(4/6) ASCO 2017: Expert discussion on the latest in prostate cancer

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Published: 12 Jun 2017
Views: 1681
Dr Neal Shore, Prof Karim Fizazi, Prof Kurt Miller and Prof Nicholas James

Section 4 - Discussion 

Dr Neal Shore (Carolina Urologic Research Center, South Carolina, USA) chairs a discussion with Prof Karim Fizazi (Department of Cancer Medicine, Institut Gustave Roussey, France), Prof Kurt Miller (Benjamin Franklin Medical Centre, Berlin, Germany) and Prof Nicholas James (Institute of Cancer and Genomic Sciences, Queen Elizabeth Hospital, Birmingham, UK).

Reflecting on the latest prostate cancer data presented at ASCO 2017, the panel covers:

-The current challenges today in prostate cancer

-Highlights from research presented at the 2017 ASCO Annual Meeting including STAMPEDE and LATITUDE

-What does the latest research mean for the immediate management of prostate cancer?

-Questions from the audience

To find out more watch section 5 here.

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

Dr Neal Shore - Carolina Urologic Research Center, South Carolina, USA
Prof Karim Fizazi - Department of Cancer Medicine, Institut Gustave Roussey, France
Prof Kurt Miller - Benjamin Franklin Medical Centre, Berlin, Germany
Prof Nicholas James - Institute of Cancer and Genomic Sciences, Queen Elizabeth Hospital, Birmingham, UK

NS: Congratulations Nick, to you as well, phenomenal work. My response would be ‘Wow’ to both but I want to… Kurt, you’ve been involved in so many trials and you’ve seen so many things during your career and still actively doing so many great research projects and seeing patients. What do you think of this data?

KM: Yes, it’s still, as you say, at a considerable wow factor. It’s in the uppermost percentile because that is really, in terms of consistency and in terms of the dataset, it’s really unique I would say. For me there’s no question that it will be practice changing and Nick just opened Pandora’s Box in a way, I would say where’s the limit exactly? I wouldn’t discuss de novo metastatic disease, that’s pretty clear, but then again STAMPEDE has also M0 patients, patients with lymph node metastases, so where exactly do we stop with that and that will be the questions of the future, I would think. For me, in metastatic disease I think that’s going to be the future standard.

NS: Let me get back to you again, Kurt, on this. How will this change your practice tomorrow when you get back from Chicago and you see patients? You’ve been a believer and an adapter to the chemo-hormonal approach, what are you going to do now?

KM: We’re going to send up a letter because it’s not approved yet. We’re going to send up a letter for the insurance companies to try to get this financed because it will take about six months until approval is through the process and until that time most probably patients will ask for it. News is around very, very quickly so I think that’s the first practical step. We discussed this yesterday among German urologists and to get the patient to this treatment we would need to convince insurance companies. There is some financial toxicity in comparison with chemo-hormone therapy so that’s the only hurdle I would think.

NS: We are going to have a polling question and we’ll take the financial toxicity off the plate. I think it’s really important that the audience heard the data, the safety, the tolerability. When abiraterone acetate was first approved, as well as the androgen receptor signalling inhibitors enzalutamide and the newer ones that are out there, it was in the advanced CRPC setting, post-chemo then pre-chemo. I think many people thought at the time we can’t give these in the androgen sensitive state, there will be too much long-term toxicity. I’ll start with you, Karim, and, Nick, I would like you to weigh in too. Were either of you surprised with the incredible stability of in the safety adverse event profile? It's quite amazing for the duration of patients being on drug for so long.

KF: I guess you’re very right. Actually I had the same fear some years ago when we moved from [?? ] 1 to [?? ] 2, which was basically the post-PIVOT, post-docetaxel phase III trial when we know we were not using abiraterone for a long time to the pre-docetaxel setting where some patients who had received abiraterone for years and years. Actually I was quite reassured when I saw that even with long exposure to abiraterone prednisone there was no real increase in the toxicity burden. Actually it’s pretty much the same thing here, in order to trials in castration sensitive disease. Having said that we need still to be cautious - these patients need to be monitored very closely in terms of hypertension and kalaemia and also their liver test needs to be monitored. For specific patients who are at risk for cardiovascular issues we need also probably to take our time, refer the patients to the cardiologist, make sure we can really handle the cardiac problems as best as we can before considering the drug. But generally speaking this drug is quite well tolerated.

NS: A great comment regarding our patients who start off with ADT and/or now abiraterone, those who have baseline cardiovascular morbidities we have to be more careful with them and so on

KF: I think so, yes. Actually we have a little time because in the trials the patients had the possibility to start with castration alone and then be randomised after a month or two. So this probably gives you a nice opportunity to discuss with the cardiologist in these specific cases.

