(5/6) ASCO 2017: ASCO highlights in prostate cancer

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

Section 5 - Other ASCO highlights

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 6 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: Fantastic. Now let’s go over and have just a quick review of several early provocative abstracts. Karim, please.

KF: Thank you Neal. I selected two abstracts, one is the PLATEAU randomised trial that was presented Saturday by Gerhardt Attard. It’s really looking at an important question which is basically in patients who are progressing while on enzalutamide should we just continue enzalutamide when we’re using another drug as a salvage treatment? This is the design of the trial, many men were enrolled and screened, so they were men with castration resistant disease, metastatic castration resistant disease, who received enzalutamide. At progression they were randomised to receive abiraterone plus a placebo or abiraterone plus enzalutamide. So the key question again was should we continue enzalutamide when it’s failing. The primary endpoint was PFS and there were other secondary endpoints with a key secondary endpoint of radiographic progression free survival.

What the data show is that by the primary endpoint it’s a negative trial so PFS is pretty much the same, less than six months, when you’re combining ABI and ENZA in this manner and six months also when you’re using abiraterone alone. Now, for the key secondary endpoint there is a strong trend supporting better efficacy for ENZA plus ABI, ten months versus seven months. I wonder whether also this is clinically meaningful. If you’re looking at the PFS events it’s true that less patients are progressing radiographically when they’re receiving the combination, 38% versus 55%, but actually it goes the other way around. When you come into clinical progression, which are obviously meaningful, 25% of events in the combo arm versus 18% only in the abiraterone arm. So I’m not sure having an image worsening is really a signal that we should use a combination treatment when the clinical assessment is doing worse.

So the conclusion for this presentation is that it’s a negative trial. There is no good reason at the moment to support combining the two treatments at progression, at least when we’re using the sequence of ENZA first and abiraterone second. Again, regarding the signal in our PFS, I’m not that sure that it’s really meaningful given that the clinical progression went the other way around. I actually prefer having the patients doing well and imaging worsening if I have to choose. This is it for this abstract.

NS: Thoughts on the data from this abstract, Kurt?

KM: We would seldom stick to the sequence ENZA first and ABI then because what we know from admittedly very small datasets is ABI works not very well following ENZA. Then I’m not sure if that is really relevant for clinical practice, if we should continue giving ENZA in that setting. As Karim said, it’s a negative study so for me this is off the table.

NS: Nick, your thoughts?

NJ: Yes, I would agree with that. We’re not allowed in the UK to use… we have to choose one agent or the other then we have a three month window to switch if there are tolerability issues but after that we can’t switch. So this is a non-issue for us and none of the UK oncologists have felt it necessary to make much of a fuss about this. We don’t think the sequence is very good.

NS: There are some interesting things about the theme of is more necessarily better? So here ENZA ABI, theoretically maybe it’s more powerful, I guess it was trying to show that. But yet in the LATITUDE and STAMPEDE we’d combine to get a more powerful response. Different patient populations, different therapeutics but it’s in that concept of sometimes more is better, sometimes it’s not.

NJ: Yes, I think it’s in the context of adding things when you’re winning versus adding things when you’re losing, clearly the biology is different is what you’d conclude, isn’t it?

NS: Absolutely.

KM: The second abstract I selected is about, again, precision medicine basically because this is really something that we need more efforts and hopefully more victories about. We’ve been trying to identify biomarkers predicting for sensitivity or resistance to docetaxel for years in France and this is a report from two phase III trials that we conducted within the GETUG, so the French group. We were looking at various biomarkers that we hypothesised might have a role for prediction with regards to docetaxel efficacy.

GETUG-12 is in high risk localised disease and we randomised the standard of care of radiation plus ADT plus or minus docetaxel. GETUG-15 is an up-front metastatic phase III trial where we were randomising the role of docetaxel on top of ADT. So different situations but basically the same question – should we use docetaxel, yes or no. Regardless of the results we were trying to collect tissue and we looked at the expression of ERG, PTEN or PTEN loss, Ki67 and Rb. We were doing that by immunohistochemistry just because at this time we didn’t really have methodology to do much more than that and we didn’t really have access to frozen tissue.

The primary endpoint that we looked at was relapse free survival, progression free survival. What we saw regarding ERG is striking. We know that approximately half of prostate cancer have TMPRSS to ERG aberration, so the TMPRSS2 gene and the ERG genes are put together. Because of that  these results see an increased ERG expression and ERG is an oncogene. So what we saw was that for patients with a high ERG expression docetaxel seems to work and that was quite clear across trials. For example, when you’re looking at time to relapse in GETUG-12 or relapse free survival 80% in men who received docetaxel, 68% in men who did not so quite a big difference for patients in high risk localised disease while for patients with negative ERG expression there was really no difference. The same pattern was seen in patients with metastatic disease in GETUG-15, for patients with ERG positive cancers basically their median relapse or progression free survival was almost double, 19 months versus 11. There was not much improvement in patients with ERG negative cancers.

