ASCO 2015
ASCO 2015: Latest developments in prostate cancer treatment
Prof Cora Sternberg – San Camillo and Forlanini Hospitals, Rome, Italy
Prof Noel Clarke – The Christie Hospital, Manchester, UK
Prof Eleni Efstathiou – MD Anderson Cancer Center, Houston, USA
Prof Karim Fizazi - Institut Gustave Roussy, Paris, France
CS: Hello, my name is Cora Sternberg and I’m here with ecancer.tv at the 51st Annual Meeting of the American Society of Clinical Oncology which is being held in Chicago. I’d like to welcome my esteemed colleagues, Karim Fizazi, Noel Clarke and Eleni Efstathiou. We heard some very interesting presentations this morning about prostate cancer and we’d like to discuss them with you. I think I’ll start off with the STAMPEDE trial; there has been a lot of interest about the STAMPEDE trial. This is an English trial in which they had a very innovative trial design. The trial ultimately has some ten different arms and they keep changing the arms as we are changing our way of thinking and the way we’re treating prostate cancer. What was presented today was patients with hormone naïve disease who were treated with zoledronic acid and LHRH analogue, or were treated with docetaxel chemotherapy and LHRH analogue, or the combination, as compared to LHRH analogue. What they found was an amazing improvement in overall survival for those patients who received docetaxel chemotherapy with LHRH analogue. The zoledronic acid arm didn’t seem to add much to the results. There was a 22 month improvement in overall survival for patients, particularly patients with newly presenting M1 disease. I’d like to hear your thoughts about that, Karim, maybe you could try to put this into context with the GETUG trial and the CHAARTED trial that we heard about last year, at last year’s ASCO?
KF: Thank you Cora. I guess I absolutely agree with you, we now have three trials all pointing to the same direction for M1 disease, specifically de novo metastatic disease. The design of the three trials, or at least this part of STAMPEDE, were really the same: ADT versus ADT plus docetaxel up front for these patients. In the three trials, GETUG-15 CHAARTED and STAMPEDE, progression free survival was met and overall survival tended to the same direction with significance being met in both STAMPEDE and CHAARTED, and actually the difference is quite big an interval. The same trend was found in the French trial, not significant but really the French trial was smaller, we have to recognise that. To me today this is STAMPEDE showing that we should change the way we treat these patients and really my next patients with M1 disease will be proposed docetaxel as far as we’re talking about fit patients and, of course, patients who would accept chemotherapy.
CS: So you would propose this for all patients or would you use the CHAARTED definition of those patients with more high risk or volume disease having visceral metastases, lung or liver, or having more than four bone metastases outside of the axial skeleton? You would propose this for all M1 patients?
KF: Right, probably at least all patients with bony metastases and/or visceral metastases. Lymph node disease is perhaps a little different. This is because in the CHAARTED trial the magnitude of the benefit, as measured by the hazard ratio, was pretty much the same in what they called low volume or high volume. Now, of course, because high volume patients are much more likely to die soon the median were reached much more rapidly and the curves show better on the screen. Also they had a much lower proportion of patients with low volume disease and this is probably why in that particular subgroup the p-value doesn’t look significant but probably the hazard ratio is the same. Biologically speaking, we have no real reason to believe that chemotherapy would work differently in patients with two metastases versus four or five metastases. And again STAMPEDE reported data for all M1 patients, not according to a measurement of the volume of metastases. So I guess the data should apply to all metastatic patients.
CS: Eleni, what are you going to do? Are you going to change your practice based on these trials?
EE: I’m definitely changing the practice with regard to the high volume disease. However, from a more conceptual perspective I’m taking issue with the fact that in my mind we’re still assuming a unidimensional approach whether we’re dealing with phase III trials of novel agents or chemotherapy. We’re in 2015 and, as we were discussing during the session, we’re making around the same objective. Instead of identifying the heterogeneity of these patients at the biological level and identifying which would be the ideal treatment, we’re still having to decide one or the other based on these types of trials and we need to change that paradigm is my concern and I would like to hear more.
CS: I agree with you. Many of these are old trials; the STAMPEDE is not an old trial but the SWOG trial was an old trial that went on for a long time and I think we are definitely changing our paradigm. The other trial, Karim, discussed by Howard Sandler, was with using early chemotherapy with radiation. Do you want to mention something about that?
