ESMO 2012: Vienna, Austria

Advances in advanced prostate cancer from ESMO 2012: focus on abiraterone acetate

Dr Chris Parker – The Royal Marsden, London

Dr Charles Ryan – UCSF Helen Diller Family Comprehensive Cancer Center, USA

Professor Karim Fizazi – Institut Gustave Roussy, France

CP:            Hello, I’m Chris Parker, oncologist at the Royal Marsden, and I’m here in Vienna at ESMO 2012. I’m delighted to be joined by Charles Ryan from the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco and also by Karim Fizazi from the Gustave Roussy. So Charles, you’ve presented some data here from the Cougar 302 study, can you tell us about it?

CR:            Sure. The Cougar 302 study was a study of abiraterone versus placebo in patients who had not yet received chemotherapy for castration resistant prostate cancer. We presented the data at ASCO showing a very significant benefit in terms of radiographic progression free survival. A key aspect of that analysis was that investigators were charged with reading bone scans and determining whether the patient had experienced progression on the bone scan. We also had a central radiographic review, so the purpose of the analysis was really to test the performance of the investigators and the central radiographic review. The good news is that our data seemed to suggest that there’s a fair amount of concordance; that investigators were able to evaluate progression and that it generally agreed with what the central radiology reviewers were seeing. So that was one aspect of it, the other aspect was to develop a statistical association between the radiographic progression free survival endpoint in prostate cancer and overall survival. As we’re all aware, the development of a surrogate endpoint for a phase III study would really advance our field quite a bit if we can conduct phase III studies using intermediate endpoints and not have to always rely on the overall survival endpoint to determine whether a study is positive.

CP:            So, forgive me for asking this, isn’t it obvious that RPFS would correlate with survival?

CR:            You would think, however, we need to show that, number one, and we need to quantify it. So the degree of quantification of an association is also important. From the standpoint of biomarkers there are associations of biomarker outcomes with survival that have correlation coefficients of 0.4 and 0.5, that’s a positive association but it’s a relatively low correlation coefficient. Our correlation coefficient at 0.7, a little bit higher than that, is actually very favourable in terms of demonstrating an association with survival. But the key factor is, of course, that treatment with abiraterone on this trial, or in any clinical trial treatment with the study drug, occurs during the course of treatment on the trial and when the patient is no longer being cared for under the trial, there is the potential for other active agents to interfere with, if you will, the survival endpoint. In other words, patients can have a prolonged survival based on what they receive after the clinical trial as opposed to what they received on the clinical trial as well.

CP:            So are you going to go on to test RPFS for surrogacy?

CR:            That’s an interesting question, it’s not a formal plan within the statistical framework of this trial. Whether or not we’re able to show that that association is strong enough has yet to be determined. It will depend, of course, on the long-term overall survival data as they mature and emerge and also the regulatory community on whether or not they’re open to that discussion of whether or not RPFS is a surrogate outcome measure for survival.

CP:            Perhaps I’ll turn to Karim now. Do you think, Karim, that future trials are going to use this RPFS endpoint as a primary endpoint?

KF:            That’s a very tough question, honestly. So far both the agencies in the US and in Europe have been willing to look at overall survival data first to give a green light for a drug to be approved or not. Obviously, they will need to move from that and this is because we’ve got so many drugs of a label, already or in the near future, that it’s going to be very difficult to demonstrate an overall survival benefit, even if a drug is very potent and very active in that disease. The limitation of progression free survival in assessment in prostate cancer is that it has been mostly based on a bone scan assessment and bone scan is not a direct measure of a cancer, it’s really an osteoblastic assessment. RPFS criteria could be used but only in a minority of patients, 20-25% or so, so there are definitely limitations for RPFS. The ideal, probably, it would be nice to have another clinical endpoint that would not be overall survival, that would not be radiographic progression free survival but which would be related to the symptoms because in general in oncology the ultimate goal, of course, is to increase overall survival but also to do some good to all the patients in terms of symptoms. But it’s very difficult to measure.

