Key developments in non-metastatic and metastatic hormone-sensitive prostate cancer

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Published: 4 Jun 2018
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Dr Eleni Efstathiou, Prof Nicholas Mottet, Dr Andrew Armstrong and Prof Maria De Santis

Dr Eleni Efstathiou, Professor Nicholas Mottet, Prof Maria De Santis and Dr Andrew Armstrong discuss the latest data from ASCO 2018 for patients with hormone sensitive prostate cancer.

The group discuss a series of phase II trials, predictive biomarkers and signpost emerging therapies from the congress.  The discussion begins with reference to a Scandinavian adjuvant study (SPCG-13). Which was a randomised phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy for intermediate and high risk prostate cancer. The group comments that the trial was negative and did not improve BDFS.

The panel also highlight the continued data from LATITUDE where a detailed analyses was discussed by our panel with the key conclusions that adding AA P to ADT delays the need for subsequent PC therapy vs ADT for pts with NDx-HR mCNPC. Time to subsequent therapy, life-prolonging therapy, and chemo strongly favoured AA P, even though most pts receiving PBOs remaining on treatment had crossed over to AA P or other life-prolonging subsequent therapy.

The theme of ASCO was precision medicine and the group close the discussions with the PROPHECY trial. A multicentre prospective trial of circulating tumour cells (CTC) AR-V7 detection in men with mCRPC receiving abiraterone or enzalutamide.

Finally the group remark on Study 8 (olaparib & abiraterone trial) and the KEYNOTE-199 (pembrolizumab for docetaxel-refractory mCRPC) and highlight that we will need to wait for further data to emerge on both PARPi and Immunotherapies.

 

SPCG-13 study of adjuvant docetaxel after radical radiotherapy
RTOG-0521 study of adjutant ADT in high risk prostate cancer
Treatment recommendations for high risk advanced disease
Long term followup from LATITUDE
Treatment choices for hormone naïve prostate cancer
Olaparib abiraterone acetate
Pembrolizumab efficacy in prostate cancer
PROPHECY study: predictive assays

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

 

Dr Eleni Efstathiou – MD Anderson Cancer Center, Houston, USA

Prof Nicholas Mottet – University Hospital of Saint-Etienne, St Etienne, France
Dr Andrew Armstrong – Duke University School of Medicine, Durham, USA
Prof Maria De Santis – Warwick Medical School Cancer Research, University of Warwick, UK


EE: Hello, I’m Eleni Efstathiou. I’m a medical oncologist from the MD Anderson Cancer Center in Houston, Texas and we’re here in Chicago.

We’re just wrapping up ASCO meeting and this discussion is going to focus on new data that has emerged and will contribute to shaping or, let’s say, improving, maybe, our practices or not.

And I will let my esteemed colleagues introduce themselves.

So, Nicholas.

NM: I’m Nicholas Mottet, I’m a urologist based in France.

MDS: Hello, I’m Maria De Santis, I’m a medical oncologist based in Berlin in Germany at the Charité University Hospital.

AA: Hello, I’m Andrew Armstrong, I’m a medical oncologist and Associate Director of the Duke Prostate and Urologic Cancer Center.

EE: So, as you can see, we only have one representation from urology but if there’s somebody who can put us in our place it’s the person who is mainly involved in making the guidelines for the European Urology Association.

On the other hand there are three oncologists but, again, the balance is there because we have two US-based and I can still say that I’m part European, part United States, but come on, Maria, you’re the whole of Europe right now so you have experience for everywhere.

And I think that in the discussion it will play an important role.

So we decided to discuss starting from what has become more of the interest of the day which is the hormone naïve disease, probably because we believe that there may be an incremental change that may lead to improvement in the lives of our patients.

And we’re getting a lot of data along these lines.

Now, there were some data that evolved today and we saw it reported in the oral session about using docetaxel in this adjuvant setting.

I would actually ask Nicholas, as a urologist because the trial had radiotherapy involved, to provide the first comment on this study that was unfortunately negative.