So perhaps for the first time, and of course we are cautious in that, we still need validation, perhaps for the first time we have a gene or a protein that might help us for decision making, if this is confirmed, to try to better select men who are more likely to benefit from docetaxel. So we’re very happy about this data, of course we need confirmation to make sure that this is true.

NS: That’s excellent. Nick, Kurt, thoughts on this? Getting more precision based so we really know right therapy right patient?

NJ: As Karim said earlier on, it’s strikingly different between prostate cancer and, say, breast cancer where the disease has long since been sliced up into different subcategories by biological markers and it’s long overdue that we’d start doing it in prostate cancer. These data look interesting, for sure. It’s great work.

KM: I can echo this, that’s what we need for the future, to get better differentiation. Now we’ve got many more treatments and we need to know who is the candidate for this treatment, who is one for the other and that’s a step in the right direction, definitely.

NJ: So the two abstracts that I’m discussing, the first one was one presented by Maha Hussain. This is something we’re very interested in because obviously there’s an emerging story, as again already mentioned, around patients with certain DNA repair mutations, BRCA2 and so on, being susceptible to treatment with PARP inhibitors. This is a study that mirrors the TOPARP study which Johann de Bono’s group has been doing at the Royal Marsden which showed that if you had the right mutations you responded to PARP inhibition. This is a variant on that where the group were testing a PARP inhibitor, veliparib, plus abiraterone in a randomised fashion and then they collected and analysed the genomic data.

A straight randomisation, in this case looking at ETS status for stratification. The primary outcome was PSA response rate with a range of secondary outcomes – objective response, progression free survival and so on. On the primary outcome measure for the whole population, essentially this is a negative trial; the PSA response rate is a little bit higher with veliparib but not statistically significantly so. But the thing that was interesting really relates to the behaviour in the different subgroups. A number of the genes, PTEN, p53, PI3 kinase, were associated with different PFSs which is interesting, although oddly it appears not necessarily quite what we expected to see. But also the response rates differed according to whether you had the DNA repair deficiency or not. So basically with the DNA repair deficiency you saw a much bigger benefit with veliparib which mirrors the TOPARP study. Also various prognostic factors around biological markers, there was some debate as to whether these directions of effects were in the right direction but the bit that was interesting for me was the association between the DNA repair deficit and the PARP responsiveness going up which replicated the TOPARP study. That was the thing that was interesting.

NS: Kurt, any thoughts on the use in the trials, there are a lot of them out there now, on using PARP inhibitors and the landmark paper in The New England Journal, Mateo and de Bono’s TOPARP study? Now there’s really a plethora of all these trials.

KM: Yes. I think what Nick mentioned, that the direction probably in the future we’re going to test these patients. Actually I do see patients where I discuss this. PARP inhibitors obviously are not approved for prostate cancer yet but they are approved for ovarian cancer and the testing is also approved for [??] cancer and that’s probably the next step. The interesting thing here was, if I get that correctly, also even for ABI alone you saw better results when the patient had this DNA repair deficiency which is a counterintuitive thing. So that’s something we need to clarify more, I think.

NJ: The trial was odd in that respect and the things that we thought should make you do worse appeared to make you do better in the data Maha presented. Also the second abstract that I’m going to talk about now, it has looked at some genes overlapping and saw the opposite directionality of effect. So clearly there’s an issue, I suspect, around validation of assays, how you’re doing the tests, what exactly it is you’re testing.

This is a sort of variant on one of the papers Karim looked at which is a crossover trial. Patients were randomised between receiving abiraterone and receiving enzalutamide and they then crossed over to receive whichever agent they hadn’t received and then you’re looking at the time to progression over the whole two treatments as the primary endpoint. So is there a better sequence – ABI-ENZA or ENZA-ABI? The short answer to that is no but the thing that is more interesting here was that they collected circulating tumour DNA and looked at the impact. There are two things interesting about this, one is that circulating DNA is a much easier thing to collect than circulating tumour cells and they were able to show that if you had DNA repair deficit collected from the circulating DNA you did substantially worse, so the opposite finding to Maha’s paper. But it’s the methodology that’s interesting here because this is a technology that’s replicable. Similarly for p53, AR mutations, Rb as well, they were all associated with worse outcomes from circulating tumour DNA. This is coming back to where we started around biomarkers; this is a technology that is easier to replicate in the clinic and will find its way into both selection of therapeutics, because you predict the DNA repair ones should be amenable to PARP inhibition. It also raises the possibility you can maybe use it for monitoring – does the circulating marker disappear if you give a PARP inhibitor, for example. That wasn’t obviously addressed in this study but it’s a very obvious extension from it.

As I said, in terms of the ABI-ENZA, ENZA-ABI there’s no difference, it doesn’t matter which way round you do it and I would argue just do one. But it was the circulating tumour DNA outcomes which were interesting because they both appeared to have prognostic significance but potentially predictive significance in relation to therapeutics that are now in clinical trials.