CP:            Would you like to suggest an endpoint?

KF:            Not exactly, it’s really much more a kind of reflection. You can think about assessing pain because pain is really something very important in this disease so, firstly, if you look at pain you capture the big thing. But pain is not the entire thing so you might be willing to look at skeletal related events; they also have their limitations and it really depends on the way you measure that. You might be willing to look at quality of life, actually all those two or three parameters are trying to capture doing some good to the patients besides improving survival.

CP:            I liked Ethan Basch’s presentation of the 302 data looking at time to functional deterioration and time to opiate use. I was wondering whether, in the future, they might become approvable endpoints.

CR:            If I could add, the RPFS endpoint that we described, one of the sensitivity analyses that we did do was whether or not the use of this unequivocal clinical progression endpoint altered the outcome. So in our study patients who went on to receive chemotherapy, who required opiates, who had a functional decline or needed radiation or surgery, were felt to have… that was a progression event in and of itself. When we added those in to the radiographic progression it didn’t alter the statistics, it didn’t alter the outcome that much. With that said, Ethan’s presentation is very important because it showed that treatment with abiraterone preserved functional wellbeing, preserved emotional wellbeing and preserved overall quality of life. It’s also important to point out that those are pre-specified analyses and so the statistics that he showed accounted for multiple testing and that’s a very important thing to understand when we evaluate secondary analyses such as this.

CP:            I want to bring us down to earth, every day in the clinic. You’ve got data now about the frequency of a bone scan flare when you start abiraterone, so tell us about that.

CR:            In the study we did a bone scan after only eight weeks of therapy followed by another bone scan after sixteen weeks of therapy. We did this to account for the possibility that early changes in bone scan could lead to premature discontinuation of the therapy and we’ve published on this before. What we saw was about 100 out of the 550 patients allocated to the abiraterone arm had a worsening bone scan after eight weeks but of that, it was 108, of that 108 92 did not experience further progression. So bone scan flare turned out to be around 20% or so, a little bit under 20% and those are patients in whom, if a clinician is doing a bone scan that early, may erroneously discontinue the therapy based on increased intensity of lesions or even the appearance of new lesions that don’t progress further. So the key is whether or not we should actually be doing bone scans in real life at week eight and I would advocate that no, we really don’t need to do those.

CP:            I agree with you, I think we should avoid bone scans for the first eight weeks because you can’t interpret them.

CR:            Absolutely.

CP:            So, Karim, when do you imagine somebody who is on abiraterone?

KF:            I guess the trial was the trial, obviously, but in normal life I actually do minimal imaging to the bone just to assess progression overall response because it’s really tough and we all know the limitations of doing that. I do bone imaging when it comes, for example, to try to prevent spinal cord compressions and this is an MRI, and I guess this is much more clinically important rather than doing bone scan after bone scan, honestly.

CP:            So what would prompt you to get an MRI scan of the spine?

KF:            There is ultimately no clear recommendation on that but in my practice a gentleman with multiple spots on the bone scan on the spine should probably get an MRI. Now, how often should you repeat the MRI is something we don’t really know because spinal really, when you’re talking about strong morbidities spinal cord compression is really the worse thing so this is really the thing we want to prevent.

CP:            So how about you Charles, when do you image patients who are on abiraterone?

CR:            Outside of the context of a clinical trial, if a patient does not have a high burden of disease and they’ve experienced a PSA decline and they are asymptomatic and doing well overall, I will not scan for response because a scan for response doesn’t direct my therapy. I will scan when the PSA begins to rise or if new symptoms develop. Karim’s point is a good one, if a patient has a high burden of spinal disease you may need to follow that with serial MRIs to avoid or prevent a spinal cord complication which, fortunately, is rare and I think probably going to be even less common as time goes on.

CP:            So you’ve got a patient on abiraterone, PSA is rising, you’ve re-imaged, the imaging is actually better than it was when they started abiraterone, what are you going to do?