NM: Well, the study was negative as a whole.

The first comment is that I was surprised by the design, combining intermediate and high risk is unusual. Especially treating high risk with just one year of ADT is far away from every guideline.

Having said that, the trial as a whole is totally negative, a complete overlap of the two curves.

I remember there was a trial presented I think two years ago when there was a clear trend suggesting there might be a benefit.

It was a little bit early but this trial, at least, is completely negative.

EE: So, on the US side Andy, do you think we’re missing an opportunity to identify a subset if we’re going towards these types of designs?

AA: Absolutely. You’re referring to the RTOG-0521 study, it’s still not published but it has actually been incorporated into some of the NCCN guidelines as an option for men with high risk, very high risk, disease.

And that’s based on a survival benefit that was seen in the adjuvant setting with two years of ADT in very high risk men, very different than the Scandinavian study that really enrolled mostly intermediate to lower high risk men.

In that setting they gave inadequate hormonal therapy, as you mentioned, the RTOG study gave two years, and the six cycles of docetaxel did improve survival, it was really just an incremental advance – 4% at ten, fifteen years.

But for a young patient with aggressive prostate cancer who wants to do everything possible to be alive at ten years this should be an option.

Now, what’s even more intriguing is some of the abiraterone data in that STAMPEDE trial. Abiraterone has kind of replaced docetaxel for many patients who have chosen an oral therapy, so LATITUDE and STAMPEDE have moved that conversation more towards potent AR inhibition.

But I think what’s most intriguing is STAMPEDE allowed patients getting radiation in a curative intent setting and shows phenomenal activity.

Not yet survival but relapse free survival that is substantially delayed with radiation and two years of ADT with abiraterone.

EE: I could not agree more but, again, we would have to say that there was similar incorporation in STAMPEDE docetaxel.

So, Maria, to you. And for the people who would go back tomorrow to practice and see a 52 year old man with a Gleason score 9, high risk locally advanced disease, it’s a challenge; and let’s say a low PSA producing.

I would be inclined to follow your guidance with regard to the data of the STAMPEDE but again you also have docetaxel data.

So you would probably do a multidisciplinary meeting in Germany, as we would do everywhere, what would be your inclination for such a patient?

MDS: You mean a patient with metastatic hormone naïve disease or in the non-metastatic locally advanced?

EE: Localised.

MDS: Localised high risk.

So, in Germany additional docetaxel or even abiraterone would be too early to recommend.

I think this would be not our first choice for these patients in the MDT.

So I think we would need to wait for the results or a longer follow-up for the STAMPEDE trial, for example, to get the data and then base our recommendations on level 1 evidence.

EE: Absolutely. So I think we would agree. Go ahead.

AA: And NCCN guidelines agrees with that although it was a controversial discussion.

The relapse free survival was 90% in the abiraterone treatment group but overall survival not yet seen.

So do you wait for that and what do you do for the patient in front of you in your office the next day?

We do have clinical trials, clinical trials are always recommended to answer that survival question.

We have many potent AR inhibitors moving up well beyond the metastatic setting and enrolment on those trials will be imperative.

EE: So the jury is still out. We can’t answer this question; we’re trying to do the best for our patients.

You’re working me up to what I presented today which had to do with those men who are relapsing.

And because you voiced your concern about just trying to improve the PSA relapse-free survival.

So, just to give you a short overview, what I presented was one of those trials that is looking into the intermittent use of androgen deprivation, going back to the Clot school, the Canadian school, of trying that for those men who don’t have metastatic disease in an effort to improve quality of life and shorten androgen deprivation duration.

As a phase II it was not addressing the big questions, so we were just focussed on this part and that’s what we were trying to show – no difference in testosterone recovery, a delay in the PSA recurrence.

NM: A significant one.

EE: But the thing is, we want to get to the point where we don’t even have that.

That’s why the results of these adjuvant treatments will be very important and the molecular profiling of these agents.

