefit as if you put it earlier. It gives us thought for all those trials that are on-going in earlier disease settings and we’ll be expecting some data. I’m sure that Bertrand can elaborate more on this since he brought it up during the discussion.

KF: Thank you. Bertrand, any comment on that?

BT: Yes, just that by choosing to cross over they basically made a major transformation on the philosophy of the trial and what they did is basically an early versus delayed abiraterone trial. My worry is that people will look at the benefit and say, “Yes, there is a benefit but it’s only 20%.” Actually the truth is that that number doesn’t mean anything anymore, it just means that if you take 100 patients who receive abi versus 50% of patients who receive abi, the first one does better and they live longer. The hazard ratio probably, even surely, underestimated largely the true benefit of the drug. As Eleni mentioned, as a urologist we know that with all hormonal treatment that it improves survival but earlier doesn’t do much better than later. So it does better but not much. So my worry is where is going to be the tipping point where actually it goes in the other direction. People told me it’s never going to happen; it happened at least with one drug and that was bicalutamide because at some point we used it so early that we inverted the benefit. So to me the challenge we’re facing with abi and enza is now really to understand when should we start it. Not too early and not too late because too late you won’t get any benefit. But the fact that these drugs are now central to the management of these patients, we knew it and that’s just a confirmation.

KF: And, as Eleni alluded to, there are trials also addressing the question as to whether we should use them even earlier and we’ll see the results in the coming years.

BT: Yes, because this trial as well will be… If you take a drug like with the Aragon compound it is going to be early Aragon versus late enza. So that’s going to answer these questions as well.

KF: Staying with enzalutamide, because this is also the other drug that could show overall survival benefit on top of progression free survival benefit in this setting of asymptomatic metastatic castration resistant disease, today we’ve heard data about the PREVAIL trial with regards to quality of life and, importantly to me, a part of the COU-AA-302 presentation was also regarding the skeletal related events which are basically fractures, spinal cord compression, major pain requiring radiation. Besides the overall survival benefit that we saw with abiraterone, it was really postponing the severe morbidity by ten months or so, thanks to the abiraterone. So it’s not only prolonging life, it’s really good life that is being prolonged. What is your take home regarding the PREVAIL data that we’re presented with.

BT: Exactly the same as you mentioned to me. Overall survival is important, to be sure we don’t shorten the life of the patient, but what we are buying for these patients is quality life. Most of these guys, they are in their seventies, they’re OK to go to chemo but they don’t like it too much. So really what you do is using drugs that both have very acceptable toxicity profiles you prolong the time of freedom. They die faster once they progress, OK, but in the meantime we offer, and that’s what you and your collaborator have been showing with PREVAIL, is that every quality of life endpoint, even the new one like time to chemo or skeletal related events, it is prolonged. It’s not prolonged by two or three months, it is significantly prolonged. In the end, on average we’re buying twice more good time than time, so to me this is where really the benefit of these drugs are.

KF: Stephane, there were also some negative findings today, some large phase III trials that could not confirm their original hypothesis. For example, the docetaxel plus or minus curcumin compound failed to demonstrate overall survival and we also had the update of the ipilimumab in the post-docetaxel setting trial. Can you comment on the curcumin trial, for example?

SO: Now and since a long time ago we have tried to combine docetaxel with targeted drugs but without trying to find out whether or not the target is there, whether or not the target is working and whether or not the drug is really going to inhibit the target.Because we have to look at it with a perspective; we have to look at exactly what it means to define as a high volume of disease. We have to take into account the previous trial, your trial, GETUG 15, where you actually had enriched it more for the lower volume disease and understand the differences between the two. Chris really presented today some of the data but he didn’t go into as much depth as I would have liked with regard to, let’s say for example, visceral metastases. We know there’s a difference, even looking at other people’s work, between liver and lung metastases, bulk of lymph node metastases. So there’s a lot of discussions ahead of us before we actually change completely our practice, especially in countries like ours – North America, Western Europe, most parts of Europe, I would say.

KF: So basically I guess the three of you are quite convinced by the data, strong data from a large trial, and probably the standard is now switching for patients with large volume disease, whatever way you define that. What about low volume disease? Because here we have a problem, at least with the data that we have, with GETUG 15, that doesn’t support overall survival at the moment with the follow-up that we have and CHAARTED for these patients also shows a trend. So if tomorrow, Stephane, you will see a patient with low volume metastatic disease, let’s say retroperitoneal lymph nodes or just one or two bony metastases, will you use docetaxel as your up-front treatment on top of ADT?

