Silke Gillessen: Thanks Chris. So we, so from Gert this 10% of patients who go very well with ADT alone. Maybe Bertrand has a good idea how we can deescalate treatment in these patients?

Bertrand Tombal: Thank you. I wouldn't say it's my idea. I think we've been speaking about that, many of us, for a long time. We're going to speak about deescalation.

These are my conflict of interest.

So that's what we've been discussing since this morning. Very exciting, although there are two strange things. The first one is that if you belong to the category of metastatic patient, you are going to be receiving a combination with an ARTA, following piece one and Darolutamide. I think that we can say that we are no back to maximal androgen blockade, but that ARTA and that ADT will be maintained until radiographic progression, which from some low volume patient, may be actually very long. When you are high risk localized, then you're going to receive only two years of ARTA, plus ADT.

Although we've been discussing about modern imaging, blah, blah, blah. I mean, one thing we can say is that M0, M+, M1, this is a standard dichotomization that maybe we should not use anymore, and recognize that between the high risk and the high volume, it's more like a continuum. We don't use that continuum very much to decide on what duration, what dose of treatment.

I think that it results in situation like this. These are actually two cases with similar PSA, similar age, similar T3, similar Gleason. Mr. Z, actually, is an N1 on standard imaging, he's got enlarged lymph node, just that nobody believe in standard imaging, so I show up at PSMA. The other one is an M1B, he's got one single metastasis, actually bone metastasis. Mr. Z will receive two years of treatment, where Mr. W will receive treatment for a long period of time. So, that's strange that I don't believe that these patients are very different.

What is treatment optimization, like we prefer to call, instead of deescalation? It's a process intended to enhance the long term efficacy, other than safety, convenience, and affordability of a therapy. Actually, that affordability is a very important component, not maybe for the majority of the people who are sitting in that room, but surely for the majority of patients who live on the planet. Two years is very different from five years. This is very high on the agenda of the regulator. This is a meeting EMA and EORTC have organized together, it's called a Cancer Medicine Forum. It's a huge movement in Europe with academia, including not only cancer people, to optimize cancer treatment. In North America, there are similar initiative. This is Ian Tannock, Optimal Cancer Care Alliance that ensure that patient receive optimal dosage. So I think that it's high on the agenda.

So what do you do? And what is the question, actually? The question is what is the minimal duration of ADT and/or ARTA to be administered, to obtain a similar efficacy while improving quality of life and reducing resource utilization? And that goes well beyond simply the finance. So it also covered this from form of the intensification. You can stop everything and then you're back to maximal androgen blockade. That's what you do when you give two years of Abi and ADT. We could imagine just to stop the ARTA. Some people would say, "Oh, that's the most expensive. This is the one we should stop." But I would argue that that's probably the most effective, and ADT probably the more toxic. So, maybe we should think also about ADT plus ARTA, just followed by the ARTA.

Why should we think about that? Because, honestly, that's where we were before all of this started, before Dr. Sweeney came with this chartered trial. We, the urologists, we had entire meeting speaking about the relevance of doing intermittent androgen suppression. This is a very famous paper by Dr. Hussain showing that, basically, if you look at the boundaries of non equivalence, I mean, many people discuss about what the meaning of that trial, but honestly we can say there was no major difference between continuous therapy and intermittent therapy. There were meta analyses and no wonder that Ian Tannock was a promoter on the thing. So this is a meta-analysis by Ian Tannock's group showing that overhaul same observation, if there is an action-favoring continuous androgen deprivation therapy, it's not that big.

In contrast, the benefit on quality of life is very important. If you do maximal androgen blockade or intermittent androgen deprivation therapy, like I still do, I mean, the patient can tell you very happily if they're on and off. And this is supported by a lot of quality of live analysis. So just, if you look at physical capacity, sexuality, and you could spend hours, there are many benefit of doing drug holiday on intermittent regiment. So, this would be a very complicated trial I'm not going to speak about that. I think that we have to focus on simple trial trying to say whether actually we can extend the concept of a fixed duration. I won't speak about six month, eight month, but the fixed duration like Gert has shown for the M0, into a subgroup of patient that started metastatic disease.

One of the big frustration of all the trial we've done, at least for me, was that the concept of intermittent androgen deprivation therapy was based on a conditional randomization system, meaning that you need to achieve a certain condition before we were randomized between stopping and continuing. So really here, the question is what are the selected patient?

If we come back to Dr. Hussain's contribution, I believe beyond the result of the trial, this was probably the most important. This was the observation that a very cheap biomarker, which is PSA, actually stratify patient in term of overall survival. When we discussed a lot about high volume, low volume, you see that the difference between those who achieve a PSA below 0.2, and those who achieve a PSA above four is actually much bigger than the difference between low volume and high volume in any of the trial. So I think we probably have missed that opportunity of conditional randomization.

These are data from Chris who basically do actually the same observation that the subgroup of patients who have a PSA below 0.2 are those who live longer, and this is not a small group of patient. Let's look at the ADT alone, we're speaking about roughly one third of the patient, so that's a significant group.

These are data from Kim Chi, from ASCO. So you see for Titan, either you look at PSA, 50% response or 90% response, same observation.

The final question is PSA enough? Can we embark, like we were 13 years ago, and can we embark just by selecting patient on PSA? I think that's a research topic. I think that's really where all these new imaging modality may help us. This is purely hypothetical.

This is not a PET PSMA, this is a whole body MRI, I call that the "PET PSMA of the poor." Actually, that's a patient who had low volume disease, one single bone metastasis. He had radiotherapy of the primary, metastatic targeted therapy, and androgen deprivation therapy. You see that after roughly one year of treatment, you can still see the metastatic deposit on the whole body MRI. Treatment was stopped and after one year, the patient did progress very rapidly.

On the contrary, this is another patient who had three metastatic deposit, ADT plus Docetaxel six cycle. He's got a complete PSA response and also a complete imaging response. Interestingly, that patient, five years down the line is still with an undetectable PSA. So this is just case chasing, but I think it needs, we may end in trial. We need to embark genetic, we need to embark imaging to try to refine the definition of selected patient.

So, in conclusion, I think that is clearly an opportunity to optimize deescalate intensified treatment in selected patient. This require a proper trial, otherwise, going to be like PET PSMA. In five years from now, we're still going to be deciding whether we should do it or not. We should not break the equipoise simply because we believe or not in the concept. This trial will be long and difficult. The funding will be very funny, but we should do it.

Thank you very much for your attention.