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Alicia Morgans: Hi, I'm so excited to be here today with Professor Bertrand Tombal, who is joining me from Brussels, Belgium. Thank you so much for being here with me today.

Bertrand Tombal: My pleasure as always.

Alicia Morgans: Wonderful. Bertrand, I just wanted to give you the opportunity to present some data that you spoke about at EAU 2024, giving us an understanding of the European population within the ARASENS data set. So, I would love to see your slides and hear more.

Bertrand Tombal: Okay, so thank you for giving me the opportunity to quickly present that update of the ARASENS trial, where actually we focus on the European patient. So, ARASENS was a global trial and every time you do a global trial, different regions in the world say, "Yeah, but is it the same in my region?" And especially in Europe where there's still a lot of discussion about the triplet. We believe it was very important to present this data.

So as you will remember, ARASENS was a study looking at the benefit of adding darolutamide in patients who were treated with ADT and docetaxel for newly diagnosed metastatic hormone-naive prostate cancer patients. Actually, it was the only trial that was designed from scratch to answer that question. The question being, actually, is ADT plus docetaxel alone enough when you have a molecule like darolutamide, apalutamide, enzalutamide, and others available?

So in the ARASENS trial, adding darolutamide on top of ADT and docetaxel significantly reduced the risk of death by 32.5%. People would say, "Oh, okay, it's nice," but keep in mind that roughly at the same time, such benefit was not shown, for instance, with enzalutamide. So, it was important. Darolutamide also improved key patient-relevant secondary endpoints, such as time to CRPC, time to pain progression, and others. So since then, many guidelines have incorporated that triplet with ADT, docetaxel, and darolutamide as one of the standards of care for these patients.

So here, we have a focus on the subset of patients from Europe. Actually, it's a large subset. It is close to between one half and one-third of ... It's 472 patients. Some people will say, "Okay, it's Europe at large," because indeed it includes Russia. But you see that it was distributed over all the other European countries. When it comes to the primary endpoint of overall survival, there was no difference between the overall subpopulation and the European subgroup. Once again, this seems to be easily shown like this. But I remind you of a trial like LATITUDE, where actually there was quite some difference between the different countries. Here, no, it's the same. The hazard ratio is even a little bit better and still statistically significant.

The same for all the time to castration-resistant prostate cancer. I like this one actually, especially for the placebo. Because many people would say, "Should we delay the introduction of a drug like darolutamide and ADT when you give ADT and docetaxel?" But actually, in that population, which was kind of towards a very advanced stage, we see that roughly 30% of the patients had already progressed in the placebo at one year and more than 50% at two years. So, I think that this is important data.

Where there was a lot of question was whether European patients would be treated subsequently in the same way that patients in the rest of the world would be, because that could actually influence overall survival. And you see that the treatment was distributed in the same way, maybe a little bit more cabazitaxel in Europe. Europe has always been keen to use chemotherapy as you know. And drugs like Sipuleucel-T and apalutamide that were not yet available in Europe by that time and very low Lutetium-177. That was not yet broadly available.

In terms of toxicity, very interesting. You see that neutropenia was actually much lower than in the rest of the world. I really believe this comes from a more systemic use of prevention with GMCSF, which is part of the standard guidelines. So we had less neutropenia on average than in the rest of the world before the rest of the toxicity was very similar. So, in conclusion, I think that what we've seen with darolutamide all over the world is also maintained in the European subgroup. Darolutamide was well-tolerated, and we have even a similar, if not lower, incidence of treatment-emerging adverse events. So, I think that the European physician may be reassured about speaking of the same benefit.

Alicia Morgans: Well, thank you so much for that, Bertrand. That was really, really important and certainly, as you said, really reassuring. One piece I'd love to dig into a little bit, it looked like in the subsequent therapies for patients who were European patients being treated in this analysis, about 70% of them received subsequent AR signaling inhibitor treatment. And I would love to hear your thoughts. Because a lot of people say, "Well, we can just sequence these therapies. We don't necessarily need to do the triplet." And I think in most cases they're talking about docetaxel. Really, that's part of the argument. But I mean, that was pronounced that there's such a difference in those curves with that later administration of the AR signaling inhibitor. And even though most of those patients got an AR signaling inhibitor, I wonder what your thoughts are there.

Bertrand Tombal: I think it's just a bias of a placebo-controlled trial.

Alicia Morgans: Yeah.

Bertrand Tombal: And actually, I would say even it's in favor of darolutamide, because this was a placebo-controlled trial, you could not break the count at progression. You could only in case of severe toxicity. So, imagine that by the time the patient was progressing, the treating physician had no idea whether the patient was on placebo or darolutamide. And with all these treatments, we already tried to guess, "He had some fatigue. He had some rash." So in all the previous trials, we always tried to guess what the patient was on. But here, as it is reflected in the toxicity profile, there's not much difference with placebo. So I mean, the physician usually assumed the patient was on placebo and would treat with what... which was the standard second line of treatment, which was enzalutamide or abiraterone. Know that if the trial was open label and we had discussed this intensively before starting the trial... if the trial had been open label, I guess the distribution of second-line treatment would've been totally different. And this doesn't say in any way that enza or abi would be beneficial after darolutamide. So, I think it's just a typical bias of a placebo-controlled trial.

Alicia Morgans: But really interesting to that point that if there was... with 70% of patients in the placebo arm getting an AR signaling inhibitor, and actually that AR signaling inhibitor was, I think, the most common second-line treatment for patients in the darolutamide arm as well, to your point. I mean, if anything, that would potentially make those survival curves come closer together because you're using an ineffective second-line AR signaling inhibitor and then you're using an ineffective treatment. Yet still, there's quite a difference between those patients who had darolutamide upfront and then those who had it as a first-line for MCRPC. I just think it's so pronounced and so important that we use these agents upfront, early on when we know that they can be so effective. I would love to hear your thoughts, just final comments, clinical implications from this, of course, reassuring to European patients. Anything else you want to share that you can take to the clinic next week?

Bertrand Tombal: Yeah, yeah. Clearly, exactly, we insist on what you said. It's not the fact that you give an AR pathway inhibitor at some point to the patient, because this is something we hear many times, "I've got a drug I'm going to give it later to use it later." No. When you have such a high proportion of patients who receive a second-line treatment, it's not about the drug, it's about the timing. The benefit is because you give it early. The study is not about daro versus apa, versus... It's really early darolutamide versus a late AR pathway inhibitor. And the benefit is such that it confirms that even when you give docetaxel, an early introduction of the AR pathway inhibitor is critical for the survival of these patients.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your expertise. Thank you for giving us these updates on European patients and really sharing those differences that occur even though a majority of these patients, whether they were in the darolutamide arm or in the placebo arm, got an AR signaling inhibitor. It's a really powerful message and I appreciate you sharing it with us today. Congratulations on your presentation, again.

Bertrand Tombal: Thank you so much. Always a pleasure.