KF: Sure. That’s also a very interesting concept because in most cancers where chemotherapy is active we’re using chemotherapy adjuvantly together with any local treatment, either surgery or radiation therapy. That’s true for breast, for colorectal, for even lung cancer and others, but not prostate cancer though chemotherapy, obviously, is active in this disease. So approximately ten years ago a series of randomised trials started asking the question as to whether we should integrate docetaxel chemotherapy in the earlier stages for patients with high risk localised disease. We now have data from three of these trials, and that’s very recent, in the last three days basically. We have GETUG-12 which actually met its primary endpoint of relapse free survival and this is just published two days ago. This was again the primary endpoint. Overall survival is too early, even with an eight or nine year median follow-up we need more time to see overall survival because many of these patients are still alive. We have also STAMPEDE which has a category of patients with localised disease who were indirectly randomised to receive chemotherapy or not, the same thing: relapse free survival is met, overall survival is premature because most of these gentlemen are still alive. Now we have the RTOG 12 which was reported this morning by Howard Sandler. This trial was looking at overall survival as its primary endpoint and I believe it was reported perhaps a bit too early because they looked at five year overall survival. What they reported was a 93% versus an 89% rate for overall survival, so it’s a 4% difference. It looks significant but really they used a one-sided p-value which is not necessarily correct in such a large phase III trial. So I guess to me this is a good sign. The three trials definitely point to the same direction, that chemotherapy can probably prevent relapse or defer relapse. Now, whether we should integrate it in daily practice, my personal answer for today is no. This is still experimental at the moment, we need a longer follow-up.
CS: It’s still too early. It’s funny because we’ve been for the last few years talking about all these novel agents and how we wanted to just delay chemotherapy and push chemotherapy only in castrate resistant prostate cancer patients. Now we’re really talking about giving chemotherapy early to patients who have not even had hormonal therapy. So our paradigm is changing and changing all the time. Noel, there were two presentations this morning about early hormonal therapy and giving hormonal therapy in patients with localised disease. Do you want to say something about those trials?
NC: Yes, I’ll start with the TOAD trial which is a New Zealand and Australian study run by the Trans-Tasman group. This is the latest in a series of studies which has addressed the question of early versus delayed hormone therapy. For those who know the history of these trials, there are a number over the years which have addressed this question but never really recruited the number of patients that they needed to recruit. So, for example, the MRC study did a trial of early versus delayed hormone therapy in patients with M0 disease; there are two EORTC studies, one by Fritz Schröder the other one published in the Journal of Clinical Oncology 2006 by Urs Studer. So, to give you an example of that, the Studer trial which was looking at then clinical T3/T4 N0/M0 patients randomised to early versus delayed androgen deprivation, what that showed was that there was little difference for the majority of patients and about 43-45% of the patients on the delayed androgen deprivation therapy arm didn’t actually need any androgen deprivation therapy at all because they died from other causes. But, again, that was somewhat under-numbered, an old trial. Now, the TOAD trial was looking at this early versus delayed concept in a different setting and that was in patients who had undergone prior attempts at curative treatment, either with radiotherapy or surgery, and then had randomised the patients to receive early or delayed hormone therapy on relapse. This study was planned to recruit about 750 patients and it came in recruiting roughly about a third of its target population, so quite a way under-numbered. What it showed was that there was a small but significant difference in survival and progression for those patients who had continuous hormone deprivation at the point of relapse. But, of course, there was a higher complication rate or side effect rate in that particular group of patients. The other thing to say is that in those who had delayed therapy roughly about a third of those started androgens within a couple of years but, again in a manner commensurate with the Studer trial from 2006, about 40-45% actually didn’t need any androgen deprivation at all. So the conclusion overall from that study was that if a patient is to have androgen deprivation there are benefits to starting early but there are trade-offs and the trade-off is that the patient is on androgen deprivation for a longer period of time and they will have more side effects. The benefit, actually, is relatively small, about 10%, something of that order.
