Alicia Morgans: Hi, I'm so excited to speak today with a good friend and colleague, Professor Bertrand Tombal, who presented a lovely oral presentation at EAU 2022 discussing outcomes in ARASENS by metastatic subtype. Thank you so much for being here with us today, Professor.

Bertrand Tombal: My pleasure.

Alicia Morgans: Wonderful. So Bertrand, can you tell us a little bit about the ARASENS trial, and then what you and the team really did in this additional analysis?

Bertrand Tombal: So, if you remember, ARASENS is a trial investigating the benefit of darolutamide, which is what we're going to call the third AR antagonist, but specifically in the group of patients who are selected to receive ADT plus docetaxel. So, we had that idea in 2014, 2015, with people like Matthew Smith, Fred Saad, Karim Fizazi. At that point, it was always, we had the first result with abiraterone, so we understood that the question was, would you give docetaxel or one of the AR-pathway inhibitors?

But our question at that time was, is ADT plus docetaxel alone, enough? So, we wanted to test adding darolutamide on top of this combination. Why darolutamide? Why we choose darolutamide? Because the drug, as you know, is extremely well-tolerated, and especially, has very little drug-drug interaction, which in the past has always been a problem when you combine with docetaxel. We've done more than 20 trials in castration-resistant prostate cancer; it never worked.

So, we did that trial, ADT plus docetaxel plus darolutamide versus placebo. It was a 1300-patient trial. And actually, the benefit in term of overall survival was very, very, very, very important, was a risk reduction of nearly 40%. But then interestingly, although we kept repeating that the question was, "Do you have to add something on top of ADT plus docetaxel?", everybody's asking us, "Do you have to add docetaxel on patients receiving ADT plus one of the AR pathway inhibitors?" So although we keep saying, "We don't have that answer," at least what we have tried to do is provide information by volume, to be sure that at least the benefit of darolutamide was seen across a whole subgroup of patients. And I must say that question was especially raised after the release of ENZAMET, where you know that in high-volume subgroup of patients, there's not a huge benefit of adding enzalutamide on ADT plus docetaxel.

So we hadn't stratified patients according to the standard definition of high-volume/high-risk, because it was not very common at that time in 2014. What we have done is stratified patients by extent of disease, M1a, so lymph node, versus M1b, bone metastasis, versus M1c, visible disease; and also, based on normal versus abnormal ALP. Why ALP? Because it has been shown, since a long time, more than 20 years, to be one of the most powerful prognostic markers as a single agent. That's been shown already by [Gwenell Cravis 00:03:42] on the GTAC-15 pilot, that if you certify a patient based on normal versus abnormal alkaline phosphatase, you have a huge difference in terms of overall survival. So what we've done is to take these two criteria, tumor volume and ILP, and see whether the benefit of adding darolutamide was preserved.

First observation and I'm quite very happy with this, is that there's very little M1a most of the patients were either patients with bone metastasis or patients with visceral disease, almost 20% of patients with visceral disease. So that was reassuring because when we planned the trial, we wanted to be sure that patients that would receive ADT plus docetaxel, were patients that needed it, that we didn't have too much low volume at that point.

So then we looked at the hazard ratio, M1b versus M1c, it's actually a very similar hazard ratio of 0.66 for M1b, and 0.76 for M1c. And when we look at alkaline phosphatase, which I believe personally is even a much better surrogate or proxy for volume, the hazard ratio is absolutely similar: 0.65 for a patient with low alkaline phosphatase, and 0.69 for a patient with elevated alkaline phosphatase.

So in contrast to what has been seen in ENZAMET, we don't see any difference in benefit. And if we take the kind of dose at lieu, at least we are sure there are probably high-volume, meaning those with elevated alkaline phosphatase, and those with MR M1c. The benefit of adding darolutamide is preserved. So at this point in time, although we first repeat, we can't guide who needs docetaxel, but we can discuss about that. What we can say is that we see a benefit, which is consistent across all subgroups of patients that fit the description of being candidates for ADT plus docetaxel. So that's very reassuring.

Alicia Morgans: That is really helpful. And I think, to your point, the M1c patients are, clearly by definition, those are going to be high-volume patients. The M1a patients who have lymph node-only metastatic disease also seem to have a benefit here with the treatment of darolutamide on top of docetaxel, which I think is also really important. And as you said, not necessarily as clear in the ENZAMET trial, but of course, this is a trial that was not powered or designed, either, to answer this particular question. So really they can only answer the questions that they're designed to answer.

But the M1a population, as you said, just to confirm, that population also seemed to benefit from the addition of darolutamide to ADT and docetaxel, correct?

Bertrand Tombal: Yes.

Alicia Morgans: That's important. This was a lower-volume patient population by definition, because these are only lymph node metastases. So as you think about this, and as you're trying to make decisions, of course, the ARASENS population, I think, included a larger proportion of patients who had "de novo" metastatic disease. And then we see the subgroup analyses in this way. How do you make choices in your clinic about when you're going to apply the ARASENS data to the patient who's sitting in front of you?

