Latest in prostate: Updates from TITAN, CARD and the era of personalised medicine
Prof Karim Fizazi – Institut Gustave Roussy, Paris, France
Dr Elena Castro – Spanish National Cancer Research Center, Madrid, Spain
Prof Axel Merseburger – University Hospital Schleswig-Holstein, Lübeck, Germany
KF: Hello everybody, welcome to this ecancer conversation about prostate cancer. We’re here in San Francisco for the ASCO GU meeting 2020. I’m really happy to be today together with Elena from Spain and Axel from Germany, so this is a very European oriented discussion or session. I think we’ve learnt a lot of great news in the last year and, again, at this ASCO GU meeting some fine tuning, obviously. For example, for M1 metastatic prostate cancer we’ve learnt quite a lot in the last five years with numerous phase III trials delivering good news for all the patients. One of them is TITAN which is positive, obviously, and we had an updated analysis presented here at ASCO GU. Axel, can you tell us more about it?
AM: Karim, thanks for inviting me here, a pleasure to be with you. Yes, since we had this mHSPC year in 2019: after CHAARTED, after LATITUDE and the British STAMPEDE trial, last year we had the publication led by Kim Chi on TITAN where we show for the all-comer indication metastatic prostate cancer an overall survival benefit, 33% advantage, when adding apalutamide towards the classical ADT compared to just ADT in this indication. This also translated into an rPFS benefit as we have learnt at last year’s ASCO. So with the ENZAMET, ARCHES and TITAN this was really the mHSPC year 2019. Now we are here in San Francisco, year 2020, having an update on PFS2 from the TITAN trial. PFS2, it’s somehow a modern endpoint we are having here. It includes first progression and then time to next progression, so this whole time period somehow covered. When looking at the TITAN data and the subgroup analysis presented by Dr Aggarwal yesterday in the plenary, it showed that regardless of secondary hormonal therapy, regardless of what has been given afterwards – if it’s docetaxel or abiraterone or enzalutamide – there was a significant and clinically relevant benefit for adding apalutamide. So PFS2 was benefit, was positive in the trial, and this was a key finding. No further safety signals reported by Dr Aggarwal out of the TITAN group and this is important. There was some question derived in the discussion later on – so what’s the time from first progression to second progression? This is still something that is under discussion and also what is the best treatment from first progression to second progression. So there are still some open questions but to start with apalutamide in mHSPC is surely no mistake.
KF: Right, so just for clarity does it mean that the second agent that is being added when apalutamide fails also works? Or do we have data on that? Because I know people are being confused about the PFS2 concept?
AM: Yes. So it works but it hasn’t been really cut into pieces, the results, so we have to await further subgroup analysis with regards. This was in the discussion also with Dr Aggarwal where he was alluding to the not final analysis of this question you just raised.
KF: So I think it’s very important for people to understand that. Apalutamide, and that’s true, to be honest, with other drugs – abiraterone, enzalutamide, etc – so all these drugs worked so nicely for a long time, for the first progression free survival period, that even if a second period doesn’t really add much overall one plus two is big so PFS2 is big. So I just want to make sure people understand that PFS2 is significantly improved doesn’t mean that the second agent added on top of, say, apalutamide is necessarily beneficial. We don’t really know, we need to look specifically at this data.
AM: I totally agree and also there is basic research regarding to the androgen receptor that in theory even abiraterone plus apalutamide progression should work. But you’re the expert on abiraterone. So I think this should really work and we will have to await further sequencing data, especially in the mHSPC situation where we have all those great first line approvals now, having abiraterone approved in Germany and Europe now since a couple of weeks, what comes next after failure. So there are some questions but still some good data for PFS2 for apalutamide here.
KF: All very nice. I guess it’s also fair to say that 2019 was really the first year when prostate cancer entered the personalised medicine era thanks to the PROfound data. Because it’s really the first time we’re going to use a biomarker to decide whether we should give a drug, yes or no. Can you sum up what we’ve learnt, and you gave yesterday a beautiful presentation about the DDR concept and PARP inhibitors, so where are we at the moment with PROfound and other PARP inhibitors, Elena?
EC: Yes, absolutely. The PROfound study has really started a new time in prostate cancer. So the PROfound study was presented at ESMO some months ago and it proved the benefit of olaparib to treat patients with castration resistant prostate cancer and defects in the homologous recombination genes who have already progressed to an androgen receptor signalling inhibitor. So treatment with olaparib prolonged radiographic progression free survival compared to a second hormonal agent. The study has two cohorts and cohort A included patients with alterations in BRCA1, BRCA2 and ATM and cohort B included patients with alterations in another twelve homologous recombination genes. So the benefit was greater for patients in cohort A but there was also a benefit observed when all the patients were analysed together. So there has been presented also an exploratory analysis of the benefit for patients considering the different alterations and it seems to be a very good benefit for patients with BRCA2 mutations and that is clear. For patients with ATM alterations it seems that the benefit is quite limited but for patients with other alterations at the moment we don’t have enough data because there are some alterations that are less prevalent and we need more information. What is being presented here is actually the data on the samples that were analysed and it’s important to remember that approximately 30% of samples fail analysis because otherwise the clinicians may feel that they are doing something wrong or it’s not worth testing.
