ASCO 2018: Latest developments in non-metastatic and metastatic castration-resistant prostate cancer

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Published: 3 Jun 2018
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Dr Neal Shore, Dr Simon Chowdhury, Prof Matthew Smith and Prof Boris Hadaschik

Dr Neal Shore is joined by Dr Simon Chowdhury, Prof Matthew Smith and Prof Boris Hadaschik at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

The discussion opens with comments on the day's poster sessions here at ASCO 2018, including genomic profiling of tumours from mCRPC patients, which gives promising findings.

Following this there is a discussion about the P3 SPARTAN trial, investigating Association of metastasis-free survival (MFS) and overall survival (OS) in nonmetastatic castration-resistant prostate cancer (nmCRPC), led by Prof Smith.

Prof Hadaschik comments on the Phase 2 randomised cross-over trial of abiraterone prednisone (ABI P) vs enzalutamide (ENZ) which give 2nd line therapy results. He believes the results point towards no large difference between the drugs, and at this point in time it should be down do a discussion with the clinician and patient. The panel discuss this further in the context of their own work.

Dr Chowdhury comments on the Phase II randomised trial; Olaparib combined with abiraterone in patients with mCRPC, and describes why he believes some of the results were unexpected, and also discusses some of the toxicities.

This leads on to Cora Sternberg's randomised phase 2 study investigating 3 dosing regimens of radium-223 dichloride (Ra-223) in bone metastatic castration-resistant prostate cancer (mCRPC) with comments from Prof Smith particularly highlighting the changes in toxicity as the dose increased.

The discussion ends with a roundup of the Australian study with Lutetium and PSMA Gallium, Prof Hadaschik gives a detailed overview and opinion.


Genomic profiling in mCRPC
SPARTAN trial and metastatic free survival
Abiraterone and prednisone vs enzalutamide 
PARP inhibitors for prostate cancer
Dosing of radium-233
Lutetium-177 PSMA testing

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

Dr Neal Shore – Caroline Urologic Research Center, South Carolina, USA
Dr Simon Chowdhury – Guys’ Hospital, London, UK
Prof Matthew Smith – Massachusetts General Hospital Cancer Center, Boston, USA
Prof Boris Hadaschik – Essen University Hospital, Essen, Germany

NS: Hello, and welcome to It’s the 2018 ASCO. My name is Neal Shore, I’m the Medical Director of Carolina Urologic Research Center in South Carolina. I’m really thrilled and honoured to have three wonderful colleagues here today to go over some really cutting edge aspects of the abstracts that are being presented. Immediately to my left is Simon Chowdhury from London, England, and then we have Matthew Smith from Boston in the US and Boris Hadaschik from Essen, Germany. So I apologise to my medical oncology colleagues - you’re bookended by urologists. There’s something not right about that at ASCO but in a way it is true – we’re really trying to develop more integrative care globally and multidisciplinary care. So we’re going to talk today about some of the advances and really interesting abstracts in advanced prostate cancer. So I’ll start with you, Simon, maybe you’d like to comment on this paper by Joaquin Mateo, who you’ve worked with extensively, on genomic profiling of prostate tumours from patients who develop metastatic castration resistant prostate cancer, a field that has really just exploded in so many different ways. Maybe you want to comment on that.

SC: Thank you, Neal. Yes, I think a really important abstract and one from the Institute of Cancer Research not far from where I work in London. What they looked at was clinically significant prostate cancer, so primary cancers that have become metastatic castrate refractory. They had 470 primary samples from the original patients which they profiled and they had 48 samples from that group who had developed metastatic disease. So paired metastatic castrate refractory biopsies. The take home message, really, was that what was very interesting was that there was a high frequency of DNA damage repair deficiency which we’re starting to see and has relevance in terms of the new drugs emerging, particularly the PARP inhibitor studies that are taking place. And they saw about 20% of the abnormality there – 5% BRCA, 4% ATM – so some really relevant gene abnormalities. What was interesting was looking at the patients who had the subsequent biopsies that have evolved over time and under selection pressure with treatment that those abnormalities seemed to be persistent, they hadn’t changed, those particular DNA damage repair ones. So it seems as if we can use the primaries to then drive treatment later. I think we should be doing re-biopsies but I thought that was very promising and provides an approach for some element of moving away from treatments for everyone.

NS: Gentlemen, thoughts on somatic mutations as opposed to germline mutations and advice for our colleagues?

BH: I think it’s reassuring that for men that are at very high risk in the beginning of their disease we might be able to predict who to take extra care of and who to maybe watch more closely. So I was happy to see that abstract as well because it seems to allow us to focus on a very high risk group just from the start where we, as urologists take care of the patients. This might be an opportunity for future clinical trials in that setting.
NS: And the implications of therapies along the disease continuum, not to mention the potential for downstream implications for family members. So, Matthew, let me ask you, given your leadership in the SPARTAN trial, and congratulations on a wonderful global phase III trial, your New England Journal article and your presentations. Here at ASCO you’re reviewing the association, and it’s an endpoint that has met a regulatory approval and it’s a new endpoint for many of our colleagues to understand, that’s metastasis free survival. You have an abstract here on the association of MFS and OS in non-metastatic CRPC patients. Tell us about that.