Bertrand Tombal: It's funny, because that's really the question, though: who are the candidates for ADT plus docetaxel? And I'm not going to say what I say, but rather quote what I've been hearing at two places. The first one was the Commercial Symposium organized by Bayer that I was sharing with two German oncologists, which the German urologists have been giving docetaxel themselves. And then the next day, the study was discussed by a young German uro-oncologist.

And they all made the same recommendation, which actually I find very useful. And they say what you should do is project yourself four, five years ago at the time it was ADT versus abiraterone. And we know that in every single MDT, the AR patient, we would've said, "That guy needs docetaxel." Usually high volume, high risk, young people, aggressive disease.

So something that we can't really describe because we've been trying to do that for 10 years, we couldn't do it, but they say ... Interestingly in Germany and every MDT, still, you had 35, 40% of the patients, they would say, "I'm going to give docetaxel to that patient." And what they said is, "That is simple. That is the patient you're going to give the triplet." Because these were the patient you believe they needed docetaxel. Then they say, "When ENZA, APA came, there was a lot of discussion." Then COVID came. And all said, "We may have probably abandoned docetaxel too rapidly. And we should come back to this, 2015, 2017." And in Europe, it's easy, because, in many countries, MDT is obligatory by law. But whenever the conclusion of the MDT was docetaxel, they say, "We should still give docetaxel to this patient, and not make it a triplet."

One very interesting comment, also, they made is that every place we've been, I always ask, "Okay, but what AR pathway inhibitor would you use at the present time?" And everybody says, "Okay, at the present time, it has to be abiraterone, because this is the one for which we have the result and the access." And when darolutamide was going to be there, it's probably going to be darolutamide, because for the urological community like mine, it's much easier to do so.

Very interestingly people say, "No, there is still a role for triplet. What are the patients, those we treated with chemotherapy a few years ago, and now we should give triplet? And they all say "Abi or Daro."

Alicia Morgans: So really interesting conversations that are happening around the world and in these symposia in Germany, of course, as well. And I think it's important to hear that take-home message when it's appropriate to use chemotherapy in a patient. If this is a patient to whom we would have suggested docetaxel in the past, we can now add darolutamide or potentially abiraterone and get a benefit from triplet therapy based on the ARASENS data. And of course, the PEACE-1 data that we've had for some time, as well. And I think this is just so important as we see these patients and try to apply these data in clinic.

So when you consider your EAU presentation and the work that you and the team continue to do on these additional analyses within the ARASENS data set, what would your recommendation be to folks who are trying to understand your most recent data and your contribution to the field in this way?

Bertrand Tombal: But I think that we are probably going to torture this data as much as we can. And my guess is that we are not going to find a subgroup of patients that don't benefit from the combination, because there was a high level of selection of patients at the beginning. And I'm very reassured to see that they were all good candidates for ADT plus docetaxel. Beyond that, I'm not sure we're going to find a subgroup that benefits more or less, so the question will remain about docetaxel. And what I can say is that those who used to treat these patients as a clear idea of who needs chemotherapy, and we should not abandon it because it's still very important for many patients. So that would be my recommendation.

And my fear, to be honest with you, is a kind of cooperatist approach. And I can say that because I'm a urologist, and in Belgium, we don't give chemotherapy anymore. It's done in the floor, and the floor is overtaken by medical oncologists. So you don't want to just dismiss chemotherapy because you are a urologist. And indeed, it's so easy to give APA and ENZA. So, we really have to do the effort of thinking for this patient and really trying to find who we believe ... There will be borderline patients; but if a guy pops up in your consultation, the guy is 65 years old, he's got a PSA at 937, liver metastasis and bone metastasis like we discuss at the MDT today, the discussion lasted for 30 seconds. It's clear that we recommended chemo.

The beauty of the ARASENS trial is that it's very pragmatic. You start your antagonist because the guy is metastatic. You order your darolutamide, you do your paperwork; two, three days after, you can start your darolutamide. And one week after when the guy is understanding what's happened, you can start the chemotherapy. You can do it really like we did before, and you can really use, actually, your darolutamide like we've been using bicalutamide for flare protection five, six years ago. So it's very, very easy. Very pragmatic, very easy. So I think that why not to do it?

Alicia Morgans: Well, I think that makes a lot of sense. And as we've seen and as you've presented, across the subgroups that were assessed by metastatic status, M1a, M1b, M1c, and by [inaudible 00:13:32] level, there was a consistent benefit to the addition of darolutamide to ADT and docetaxel for these patients in the ARASENS trial. So thank you so much for presenting this information.

Bertrand Tombal: You're welcome.

Alicia Morgans: And for your expertise, as always.

Bertrand Tombal: Thank you.