KF:            I’m going to ask first my patient what about his symptoms even before looking at his PSA and looking at the images because really this is the most important thing depending, of course, whether you are symptomatic or not. This is really the most important thing because you might see some PSA flare, you might also see some patients responding by PSA and then progressing very slowly and I really believe that these patients still benefit somehow from abiraterone or all those drugs. Now the question is really when do you stop? Honestly, in my experience so far, I’ve been trying to continue abiraterone in patients with a drop in PSA followed by a slow progression but still doing well clinically and with a good imaging profile.

CP:            Would you say the same, Charles? You’ve got your patient using abiraterone before chemotherapy, what would make you switch from abiraterone to chemotherapy?

CR:            That’s a very timely question because I believe what we’re going to see are multiple different facets of the disease that emerge after abiraterone. We’re going to see the heterogeneity of prostate cancer augmented in the post-abiraterone space. But certainly going to chemotherapy would be my first thought in a patient who is becoming symptomatic with rapid progression and going to further hormonal manipulations may be more appropriate for a patient who has simply a rise in PSA without symptoms.

CP:            Thank you. Karim, you’ve presented data from GETUG 15, can you tell us about that trial and what you found?

KF:            Yes, that is an academic trial that we designed almost ten years ago when we had the first data on docetaxel showing improvement in overall survival in the castrate resistant stage. We hypothesised that using docetaxel early in the disease could even improve overall survival further. Because we still see in Europe, and I guess elsewhere as well, many patients with metastasis at diagnosis, we decided to design this trial testing androgen deprivation therapy versus androgen deprivation therapy plus docetaxel in these gentlemen with evidence of metastasis at diagnosis. It took us a while, of course, to do that; it was an approximately a 400 patient trial and the data were just released yesterday, as you saw. What we found was basically that overall survival is the same and that’s probably in a large part because many patients in the control arm did receive docetaxel when they eventually progressed to the castrate resistant stage but progression free survival is quite different and this is true for PSA driven progression free survival, it’s also true by clinical progression free survival. So this really emphasised how difficult it is to make a decision right now when you have a drug, and that’s true for docetaxel in this setting, probably with other drugs, we’ve just discussed abiraterone in the asymptomatic CRPC stage. So to make a decision when a drug is able really to postpone progression but not that much overall survival or no overall survival benefit, like in the GETUG 15 trial, should we use it, yes or no, it’s of course not easy. I would say that probably for abiraterone the answer is probably going to be yes, one, because it’s a very well tolerated drug and also the second reason is that I think that the overall survival benefit that we see is clinically relevant to me and I hope that it’s going to be even bigger when we do the next analysis. We’re waiting for your data check, by the way.

CP:            But in GETUG 15 you got a progression free survival advantage, that was PSA progression?

KF:            Actually we did two analyses, one was PSA progression, and it’s quite different, and the other one is imaging based or clinical progression based without PSA and it’s also different. Again, would you, for a six or eight month delay in progression, would you prescribe six or eight months of chemotherapy? That’s probably a very different question to answer too.

CP:            So I’m wondering whether your trial shows that radiologic PFS is no good as a predictor of survival. The use of a radiologic PFS benefit but no difference in survival.

KF:            If really you’re comparing orally versus delay drug then the surrogacy or even the association between your first event, progression free survival and overall survival might not be there, that’s very true. Now if just one shot, a drug that you give orally versus nothing else, then you might well see a very good association between RPFS and overall survival.

CP:            400 patients seems very small for an overall survival study, would you agree?

KF:            Correct. Yes, that’s very true. Again, this is a trial we designed in 2003 or 2004 and at the time we had discussion with the urologists, because these patients were mostly seen by urologists, and really that was a challenge to set an academic trial pulling together urologists, radiation therapists, medical oncologists. We had to take this into account when we built on the hypothesis.

CP:            Yes, so I guess it’s worth us continuing with the STAMPEDE trial which is testing the same question but in a much larger number of patients.

KF:            Yes, I think it’s good that you guys are doing this trial in the UK. Now I hope that you will be able to look at your three specific groups in STAMPEDE. This particular group, the metastatic setting, is very different as opposed to the rising PSA which is very different to the localised higher risk group. So I really hope you will be able to look at these three subgroups in three different analyses.

