KM - Prof Kurt Miller – Charité  - Universitätsmedizin Berlin, Berlin, Germany

LMK - Prof Laura-Maria Krabbe – University of Muenster Medical Center, Muenster, Germany

KM:   Welcome everybody to this ecancer expert discussion on metastatic hormone sensitive prostate cancer. My name is Kurt Miller, I work as a senior consultant at the Charité Hospital in Berlin and with me is Laura Krabbe. Laura, do you want to introduce yourself?

LMK: Sure, my name is Laura Krabbe, I’m a Professor of Urology at the University of Muenster Medical Center.

KM:   Good. So our obviously main topic today is metastatic hormone sensitive prostate cancer and I think there have been very recent developments and presentations at ASCO GU 2022 which just finished a couple of days ago. So, what was ARASENS? It was a two-arm randomised phase III study obviously comparing ADT plus docetaxel as the standard of care versus ADT plus docetaxel plus darolutamide, 600mg twice daily, in a randomised fashion, obviously. The primary endpoint was OS. Inclusion criterion was obviously mHSPC; there were no inclusion like high risk, low risk, high volume, low volume. So there should be candidates, obviously, for ADT plus docetaxel and we had stratification on the extent of the disease and on other lab data. Then also secondary endpoints like time to CRPC, time to pain progression and so forth. The population was well balanced; actually a small minority had M1a disease, the majority, about 80% had M1b disease and there were about 17-18% of patients that had M1c disease.

The primary endpoint was met. There was a significant benefit for adding darolutamide to ADT plus docetaxel with a hazard ratio of 0.68. At 48 months 62.7% of the patients were alive in the darolutamide arm and 50.4% patients were still alive in the ADT plus docetaxel arm. This benefit actually was observable across all subgroups of patients, no matter if they were higher Gleason score, lower Gleason score, no matter of age or other subgroups. So it was pretty much consistent across the spectrum. There was no real additional toxicity when using darolutamide in addition to ADT plus docetaxel.

So overall this was a nice, positive study and the first question I would address to Laura is was it a surprise? Did you expect this type of result or was it a little bit of a surprise?

LMK: I have to say, if you had asked me about 6-8 months ago and would have shown me this, I would have said, ‘Yes, that’s absolutely a surprise.’ If you had asked me now three months ago, I might have said, ‘Well, not so much anymore.’ The reason is obviously that we have had a long journey in mHSPC with developments of therapy coming from ADT monotherapy and then adding different agents in a doublet fashion if you want to. First it was ADT plus docetaxel which obviously is also the foundation for, for example, this comparator arm in this study. Then we had a couple of trials adding oral agents to ADT, namely abiraterone, enzalutamide and apalutamide. So in some of these trials, namely the ENZAMET trial where a, let’s say, first generation doublet was compared to a second generation doublet but it was also allowed to have docetaxel concomitantly, in that subgroup of patients, and obviously it was not the whole population in this trial, but this subpopulation did not receive great benefit from the triplet of ADT plus enzalutamide plus docetaxel. Obviously, granted, this subpopulation was not powered to answer this question but at least it gave us a little bit of a feeling, we sensed. So that’s why I’m saying if you had asked me 8-10 months ago I probably would have said, ‘Well, this is a very big surprise.’

However, then, last year Karim Fizazi presented data from the PEACE-1 trial and PEACE-1, obviously, is a little bit difficult because it’s a four-arm study which has multiple comparisons but in the breakdown of what we know so far, looking at the comparison between ADT plus docetaxel versus ADT plus docetaxel plus abiraterone, for a little bit different population than we see here, namely de novo patients only, we saw a survival benefit for the triplet compared to ADT plus docetaxel. Back then, everybody was very surprised and therefore right now we’re a little bit less surprised , I would say. What was your feeling when you saw the data?

KM: Exactly, exactly the same. I was also surprised then by the PEACE-1 data that adding abiraterone actually resulted in an overall survival benefit in this group. I was also a little bit suspicious, due to the ENZAMET data because there was absolutely no difference in that ADT plus docetaxel subgroup. Yes, true, but on the other hand of course now there was a statement by Matt Smith at the end of the presentation that this is now a new standard, not the new standard but a new standard, in mHSPC treatment. How would we discuss this?

LMK: I would say it’s like a yes and no at the same time answer. Because obviously this is a very large trial, we see a very large benefit for the triplet in comparison to the utilised doublet. There we basically come a little bit to the gist of the problem. The utilised doublet, in this case, was ADT plus docetaxel which is very correct if you think about when a trial like this would have been developed. Because this trial was developed when the CHAARTED and STAMPEDE data, looking at ADT plus docetaxel, had come out and so I think it was very correct from the people designing the study, thinking that that should be the standard of care that should be used in this trial to compare the triplet to. However, in the meantime we had lots of developments with multiple doublet combinations of ADT plus an oral agent and therefore that’s a little bit what we’re missing here – that we have a comparison between ADT and an oral agent versus ADT, an oral agent and docetaxel. Because neither in the ARASENS nor in the PEACE-1 trial we have the ADT plus an oral agent only arm and therefore the question that I think still remains is what is the role of docetaxel here? Do we actually need it or would an ADT plus new hormonal agent doublet be very sufficient for many patients?