So, having said that, going to the metastatic setting we had the opportunity to try to a little bit get more information in the follow up from the LATITUDE trial during this meeting.

I know Maria, you have an interest in that.

Obviously this will make us be a little bit more precise with our patients.

What was your thought on the posters presented?

MDS: It was interesting, really, to see the longer term follow up of the LATITUDE trial.

Here I want to bring in something that was mentioned in today’s educational session because it is actually not so much about if to get abiraterone or docetaxel, for example, in this patient population as unfortunately we still don’t cure a patient.

But whether to start with AR targeted therapy like abiraterone in the hormone sensitive setting and then what to do next.

Mostly chemotherapy comes as the next step. But now in the follow up of the LATITUDE trial we saw the post-progression treatment data which was pretty interesting.

Firstly, we saw that, not unexpectedly, the need for additional treatment was significantly delayed on the abiraterone arm, like tripled – nearly three times as many patients on the ADT only arm were in need of subsequent life-prolonging treatment.

So this was good to see but was not unexpected.

There was a cross-over option so patients were unblinded and sixty patients, which is only 10% actually, crossed over to abiraterone from the control arm, from the ADT arm.

Most patients, interestingly, received docetaxel in both arms and I was pretty surprised about that, I would have imagined that most patients would have wanted, and most physicians, would have given abiraterone or enzalutamide at progression but this was actually not the case.

So I think this was really interesting to see and the long-term follow-up is always very important in these huge scale trials to inform our further treatment decisions and to learn what is really going on in the community.

EE: So Nicholas, you voiced a concern at that but also before going to that, the fact that you’ve got more patients going on to docetaxel in the comparison there. But did you discuss at all with the authors if they found out whether it was because it was symptomatic progression and there was a concern about the window of opportunity?

Was there any discussion regarding that?

NM: No, there wasn’t.

The only thing with this is that LATITUDE and STAMPEDE are by no means early versus deferred abi.

It’s early abi versus nothing initially followed by life prolonging agent, whatever, it was mainly docetaxel.

I don’t think it lowered the value of the evidence, the evidence is very clear, the benefits remain so there is no discussion on that.

But it’s a bit hematologic speaking that it’s not early versus deferred.

The same thing with docetaxel – it was not early versus deferred.

EE: So going back to that, we had a very nice meta-analysis presented in Annals of Oncology, there were actually two papers, and the Sides paper was the one that was actually using the contemporaneous arms within STAMPEDE.

And that was the only one that we even saw in last year’s ESMO that showed, at the end of the day, survival is the same whichever agent you use, especially when you don’t have any predictive markers.

Now, we have both agents available in the United States; very soon, from what I understand, the rest of the world abiraterone will be also available in the hormone naïve space.

A patient walks in your office this time, metastatic hormone naïve prostate cancer, how do you decide?

AA: It’s a great question because I face it on Thursday.

The issue and the big concern is the early use of these agents, while they improve survival, create a resistant tumour and how are you going to treat them subsequently.

But the good news is that early treatment seems to provide a greater magnitude of benefit than waiting for castration resistance.

We know that castrate resistant tumours are more heterogeneous, they have more genomic evolution, they’re very hard to treat and the survival benefit on an absolute level is measured in 2-3 months versus 1-2 years with up front either docetaxel or abiraterone.

So I think as long as you pick one you’re doing a service to your patient.

Now, some patients want to get it over and done with, six cycles, eighteen weeks, docetaxel makes sense from a cost and health economics perspective – docetaxel is cheap, it’s generic.

Abiraterone, while it’s becoming generic, is oral. In the United States some patients cannot afford it, even the co-pays, so that really plays a real important role in the decision making because it’s not based on efficacy, it’s based on can you get the drug, can you afford the drug, can your health system afford the drug?

The toxicities clearly favour abiraterone although you’re on abiraterone for 3-4 years versus docetaxel just a short amount of time.