NS: Nick, similarly a question to you regarding the AE safety profile and then a little addition to it. You used prednisolone 5mg daily, Karim in LATITUDE you used the same, so is that now your recommendation in the CRPC population too? What are our learnings from that?

NJ: To be honest I don’t know. The toxicity and safety profile is fine with 5mg, there is some concern because of the half-life of prednisolone that you’re only suppressing the ACTH feedback loop half of the time. That didn’t seem to matter very much and the differences are subtle, to be honest. Overall the toxicity, I entirely agree with Karim, was very manageable. We were concerned about long-term dosing so in the M0 patients we had capped the treatments at two years and actually capped the ADT at two years as well because we didn’t want to keep on dosing people, a lot of whom do extremely well, just to come back to Kurt’s point of how far to the left down the spectrum do you go. But basically it’s a very well tolerated treatment.

NS: Kurt, what do you think about that for urologists? Medical oncologists are extremely comfortable with steroid variation of preparation medications, maybe urologists in the beginning when abiraterone acetate first came out the notion of giving even low dose prednisone was a little bit of a new learning period, there was some concern and worry. Does this data resonate for you as well?

KM: As Nick said, I’m not sure if it really makes a difference in terms of 5mg or 10mg because with the 10mg you didn’t see much toxicity from the prednisone either. But in terms of urologists I would say after a couple of years getting used to prescribing prednisone in the meantime this is not an issue anymore. It will not be a hurdle for this type of therapy.

NS: We’re getting questions from the audience, here’s one for you gentlemen. Will this data impact patients who have just begun taking docetaxel as up front therapy based upon CHAARTED and STAMPEDE, the chemo-hormonal, assuming on appropriate inclusion criteria? Should they cross over from ADT and docetaxel to ADT and abiraterone acetate? Similar would be should they add abiraterone acetate? So two highly charged questions within that.

KM: May I take that one?

NS: Please.

KM: Okay. I don’t think a patient who has started already docetaxel and who has tolerated that well should discontinue. The benefit of docetaxel on overall survival and PFS is quite well established so if the patient is doing okay in terms of safety I would probably recommend him just to continue and complete the six cycles. Now, whether abiraterone should be added on top of that we just don’t know at the moment. We are actually randomising the question right now in Europe in the PEACE1 phase III trials where patients are actually receiving ADT and docetaxel as a standard of care and randomising the role of abiraterone and also that of local treatment with radiation therapy. So hopefully we will be able to complete the accrual in a year from now or even perhaps less than that but for now we really don’t have the answer. When we asked the question yesterday at ASCO to the attendees it was quite split in the audience as to whether people would be keen to combine already right now or wait for the data to mature and see whether we should do it or not.

NS: Nick, what do you think about Karim’s comments but then also a nuance to that question, there’s combining but then what do you do if you’ve just completed your six cycles of docetaxel to the androgen sensitive metastatic patient? Do you then at some point add abiraterone?

NJ: I’d have to agree with Karim, it’s tempting to infer that you might get the dual benefit and we know that you can give docetaxel and abiraterone and abiraterone is active post-docetaxel because we’ve got very solid CRPC experience with that. I would have to say you really need trial data because it will be a financial cost, as Kurt has pointed out. The other thing I would re-echo is within STAMPEDE the docetaxel and the abiraterone arms were recruiting for an overlapping period of time so we have about 600 men who, if you like, are randomised between docetaxel or abiraterone. So we’re going to run that comparison formally and present that, subject to it being accepted, at ESMO in the autumn. We’ve submitted a late breaking abstract place marker. But our take is that it looks, as Eric Small pointed this out in the discussion yesterday, that the CHAARTED survival advantage and the LATITUDE survival advantage in the same population look to be very similar. So I don’t think patients are missing out on survival gain by not having had abiraterone, given that they can have docetaxel. That is part of the answer as to what we’ll be saying in clinic this week when we go back is that actually you can have a treatment that will give you just as much benefit but with different toxicity, obviously.

NS: Kurt, here’s a question that’s saying, ‘In the future, going forward, I’ve been on abiraterone acetate and prednisone and ADT for my androgen sensitive metastatic disease,’ and now the patient has converted to CRPC. No new bone lesions but multiple bone lesions. What is your recommendation?