MS: So SPARTAN is a global randomised controlled trial that supported the approval of apalutamide in non-metastatic CRPC. And it was precedent setting and it was the first approval in oncology based on metastasis free survival. There is evidence from that trial of post-progression benefit – there’s a delay in symptomatic progression, for example – but, as you’d imagine, survival is going to be a later outcome and at the time of the primary analysis we don’t have mature survival data. So while we await that information we decided to have a critical look at the relationship between MFS and overall survival. We did that with landmark analyses and found a strong correlation between MFS and overall survival, depending on which method of analysis correlation coefficients of 0.63-0.69 suggesting that we explain about half of the variability of survival with metastasis free survival. So that can be considered quite robust and provides further support for it as a valid intermediate endpoint.

NS: Boris, Simon, any thoughts on this really landmark study? The first now approved agent of any type in this disease category of nmCRPC, or what some have called M0 CRPC, and now we have an approved therapeutic.

SC: Yes, I think it’s a really important study, one I was involved with to a small degree and Matthew should be applauded for having designed it right from the start. I think also this metastasis free survival is something that is going to be really important, not only for this drug but for other drugs going forward and it’s great that Matthew has done this work that shows the robustness of the data and it is a good surrogate for overall survival. I think it will be important going forward for several drugs.

NS: I think you’re absolutely right and even potentially earlier disease states, perhaps even in the biochemical relapse disease population, some of the trials that are entering and are almost on completion. So let me ask you, Boris, I think that we talked about this really interesting trial, it’s a phase II study, the first author is Khalaf. They looked at a crossover trial design of abiraterone and prednisone versus enzalutamide and came up with their recommendations and a second line therapy. There has always been a fair amount of recent controversy in small single institution, mostly retrospective, sequencing studies. What are some of the findings in this trial?

BH: Many of us have waited for the poster that now describes the more mature results of that sequencing study from Vancouver because the first part of the study was presented last year and it showed us that abiraterone maybe had little less side effects for the patient than enzalutamide. What we are seeing now is that from a perspective of response to second line therapy the sequence of abiraterone followed by enzalutamide might be beneficial, so you see more responses if you follow with enzalutamide post abiraterone. However, what is more important to me and what made me feel reassured with regards to current clinical practice is that now on the poster they also present overall data where they show how is progression free survival too. So from the time of the start of the first therapy to progression during the second therapy are there differences depending on with which drug the patient was started? There were no clinically significant differences in this 200 patient trial. So in the end it’s up to the individual discussion with the patient with which drug you want to start. The big difference is not there if you consider just the two drugs, whether we should have some other partners in-between, considering chemotherapy and all this, is something other important. But when you just look at abiraterone and enzalutamide the sequence does not seem that important but certainly we’re waiting now about the combination studies. It’s an exciting field and in this study it was important to see that when you look at the overall patient there was no difference in the overall survival.

NS: Yes, I applaud them for doing that study. I still think, though, and I’m curious, gentlemen, your thoughts on this notion of the novel hormonal agents and sequencing when we see progression, whether it’s more than just PSA progression or PSA elevation but there’s new radiographic findings and/or clinical progression. Any quick comments regarding the use of taxane therapy or radiopharmaceutical? Let’s leave clinical trials out of it, because that’s always a nice way to go and a good way to go. But thoughts, Simon first and then Matthew.

SC: Yes, I think that very much reflects my own practice. I wouldn’t go from abiraterone to enzalutamide or enzalutamide to abiraterone, as Boris alluded to, without a break. It depends on the patient mix, I’m probably moving more towards using radium in people who are bone only disease, just because you worry about people progressing and not being able to access it if they develop visceral or significant lymph node disease. So that’s probably the way that I’m going but I think chemotherapy is important and still has a big role to play.

MS: I wholeheartedly agree. Based on this data and other data there’s very limited benefit to the second AR targeted therapy. So with few exceptions I would typically give chemotherapy or another agent.
NS: Right, so back to you Simon. This was a really fascinating presentation by Noel Clarke as first author. This was using olaparib, a PARP inhibitor, combined with abiraterone in patients with mCRPC and this was a randomised phase II trial.

SC: Yes, a really interesting study and probably, for me, a slightly unexpected result. So a study of around about 170 patients, as you say randomised to abiraterone plus or minus olaparib, one of the PARP inhibitors which has shown some activity in a limited group of patients from Johann de Bono’s TOPARP study which showed activity in people primarily with DNA damage repair deficiency. What’s interesting about this study is they didn’t select on that alone, they gave it to all comers and there was a significant benefit across all comers - RPFS of 13 versus 8 months. One of the limitations of the study and it shows how the field has moved, this was a 2014-2015 study, was that they didn’t have the genomic signature on all of these patients, they only had it on about 20-25 patients and they were actually matched between the two arms. But when you looked at the whole group, the group with the genomic abnormalities, the group that were known to be wild-type and the unknown, that benefit was across all four of those groups which is interesting. That’s now going to be taken into a phase III study and that’s the way forward, hopefully with more genomic data to come from it. But very interesting if the preclinical work that shows receptor cooperation between AR and some of the DNA repair pathways actually leads to a broadening of activity. I suppose that’s what we all want to see with abiraterone.