Docetaxel – neutropenic fever, abiraterone more metabolic, mineralocorticoid cardiovascular risks.

So it’s more based on comorbidity preference and health economics.

EE: Nicholas, would you agree, from the European perspective?

NM: Completely. From the European perspective the only difference is to pay for the drug.

In my country patients don’t pay anything for the drug so either the drugs is available…

EE: Well they pay all these taxes, don’t they, for the drug?

NM: Yes, but whatever you do you’ll pay the same taxes.

EE: Sure.

AA: Society makes the decision though.

NM: The state decides if we pay for the drug in this situation or we don’t. If they don’t…

AA: Some interesting ongoing questions are alternatives – if one is good, is two better?

And the PEACE studies are answering that. Enzalutamide is emerging within the next year, we’ll hear about two phase IIIs with that agent. Of course, that’s expensive as well but involves no steroids.

EE: I am getting a little bit concerned, and that’s probably just me voicing, that we’re becoming a little bit too comfortable with oral agents and we may lose a little bit of the monitoring that is needed.

That’s my concern and I think then it falls upon the agencies that are involved in education to provide that to the providers.

So, moving on, we did not have any wow effect this year at ASCO, right?

We got it last year, we’ve been privileged. But we saw some data come forth from the therapeutics area in the metastatic castrate resistant prostate cancer arena.

What baffled me was the data and I’ll ask you, Andy, your thoughts on it, that were just presented by Noel Clarke.

So this was not as expected, the numbers are small. What Noel presented was a study that actually looked at the combination of olaparib, a PARP inhibitor, plus abiraterone acetate versus abiraterone acetate.

And I’ll let you talk a little bit about it and your thoughts as compared to other trials.

AA: Sure. The idea behind the abiraterone and olaparib trial was that the AR regulates homologous repair and Karen Knudsen and her colleagues, Charles Sawyers, have published good data supporting AR regulating DNA-PK as well as other homologous repair enzymes.

That underlies the fundamental basis for how ADT improves survival with radiation, for example.

So the idea is that if you are impairing DNA repair we can leverage that with a PARP inhibitor to fully engage DNA repair, block it and kill more cancer cells.

So they enrolled patients that were not selected based on homologous repair, in fact they didn’t even measure it prospectively, they had to go back and look at it.

Interestingly, the patients who didn’t have homologous repair defects did better.

So that was shocking, that was shocking.

But subset analysis – a very tiny number of patients with biomarkers, it was not a precision medicine study.

It is launching the PROPEL study which is the next phase III version of this but it will be much bigger, much more well powered.

The big concern about this trial is that there are safety concerns.

There is cardiovascular risk, anaemia is significant.

And I would like to point out an ASCO poster that I just became aware of yesterday which showed olaparib caused red blood cell folate deficiency.

That’s an interesting mechanism, it’s its Achilles heel of PARP inhibitors is anaemia and everybody just chalks that up to an ‘Oh, it’s a PARP inhibitor’ effect.

But why is it causing folic acid deficiency? Can you actually correct that and fix that problem?

Measure it and see if that can…  Now, it may be that folic acid supplementation does something bad to tumours, tumours may be promoted with folic acid so it’s just an intriguing toxicity.

Cardiovascular risk with hypertension from abi, maybe the added anaemia with olaparib may have led to the higher cardiovascular events.

So there was no survival benefit.

EE: Yeah, we’re scratching the surface of something we do not understand from all perspectives, even how to tackle it. So a lot to come for it.

AA: A lot to come, yes.

EE: And it was a very disappointing session on immunotherapy for prostate cancer.

Don’t get disappointed, we’ll get there, it’s just that we haven’t figured it out. So, Maria, your thoughts on the pembrolizumab study?

MDS: The pembrolizumab study was actually pretty disappointing, as you just said.

The response rate was very low and the presenter, actually Johann de Bono, tried to find out the real subsets of patients that would respond.

It is actually the case that there are the patients who are responders but it is still very difficult to define them.