Now, in the other trial, the GETUG-16 trial was looking at the use of androgen supplementary to radiotherapy in patients who failed radical prostatectomy. There are a series of three large studies which have looked at the issue of radiotherapy following radical prostatectomy, one from the US, the South-Western Oncology Group study, an old study started in the ‘80s which has shown improvements both in progression free survival and in overall survival. The second large study, which is EORTC 22911, which is about a thousand or so patients, showed a progression free survival improvement but no improvement in overall survival, in fact it was slightly worse. Then there is the German study run by Thomas Wiegel, a radiotherapist from Ulm in Germany, which again has shown progression free survival improvements with radiotherapy but no data on overall survival. Now this French study, an extremely well conducted study, about 700 or so patients randomising equally to radiotherapy or radiotherapy plus six months of androgen deprivation therapy, has shown a clear benefit in terms of progression free survival.
There is another large study to follow this, which is the RADICALS study in the UK. Currently that has recruited about 2,800 patients which is addressing the issue of radiotherapy versus six months’ versus two years’ hormone therapy. So this is a body of evidence which is gathering, which is helping clinicians make the decision as to whether radiotherapy is needed, whether it should be given early and, if it should, whether it should be given with hormones. So I suppose one asks the question now where are we in relation to hormone therapy given with radiotherapy for radical prostatectomy failure? Progression free survival doesn’t translate into overall survival, we need to wait longer for that from the GETUG-16 study, but it is promising data and it does suggest that in addition to the radiotherapy effect the hormones are potentially going to give benefit.
CS: Thank you very much. Eleni, tell us about the presentation that you gave today about neoadjuvant therapy with abiraterone.
EE: I think that it follows what we were discussing earlier and I mentioned about the biologic heterogeneity of this disease but it also follows along the lines of what Noel was suggesting, that you need probably more than one modality to treat the disease that is at a very high risk of relapsing. So if we have a window, an opportunity, for a cure, even for a fraction of those patients we need to answer that unmet need that is there. Of course Noel, as a urologist, can tell us more about the new-found interest in prostatectomy in the high risk setting. So I think it’s the perfect timing to try to understand which of these novel agents, and of course the more standard agents like cytotoxics, would be of benefit not only as neoadjuvant but probably as adjuvant treatments. Again, I believe strongly and I think the data that we showed today support that it will be in subsets of these patients. So we need to reclassify and eventually move beyond the late Gleason, who implemented this Gleason scoring that was a blessing and turned out to also be a little bit of a curse because it has held up the molecular classification of this disease.
CS: So we need genomic molecular classification to understand better which patients would benefit perhaps from combination, from novel therapies.
EE: From combinatorial modalities. So what we did is we decided, because it’s not always the best or easiest way to access tissue by pre-treatment biopsies to randomise between a failed example across the board LHRH treatment preoperatively and LHRH plus abiraterone. That way you get prostatectomy samples that you can compare and come to some conclusion with regard to the abiraterone effect. The bottom line is that the standard approaches to pathology staging of the disease do not seem to meet the threshold for identification of the cytoreduction induced by the novel therapies and some more exploratory methodologies seem to be associating well with the rate of recurrence of that disease, meaning the tumour epithelium volume, the density of the cancer cells in the remaining volume of the tumour microenvironment. Then we went on to look at that molecular marker heterogeneity at both a protein and an RNA level. What seemed to be well- aligned, let’s focus on the abi group, is that AR-V7 presence does still associate, like in the castrate resistant setting, with a resistant to abi treatment disease. That may be very well so for enzalutamide as well.
CS: How often did you find AR-V7 presence in untreated patients?
EE: Not as often as in CRPC. Low level of expression and it’s about 30% of the specimens, so much lower, as you saw in that data than what is reported in CRPC. Then we went on to look at associations with the glucocorticoid receptor because it seemed to be popping up as a signal in all the abi treated. The higher expression of the glucocorticoid receptor trended very well with higher residual tumour volume and of course, in that sense, relapse. That higher glucocorticoid receptor volume was associated well with intraprostatic cortisol creating a story for the ligand and the receptor right there. Of course, a lot of questions coming through that need to be further studied because we only used 5mg of prednisone versus 10mg and maybe 10mg would have been a better option to stabilise the receptor because that cortisol that was measured was completely intraprostatic and separate from exogenous prednisone. Some answers but more questions being produced, I think, but a lot of interesting questions to be answered overall.
CS: I think we had a very interesting session and we have a lot of questions, not a lot of answers. I think we’re probably going to use chemotherapy earlier and we still have more questions about the earlier hormonal therapy and the earlier use of novel agents. So I’d like to thank all of you for being here today and thank you all from ecancer at the ASCO meeting in Chicago.