SO: I think no, because we don’t have enough mature data so far, especially in the CHAARTED trial. I think we need more data to be convinced that it’s working both, in both high volume and low volume. So far I will continue to go for hormonal therapy, especially for clinical trials so far, because we have a lot of new clinical trials which could be addressed to these kinds of patients so far. So I recommend not to put those patients so far in with docetaxel.

KF: OK, let me switch to something else now – castrate resistant disease, which we all know quite well I guess. Abiraterone was probably the first next generation hormonal therapy to demonstrate that it can significantly postpone progression in the pre-docetaxel setting. So patients who are asymptomatic can probably remain asymptomatic for quite long term and that includes symptoms, obviously, but also PSA and also radiographic progression. Now one thing we didn’t know until today, basically, was whether we were also postponing death by using abiraterone in this setting. Can you comment on that, Eleni?

EE: Today we had the opportunity to listen to Chuck Ryan present the fourth interim analysis after a four year survival follow-up. I think we got a glimpse of what we expected. Let’s not forget the history behind this. During the second interim analysis when the benefit was shown in the radiographic progression free survival it was decided and it was considered ethical that the patients even in prednisone alone should cross over. So back then I remember you and I had discussions where I said, “Well, we’ll never be able to see the results now because we have to stop and interrupt.” And you said no, you actually told me that, I remember, “No, maybe there’s a chance we’ll see a difference,” and it turns out you were right. This is where it brings to the point that actually Bertrand discussed, well, you’re usually right, I know, but regardless this brings us to the point that Bertrand brought up during the discussion. Today is indeed a confirmation that this drug does work statistically as well as we knew in the backbone of chemo-treated and chemo-naïve disease. We were all convinced; we were using it in practice. Practically it means that patients may have more access to it in more countries than some of where we’re practising because even regulatory… it may convince the authorities that they can reimburse this agent easier. However, for our practice it doesn’t change anything; we’ve already been using it. But it brings the point of timing of abiraterone acetate and, in general, androgen signalling inhibition because it’s exactly what you had predicted, that even if you put it later in the treatment you won’t get as much benefit as if you put it earlier. It gives us thought for all those trials that are on-going in earlier disease settings and we’ll be expecting some data. I’m sure that Bertrand can elaborate more on this since he brought it up during the discussion.

KF: Thank you. Bertrand, any comment on that?

BT: Yes, just that by choosing to cross over they basically made a major transformation on the philosophy of the trial and what they did is basically an early versus delayed abiraterone trial. My worry is that people will look at the benefit and say, “Yes, there is a benefit but it’s only 20%.” Actually the truth is that that number doesn’t mean anything anymore, it just means that if you take 100 patients who receive abi versus 50% of patients who receive abi, the first one does better and they live longer. The hazard ratio probably, even surely, underestimated largely the true benefit of the drug. As Eleni mentioned, as a urologist we know that with all hormonal treatment that it improves survival but earlier doesn’t do much better than later. So it does better but not much. So my worry is where is going to be the tipping point where actually it goes in the other direction. People told me it’s never going to happen; it happened at least with one drug and that was bicalutamide because at some point we used it so early that we inverted the benefit. So to me the challenge we’re facing with abi and enza is now really to understand when should we start it. Not too early and not too late because too late you won’t get any benefit. But the fact that these drugs are now central to the management of these patients, we knew it and that’s just a confirmation.

KF: And, as Eleni alluded to, there are trials also addressing the question as to whether we should use them even earlier and we’ll see the results in the coming years.

BT: Yes, because this trial as well will be… If you take a drug like with the Aragon compound it is going to be early Aragon versus late enza. So that’s going to answer these questions as well.

KF: Staying with enzalutamide, because this is also the other drug that could show overall survival benefit on top of progression free survival benefit in this setting of asymptomatic metastatic castration resistant disease, today we’ve heard data about the PREVAIL trial with regards to quality of life and, importantly to me, a part of the COU-AA-302 presentation was also regarding the skeletal related events which are basically fractures, spinal cord compression, major pain requiring radiation. Besides the overall survival benefit that we saw with abiraterone, it was really postponing the severe morbidity by ten months or so, thanks to the abiraterone. So it’s not only prolonging life, it’s really good life that is being prolonged. What is your take home regarding the PREVAIL data that we’re presented with.