We still do not know who would be the patients who would respond.

So I think it is a little bit also early days for immunotherapy.

We have had quite some negative randomised trials with immunotherapy and now a single arm study, the PROSPECT study, for example today but with pembrolizumab which is pretty well tolerated and would be a nice drug in the later stage setting we do not see the effect that we actually wanted to see.

EE: So I’m going to turn it to you because you’re going to be the one closing the session because we’re all getting to one point. We need some kind of markers and you’ve presented a wonderful work on it today.

So if you could provide us your insight.

This was work on the two major assays that are used for AR-V7 detection, a real big unmet need.

I loved it, I think it was the highlight, truly.

This is what we need, moving forwards.

So your thought on that and your work.

AA: So the theme of ASCO is precision medicine and you heard from the immunotherapy trials that if only 6% are benefitting we shouldn’t give it to 100%.

MSI high tumours should get it for sure, it’s already approved, and then maybe we’ve learned about a new subset of CDK-12 mutant patients and that will be coming out in Cell next month.

But our study was called the PROPHECY study, this was more can you predict standard of care therapy, abi and enza we know that there’s cross-resistance.

I think that was one of the most disappointing things of the whole development of these novel AR therapies is that you really get one shot, not two.

There are patients that have responses to subsequent oral therapy and we’re excited about them but it’s certainly not 100%, it’s probably under a third.

So if you’re using those agents that’s cost and expense to society, toxicities to patients where two-thirds of the patients are not getting a response.

So our study was really dedicated towards men with CRPC who are getting standard of care, abi or enza, and it used a liquid biopsy approach to try to predict the future, thus the name PROPHECY.

The AR-V7 assays, there are really two that have both analytic validity and early clinical validity.

The analytic validity is very important for these assays, you need to set a threshold, you can’t just do RNA sequencing and measure it and say an arbitrary level.

And these are circulating tumour cell assays, not whole blood assays.

So we’re enriching for cells, we’re measuring the splice variant that has a protein product.

This protein product does not bind to the drug so mechanistically it’s understandable that the drug is not going to work if you have a tumour dominated by a ligand independent molecule like AR-V7.

EE: So I’m going to get to the punchline – who is the winner? Is there a winner?

AA: Great question. I personally think that both won.

EE: He’s being very politically correct.

AA: So officially the Hopkins assay predicted PFS, met its primary endpoint, predicted OS.

In fact, it predicted OS even better than PFS.

There were some false positives so there were three patients that had a confirmed PSA decline so the response rate was not zero if you are AR-V7 positive.

EE: Surely you expected that, the Spanish group have talked about it.

AA: Yes. So I think we need to work out in those patients was it very low levels of AR-V7, maybe we can improve the assay a little bit so that it’s a little more perfect but it’s a great start.

It’s worth ordering that test if you have this therapeutic dilemma between a second AR therapy or a taxane or enrolment on a trial or radium.

AA: The second assay was Epic, it was 100% in terms of the positive predictive value of lack of response.

So nobody responded if it was positive.

EE: So you’re pretty safe there.

AA: That validates Howard Scher’s work, it’s exactly the same data.

What’s interesting about this predictive prognostic question is that AR-V7 does go up with progression so suggesting maybe it is a driver in some patients but in some patients it may be a passenger.

So in cell lines you see that as well, sometimes when you knock down AR-V7 the tumour is happy.

EE: And the verdict? Prognostic or predictive?

NM: No idea yet.

EE: No, there needs to be a little bit more work on it.

AA: Absolutely.

EE: What we know is they are bad performers.

AA: I think there is heterogeneity.

EE: But this is progress, this is better than where we were last year.

NM: Exactly, it’s going in the right direction.

EE: And we are making, then, progress. And that’s what I wanted to end it on because you heard the disappointment about immunotherapy.

And we’ll be sitting here next year saying very positive things with regard to immunotherapy, I’m sure.

Thank you very much for your participation and attendance. Have a good night.