KM:   If we look at the different hazard ratios from all the trials they look actually pretty similar – they’re all in the 0.6, 0.61, 0.67, 0.68 range, something like that. Of course there were different patient populations. Also specifically in the ARASENS trial that we just looked at, Gleason score and saying Gleason 8 and higher might be a high risk population, although this was not exactly the definition in the LATITUDE trial, it was also number of metastases, but let’s say it’s rare that a Gleason of 8 or higher has an oligometastatic disease. So we could say it’s about 70-80% in the ARASENS trial were high risk, at least, which is higher than in other trials, except for the LATITUDE trial where only high risk was included. That might influence the results a little bit but you are completely right, I would say exactly the same.

The problem is the missing arm. And the problem is that, at least I’ve discussed this with a couple of other experts and in many countries, in most countries probably, the standard of care today is not ADT plus docetaxel anymore. I would say the majority of patients do get ADT plus a new hormonal agent like apalutamide, like enzalutamide or abiraterone. Is that what you think too?

LMK: Yes. Maybe we’re a little bit biased because we both practice in Germany but I would say that despite we’re a little bit different in our regions of practice I see the same here. And I would actually even add to this that when you look at data on how many patients in recent years, let’s say 2018 and forward, did in different systems of the world – US, UK, Europe, overall etc. – received only ADT monotherapy then obviously that’s a large percentage of patients with mHSPC. Usually in those studies it’s a third to half of the patients who received not even a doublet therapy. So the question with regards to what’s your current reality, sometimes maybe the jump to the triplet is a bit too far for what general practice is showing us, even though obviously we have those two trials here and we can discuss what patients we would focus on in a minute.

KM: Alright. I’ll just take that opportunity to ask you that – are there still indications for ADT monotherapy in mHSPC today?

LMK: I would say rarely. I think there are only a few patients who are either really too sick to have a, let’s say, adequate life expectancy to be benefitting from a combination therapy, even though I think we’re notoriously bad at judging this correctly. So I’m not even sure that should hold you back on utilising a combination. Then obviously someone who has had his primary very many years ago and now has an oligometastatic recurrence where you could think about a more locally targeted therapy, going there individually, but you’re already seeing from the situations I’m describing that these are very individual settings. So I would say most patients, and that to me is not a standard of care but the standard of care, should receive a combination therapy.

KM: I absolutely agree. I think with the exception of really severe contraindications like serious heart disease or something, today you can get these types of doublets, hormone-hormone doublets for almost any patient. As you mentioned, in parts of the world, and we’re not talking about exotic countries here, this is mainly based on US data, ADT monotherapy is still widely used. This should be probably a first step that we overcome this problem because the data of the combination therapies are definitely convincing. I just remembered the ADT plus abiraterone long-term data from STAMPEDE, I just looked that up again. It was presented in 2020 actually, and the difference in overall survival and the complete metastatic group came up to 2.8 years. 2.8 years, this is unheard of in any oncological setting, to be honest. So we are always talking about a year or longer in most of the trials. So I think to withhold this from the patient is a little bit problematic.

So, yes, this should be the standard of care and, yes, you’re right, we’re both from Germany but I talk to other experts in Canada and the US and the UK and they confirm that in all these countries 80-90% of the patients do get ADT plus hormones, new hormonal agents, as a standard of care today. So what we definitely need is to answer the question, as you said – if we add docetaxel to this newer standard of care does that get you any advantage? Currently we have no answer for this question.

So maybe we’ll talk a little bit about a similar aspect. There was a subgroup analysis of the TITAN trial looking at the subgroup of patients that had prior docetaxel before they started apalutamide. In a nutshell it turned out there was no difference in the efficacy between those who had gotten docetaxel and those who didn’t. So the difference obviously was they didn’t get docetaxel in parallel but in this setting there was no difference in the results. So I know, I’m not sure if that’s the same in your vicinity, but I know a lot of urologists who use docetaxel plus ADT, start with that and then once docetaxel is discontinued they start with a new hormonal agent. Is that something we should recommend?

LMK: So, a) I don’t think we should recommend this. That’s maybe point number one. Obviously you have to say that the percentage of patients in the TITAN trial who did receive prior docetaxel wasn’t gigantic, it was about 20%-ish, a little bit less. So that’s not a huge group to draw conclusions from but the ARCHES trial also had the option of having docetaxel and then enter the trial and also there we didn’t see a clear signal. So I think sequencing ADT plus docetaxel and then adding a new hormonal agent is not something we should recommend currently. I would add that here sometimes in the region I hear that physicians start with ADT monotherapy and then they watch how deep the PSA drops and then, depending on how big the drop is, they add a new hormonal agent. Maybe that’s also part of the reason why in other parts of the world, and maybe even including here, a fair percentage of patients get ADT monotherapy. Should we recommend that?

KM: No, we discourage this because all the trials definitely gave the patients additional new hormonal agents irrespective of the PSA decrease. So this is really not recommended from here. So what we just discussed, and this is probably also how we wrap it up – use ADT in combination with other hormonal agents as a standard of care. The overall survival advantage is really overwhelming.

With that, I think that’s a nice statement at the end. Laura, a pleasure to discuss that with you. Thanks for listening to us and thanks ecancer for giving us the opportunity to discuss mHSPC in this setting. Thank you.

LMK: Thank you.