CP:            Me too.

KF:            OK.

CP:            So, Charles, moving on, there was an interesting abstract about the effect of corticosteroid use on survival in the AFFIRM trial. Tell us about that and what you thought of it.

CR:            What’s interesting is there’s now a shift in the discussion away from simply considering that corticosteroids may be a part of the standard of care for a CRPC, which they have been for years, to potentially a harmful substance that could actually drive forward an androgen driven or a steroid receptor driven cancer. So these data, just briefly, demonstrated that in the subset of patients on the AFFIRM study which was, I think, about 30% of the patients who came into the study already receiving corticosteroids, that those patients had a worse overall survival than the other group of patients who were not previously exposed to corticosteroids. It’s obvious that there is some selection bias at play here and, in fact, the discussant very nicely showed, or the data very nicely showed, that the patients who were on corticosteroids appeared to have more aggressive tumour features, more symptomatic disease and that type of thing. But nevertheless it was the degree of association, it was the degree of the difference that really raises the eyebrows of the hazard ratio of around 0.5, I believe it was, suggesting that the patients who were on corticosteroids were twice as likely to die than those who were not. So the hypothesis that comes out of this, and this is really only hypothesis generating is that perhaps in a selected group of patients corticosteroid use may not only have little in the way of anti-tumour efficacy but it may actually have some tumour stimulation potential. That has been shown pre-clinically that corticosteroids can actually be agonists of the androgen receptor. This requires much more study and I don’t think it’s something that we should use to colour our management at this point for individual patients. Finally, one of the obvious issues that is brought up here is the comparison between enzalutamide and abiraterone and the question of whether or not the corticosteroids in the abiraterone treated patient are maybe causing harm. There’s no evidence to support that, in fact in the 302 study the corticosteroid alone arm had a PSA response proportion of 24% and an overall survival that was better than in any phase III study that had been presented previously. So we really don’t have any high level evidence that corticosteroids harm patients in the abiraterone setting and you can’t say that without underscoring the fact that the corticosteroids in the abiraterone treated patients mediate a more safe drug therapy in terms of preventing the mineralocorticoid side effects and the hypokalemia that can occur during corticosteroid use. So it’s really far too early for us to be making any changes in management based on those analyses.

CP:            And I guess even if the story was true, though corticosteroids can accelerate prostate cancer progression, it doesn’t mean you shouldn’t use corticosteroids, it just means to say that you should be careful when you stop them.

CR:            I think that’s a very good observation and I think that it would… remember, mitoxandrone goes with prednisone, docetaxel, cabazitaxel and abiraterone. So we’ve really accelerated the survival of men with prostate cancer on the backbone of corticosteroids. So it’s going to take more than one retrospective observation for us to undo all of that.

CP:            And the other point I like to emphasise is that we mustn’t tar all corticosteroids with the same brush because I’m convinced, and I think there’s data to support it, that dexamethasone is more active than prednisolone. So when we have patients who are progressing biochemically on abiraterone and prednisolone, we switch them to abiraterone and dexamethasone and we frequently see responses.

CR:            Right. Well, it’s a very interesting observation. We do similar things; the steroid and prostate cancer link, there’s a lot more there than we know. I think that one of the key aspects is the fact that corticosteroids will alter the hypothalamic pituitary adrenal axis to the point where it may alter androgen secretion. In addition, the corticosteroids obviously may have some agonist or antagonist activity on various steroid receptors. Finally, the steroid receptors themselves are modifiable, many times they’re mutated and there are other even non-androgen steroid receptors that are at play in prostate cancer. Bottom line, from this perspective this is a very good argument for us to be interrogating the tumours that we’re treating by doing biopsies of metastatic lesions and doing the best science possible on those actual biological specimens because really these observations tell us we don’t know the biology of the disease that we’re treating as well as we think we do.

CP:            Let’s discuss that another day, shall we. Thank you very much for your time.