BT: Exactly the same as you mentioned to me. Overall survival is important, to be sure we don’t shorten the life of the patient, but what we are buying for these patients is quality life. Most of these guys, they are in their seventies, they’re OK to go to chemo but they don’t like it too much. So really what you do is using drugs that both have very acceptable toxicity profiles you prolong the time of freedom. They die faster once they progress, OK, but in the meantime we offer, and that’s what you and your collaborator have been showing with PREVAIL, is that every quality of life endpoint, even the new one like time to chemo or skeletal related events, it is prolonged. It’s not prolonged by two or three months, it is significantly prolonged. In the end, on average we’re buying twice more good time than time, so to me this is where really the benefit of these drugs are.

KF: Stephane, there were also some negative findings today, some large phase III trials that could not confirm their original hypothesis. For example, the docetaxel plus or minus curcumin compound failed to demonstrate overall survival and we also had the update of the ipilimumab in the post-docetaxel setting trial. Can you comment on the curcumin trial, for example?

SO: Now and since a long time ago we have tried to combine docetaxel with targeted drugs but without trying to find out whether or not the target is there, whether or not the target is working and whether or not the drug is really going to inhibit the target. . So this is the problem and we have made more than ten clinical trials, phase III clinical trials. We have put more than 10,000 patients in these clinical trials and so far all the studies are negative. So we should not do any more of this kind of phase III study now because there is no sense at all to propose to those patients docetaxel plus something else. All these studies were based on phase I or small phase II studies looking at PSA response rates and there is no sense to use PSA response rates for targeted drugs so far. So really you need, in a small phase I or phase II study, to see whether or not you are going to hit, to have a signal, a specific single thing where the combination may work. So unfortunately docetaxel and curcumin was a negative study but, as you can see, the overall survival was around 22-23 months so we have a gain. Ten years ago it was around 18 months, now we are around 22-23 months. So maybe this is due to either the fact that now we treat those patients much earlier or due to supportive care we can handle those patients more nicely than before. So it’s a negative study but now I think it’s time to go over and to think about how to use these drugs more smartly.

KF: OK, so basically it’s really a plea for molecular enriched population to address a question in a subgroup of patients that has the target, whatever that is, rather than all comers. OK, that makes perfect sense to me even if it also has challenges. The ipilimumab trial was also updated, overall survival was not met last year. It’s an immunotherapy and the concept of immunotherapy is extremely appealing in prostate cancer. It seemed that the magnitude of benefit seems to be a little greater and, importantly, we see long term survivors, maybe some cured patients like we saw for melanoma but again this remains to be truly demonstrated. We’re waiting for a second phase III trial in less sick patients and we’ll see what happens. But again, as you said for other drugs, for ipilimumab we would love to have a biomarker predicting for efficacy. Coming back to very practical and simple things, we had a quite provocative randomised trial presented today comparing dexamethasone and prednisone. Again those are drugs that are off label, cheap, mostly used as anti-pain, anti-inflammatory treatments but the hypothesis was that one might be better than the other. What do you think about the data Eleni?

EE: We need to start with the shortcomings of this trial. It’s probably the only reported trial to date comparing head to head the two but the numbers of patients are very small and there are indeed less than 100, I believe, if I remember correctly. The endpoints that they looked at have to do more with the differences in the PSA response, again, not very valid points. But they did report on, so as a secondary endpoint, in a delay to progression and actually what was interesting, and I don’t remember if it was post hoc or if it was in the trial, they actually reported on the extra biochemical regression gained from the transition from prednisone to dexamethasone. Indeed, it is compelling and it is in line with what a lot of the investigators expected, meaning that dexamethasone, if anything, may have a modestly higher activity than prednisone because we’re essentially speaking about agents that have no proven activity in the phase III settings however, as you pointed out, for daily practice and if you don’t have access to these very more difficult to reimburse agents you may be able to use them.

KF: Which one do you use in your practice?

EE: Exactly. If I were to pick and what I have been doing is a very low dose of dexamethasone.

KF: OK, Bertrand, do you also use, and a very simple answer, do you use dexa or prednisone in your practice.

BT: Yes we use, and especially we now switch patients progressing on abi pred to abi dexa.

KF: And have you seen responses?

BT: Yes, but you would do that in patients like Eleni mentioned, really you have no other option left. Or in patients who have fatigue, deterioration for a palliative endpoint. But these are interesting studies but there are other solutions to be exhausted before using them.

KF: Stephane, do you use dexa or prednisone in your practice?

SO: Prednisone in my practice and almost never dexa. I don’t know why, it’s just a habit that we have.

KF: OK. I think we’ve covered pretty much the main messages that we’ve heard today at the congress so I wish you a very good continuation of your ESMO congress and I thank you very much. Thank you.