KM: Obviously this does not only change the way we treat hormone sensitive disease it will also change the way we treat castration resistant disease because so far I would say 80-90% of patients, at least in my country, have got either abiraterone or enzalutamide as first line therapy in CRPC. Now it obviously doesn’t make sense to give them abiraterone which they already had and it probably doesn’t make sense to give them enzalutamide with a potential 25% response rate for five months at best. So, yes, it will change the way we treat CRPC and probably docetaxel will now, again, move to first line CRPC treatment in these patients because that’s probably the best next step once you are under progression getting RB and ADT.

NS: Another question, both the LATITUDE and the STAMPEDE demonstrated highly statistically significant delays in SRE. By the way, both of your datasets had lots of zeros in those p-values, it was pretty darn impressive. Can you tell us about the use of antiresorptives in the trial? Do you have that information – zoledronic acid, denosumab?

NJ: In the up-front therapy previously in STAMPEDE we had shown pretty conclusively that up-front zoledronic acid added no benefit at all. Getting patients ONJ didn’t have an impact on bony outcomes or survival so we don’t think we have any antiresorptive therapy prior to relapse. There may be some post-relapse, it’s hard for us to capture that data but certainly pre-relapse there will have been no use, I don’t think, in the STAMPEDE population.


KF: Yes, pretty much the same. The role of denosumab and zoledronic acid is already established in castration resistant disease so some patients received it in LATITUDE for castration sensitive disease with basically no data but it’s really a minority.

NS: Here’s a question about the cost of therapy and, Nick, you mentioned the economic utility. I’m sure you must have both in your datasets more health related quality of life outcome data to talk about. So as we move to this, throughout the world, value-based care can you comment on this issue of cost versus quality of life, toxicity and making a decision between taxane based therapy and an oral androgen biosynthesis inhibitor?

NJ: We’ve just analysed our quality of life data from the docetaxel but we haven’t published it yet; the paper is in preparation. The striking thing about that is that quality of life goes up if you have docetaxel, not down, overall. You obviously have a dip while you’re having it but once you’ve had it there is a QALI, quality adjusted life year, gain in the docetaxel arms, M0 and M1, compared to the control arms in our earlier data. When we looked at the health economics of that it turned out that up front docetaxel was cost effective, in fact it was cost saving in the M0 setting and very low cost in the metastatic setting. The thing that drove that was the reduction in SREs because SREs are expensive and really hit your quality of life. So preventing a lot of SREs is very cost effective. So although there is a cost to abiraterone we’ve seen bigger effects on time to relapse and SREs than we saw with docetaxel although it factors down to the same survival effect probably. So it probably will turn out to be cost effective. Crudely you have 18 months of abiraterone in the castrate refractory setting to give you maybe six months extra survival and that was cost effective. So in STAMPEDE we doubled that to 36 months, give or take, but we probably are bolting about three years survival on. So you’ve got 18 months extra buying you an extra several years. So it probably will come in under the cost effectiveness radar threshold.


NS: Karim?

KF: Yes, I guess the analysis will be formally conducted so we need to wait for that. But I quite agree with Nick, it’s really by lancing the cost with what you’re saving on the other hand. Also, at least in Europe, the cost of abiraterone really depends how many patients are receiving it, so it’s decreasing if you’re using it in more men. So we need the data and that’s very important. All the societies just can’t afford all the new drugs coming for cancer so that’s really key. Again, given the large efficacy benefit, the good toxicity and the fact that it’s very easy to give this drug, no IV etc. etc., I think the data will be reassuring.

NS: Excellent. We have a polling question for the audience. You’ve heard the synopses of these wonderful presentations and some discussion. Based on the data that we just reviewed, how would you now look to treat a newly diagnosed prostate cancer patient approximately aged 65 with presumed multiple positive bone metastatic lesions on bone scan? He’s got evidence of visceral metastatic disease, perhaps two small liver lesions, an ECOG performance status of zero. So your answer options are ADT only; abiraterone acetate and prednisone plus ADT, your choice of ADT, it doesn’t matter; ADT plus docetaxel six cycles or ADT plus docetaxel six cycles plus abiraterone and prednisone. Please assume that whatever country you are working and living in that there is no regulatory or funding or clinical trial restrictions, so you have access to all therapies.

While the audience is going through that, Kurt, what are your thoughts regarding the role for some of the other androgen receptor signalling inhibitors out there? Are you aware of any trials or data in this same population that could be compelling your interest in the near term?

KM: Obviously, and we just saw that with the poll, one of the questions popping up now is should we also combine docetaxel and abiraterone or other androgen directed compounds. Yes, there are trials underway like for combining ODM201 and docetaxel plus ADT versus docetaxel plus ADT and the like. That’s got to be the next question, obviously, is it okay to have a triplet or is it okay with the combination of ADT and ABI or docetaxel.