KF: So what are the main reasons for failure, just to help all our colleagues to better know because this is the near future, using PARP inhibitors. So what should they do to make sure there’s no failure in the analysis?
EC: I think that’s the part that we cannot prevent and one of the things they showed was that the primary biopsy or the sample from the primary tumour is useful to detect that there is a homologous recombination defect because it’s often an early event and it’s present in the primary tumour. The issue with that is that sometimes the primary biopsy was taken many years ago and then the DNA is damaged and it’s not useful. So there is little to be done on that regards from the clinicians. Maybe the pathologists need to see how to process the samples from now on to prevent that issue.
The other issue is that sometimes the samples that we have have a small proportion of tumour. So if you have a core biopsy it’s affected with a prostate tumour in less than 5% of the tissue, so what are you going to do? So we have to try to select the sample with the biggest proportion of cancer.
KF: Do you think people should start more biopsying the metastases, especially when we’re talking about lymph nodes or liver? We all know the issues about bone but for soft tissue do you think that should become more a written process?
EC: I think that for indications that when we have a sample that is visible and is easy to take a sample from there it may be informative, not only for PARP inhibitors but in the near future we will be testing for other alterations as well because they may be predictors of response to other drugs that are coming. While for DNA repair we may be using the primary sample, for other alterations we may require metastatic biopsy. So it could be interesting, particularly if it’s something that is accessible. In other cases I think we will be able to use plasma-based assays. At the moment this technology is in development but I think in the near future we will have also.
KF: Which will make our life much easier.
EC: Much easier, definitely.
KF: So basically this was, again, probably the very first example of personalised medicine in metastatic CRPC, PROfound, showing clearly that PFS is clinically meaningfully improved and, of course, statistically OS seems also better, symptoms are better, everything basically seems to be better. But you need to analyse the tissue and at the same time it was quite funny to see that the two presentations were made just together at ESMO. We had the CARD data as well where basically that was not precision medicine. We were in the same setting of men, progressing after abiraterone or enzalutamide and a taxane, we were randomising the second taxane or the second AR axis targeted agent. So easy question, basically. And obviously cabazitaxel wins. We saw the PFS analysed data at ESMO and here at ASCO GU we had the updated analysis with pain being better, with less skeletal related events and quality of life is better, let’s say, in the chemotherapy arm as opposed to an AR axis targeted agent. So we’re learning more but now that we have this data on the one hand you have an all chemo, if you will, for all comers that works very clearly and on the other hand you have to do the analysis and then in a subgroup of men you have a drug that works.
EC: Exactly.
KF: So how are we going to deal with that? What do you think?
EC: Yes, I think that data is missing because this is probably one of the difficulties. One of the pitfalls of the PROfound study, maybe, is that we now know that sequencing hormone therapies, we don’t really know what is the benefit on there. So we need to know, we need to learn how patients with DNA repair defects do on cabazitaxel and whether it will be best for these patients, cabazitaxel or a PARP inhibitor.
AM: I’m curious, and a question maybe to you both, this is in mCRPC we are talking about PROfound and CARD data and the important health quality of life, patient reported outcomes you showed yesterday. In my situation, like mHSPC following failure, let’s say, of apalutamide and enzalutamide when you have a progressive patient will this data… can this be translated into the mHSPC situation or would you say this is something totally different? Or could you say sequencing wise after failure you give docetaxel and then the best sequence is cabazitaxel or olaparib, a PARP inhibitor?
KF: I guess it’s probably true that what we’ve learned from the mCRPC setting will still apply to the new mCRPC situation except that you have to remember that your patient has been exposed already to an AR axis targeted agent, the one you like, abiraterone, enzalutamide, apalutamide. So all trials that showed a benefit in the post-AR axis targeted agent will probably still apply in the new situation of a man developing CRPC who has received an AR axis targeted agent in the M1 setting. The biology seems to be quite the same, the cancer has adapted basically to the agent he has seen. So what do you think about the use of cabazitaxel in your countries, in your practice? Do you think the CARD data will change and that more people will be convinced that indeed we should use cabazitaxel as a standard of care in the post-AR, post-docetaxel situation? What do you think?
EC: Yes, I think so. I think the CARD trial has proved that sequencing androgen receptor signalling inhibitors is probably not the best way to treat our patients.
AM: I would agree and go along with you. However, knowing from [?? 14:17] and Kim Chi data the sequence enzalutamide-abiraterone abiraterone-enzalutamide doesn’t really make sense in mCRPC. However, the CARD population, but you’re an investigator, in the data this was very fast progressing patients so it’s a subpopulation of aggressive mCRPC. So this was under discussion if this accounts also for the ones that have stable disease for years.
KF: Well actually they were not fast progressors, to be honest, they had to have progressed within a year which is actually the majority of men on abiraterone or enzalutamide. But you’re right, it’s not the overall population, it’s fair to say. Alright, so some good news in the last month and even yesterday. So we are still making progress, it’s fun to do, GU oncologists in general or uro-oncologists. Thank you for this conversation and thank you all for listening to us today. Have a great day.