NS: Yes, it’s sort of unexpected, especially in the groups that don’t have the DNA repair mechanism defects. But what about the toxicity of the combined therapy?

SC: Yes, there was more toxicity, there was 30% versus 10% serious adverse events and some of those were cardiovascular. Some of that may be length of exposure and I know in the phase III they’re going to mandate more cardiac monitoring and probably some of the cardiac inclusion/exclusion criteria. So, the anaemia and things like that is not surprising with a PARP inhibitor but clearly going in to the phase III they’re going to have to take a lot of attention with the cardiac side of things.

NS: I’ve certainly seen that in the trials that I’ve been doing with the PARPs, there clearly is a myelosuppressive effect and having used multiple different PARPs it seems to be clearly a class effect. Matthew, let me ask you about a really interesting trial that was led by Cora Sternberg and goes back to this notion around sequencing but also do we have the best regimen for adverse events and toxicity in the context of outcome. So do you want to comment about her trial looking at radium different dosing schedules?

MS: So based on the ALSYMPCA data radium-223 was approved and it was approved for up to six cycles of therapy at a fixed dose. This randomised phase II study compared that standard dosing schedule to two different regimens – either up to six doses at a higher dosing regimen or standard dose but up to twelve cycles of treatment, or twelve months of treatment. It’s an important observation in that there was no apparent clinical benefit to either increasing the dose or extending the schedule, with very similar event free survival and overall survival between the groups but there was a greater toxicity for both of the investigational arms. So this pretty clearly provides evidence that the drug should not be given at a higher dose or at a more extended schedule in any routine manner.

NS: Oliver Sartor had done a prior trial, small numbers but basically demonstrating an interrupted use… not interrupted but six cycles, the full course, the approved course, then patients going on to other therapy, I think the majority were taxane based, and then coming back and getting another course of radium with a little bit more but not much more in the way of toxicity. So that’s interesting to put that into the context of that trial.

MS: I think you’re exactly right. So that was addressing a different question and in the experience that you describe from Oliver Sartor there’s a survivor bias. So they were selecting patients who had done particularly well with their previous treatment and then retreating them. So the abstract by Cora Sternberg couldn’t formally address that issue so I don’t think that approach is ruled out but should be used with great caution, based on the evidence we now have.

NS: Sticking with the theme of radiopharmaceuticals and novel new therapies, Boris, can you talk about the Australian study, this phase II study, with lutetium and PSMA gallium?

BH: This study is one of the highlights, from my perspective, of the poster session because it provides us with more solid data, it’s an official phase II study, where leutitium-177 PSMA radioligands were tested in a phase II setting. There has been a publication in Lancet Oncology with 30 patients, now they report 50 patients. Those patients have been heavily pre-treated and we see remarkable PSA responses in more than half of the patients – PSA reductions of more than 50%. I’m very happy to see that because the better imaging story is transforming the field because we learn, similar to the genomics, we learn just to characterise our patients better. If we can transform that knowledge to therapy that’s wonderful. With the radioligand therapy, up until the Australian study we just had studies from Germany where we observed patients because there were some regulatory issues and now we have a formal phase II study and their phase III study is coming on. For the next years I am looking forward so that we learn how to define the space where we best use the PSMA radioligand therapy because there it provides ample opportunities of combinations and then looking at DNA repair defects, whether we might have predominantly responses in those patients with a radioligand therapy. So it’s exciting because it’s a new therapy and finally we have solid clinical data that really show a good response in these pre-treated men.

NS: Yes, it’s a great point. Here we are, first the longest period of time we’ve been feasting on the androgen-androgen receptor pathway, rightfully so. But now we’ve talked about new targeted therapies and radiopharmaceuticals, diagnostic but now theragonostic. Then other novel targets – PARP inhibitors. We didn’t really get a chance to touch too much on the checkpoint inhibitors but there’s so much going on right now and there’s so much of that here at ASCO. Before we close let me just… any closing comments, gentlemen? Maybe start with you Simon.

SC: A good ASCO, nothing earth-shattering but some things that added nicely to the field, particularly as we move towards more precision personalised medicine. The abstracts that we’ve highlighted should hopefully bring that through.

MS: I agree, I think it’s an exciting time in the field. There’s continued additional evidence about the role of precision oncology in prostate cancer which is relatively new to our field. So we look forward to more of the same.

BH: Yes, I certainly agree with both Simon and Matthew. It is excellent that we are now learning more about the basis of the disease and the characters of our patients more so that we can individualise treatment more. That’s a benefit for future clinical trials because we can define subgroups where we’re using maybe earlier endpoints, have earlier results to even take better care of our patients in the short-term.

NS: Gentlemen, thank you very much for your time, I know you’re really in demand. And thank you for your leadership in advanced prostate cancer care. Thank you for the research that you’re doing. It’s been great to have a wonderful panel of experts here and thanks for listening to and all the best to everyone.