Alicia Morgans: Hi! I'm so excited to be here with Professor Jan Philipp Radtke, who is here from Germany to join us, to talk about his presentation at EAU 2022 on the ARASENS data. Thank you so much for being here today, Professor Radtke.

Jan Philipp Radtke: Thank you, Alicia. Hi everyone. I'm very glad, and it's an honor for me to present this data on the ARASENS trial here, for the audience of UroToday. Thank you.

Alicia Morgans: Wonderful. Can you please walk us through... I know you gave a wonderful review of the data that has been presented, the top-line data from the ARASENS trial.

Jan Philipp Radtke: Thank you, Alicia. The storyline for this talk will be... We started with propedeutics in metastasized hormone-sensitive prostate cancer. I think this is very, very important for our audience to get some frame where we are. We then headed over to the question if one size fits out, so if it's great for every patient or do we have favorable subgroups, and then we are moving finally to suggestions for an ideal patient, which were the end points of the ARASENS trial presented not only by Professor Tombal at the EAU, but also in the publication. The primary endpoint of course, was overall survival and we have an overall survival benefit within hazard ratio of 0.68 for adding darolutamide to the standard of care, which was in 2014 at the beginning of the trial and where the study design was based on ADT plus docetaxel is the standard of care.

The addition of darolutamide lead to this overall survival benefit, which can be transferred to 32% as combined to ADT plus docetaxel. And in fact, for counseling a patient, the four year survival benefit rate increased from 50% with docetaxel plus ADT to 63% with the combination of darolutamide and standard of care. And also interesting is the secondary endpoint. One secondary endpoint we want to talk about here is the prolonged time to castration-resistant prostate cancer, a situation in where problems for patients increase, so regularly, when in hormone-sensitive prostate cancer status, the patient is mostly well and the problems start when he transfers to castration resistance. And as you can see, we had in the ARASENS trial, also a hazard ratio of 0.36, transferring to an 64% benefit of adding darolutamide to the standard of care as compared to ADT plus docetaxel.

Alicia Morgans: Yes, I think this is so important, because as you said, ADT and docetaxel has been a standard of care for some time and is a really important option for our patients, so let me know, from your perspective. This, of course, delaying time to castration resistance, very, very important for patients. Are there other things that you think about, other endpoints that were of interest and which patients do you think of as being prime candidates for this combination therapy approach?

Jan Philipp Radtke: This secondary endpoint we chose here... I think it is important. There might be other important endpoints, which might be in fact, time to schedule events, which might be time to PFS, so progression free survival is one endpoint, which is also interesting. PFS2. So the progression free survival until next novel anti-androgen or chemotherapy is chosen, is also of interest, of course. In my opinion, this endpoint... this is secondary endpoint is of interest and yeah, let's see how this will work out in the upcoming trials we are discussing on. I think it's interesting, because it's a little bit more than overall survival and I think progression free survival, I think is important, but then we are talking about, is this radiographic or not progression free survival? So you are ending up with progression. You are ending in castration resistance, so I think this is it's well chosen.

For me, as a clinician, I find it pretty interesting. Yeah, this endpoint of overall survival in this combination and the study design is, on the one hand, it's pretty interesting because it covers the standard of care within the last, I think 6, 7, 8 years of treatment of hormone-sensitive, prostate cancer. However, in the end, it's the strength and in the same moment, the weakness of this study, because now, we are seven years in advance. And now we are talking about the question, whether to add any novel hormonal treatment like apalutamide or enzalutamide to ADT and comparing this to ADT mono, and this is the problem in this trial, so we do not have data on ADT mono and we won't get them, I think, so this is the problem, and we will wait or we have to wait until 2000 and I think 24, 25, when data on the ARANOTE trial, which is combined trial with, I think, SEER data or data from the US, on the combination of darolutamide plus ADT as compared to ADT monotherapy, will be published.

Alicia Morgans: Yes, I completely agree and I think it's so important that we see that there isn't really a question of whether the addition of darolutamide to the combination of ADT and docetaxel is helping. It's so clearly beneficial, not just on intermediate type endpoints, as we discussed in terms of progression time to castration resistance and others, but also of course, on overall survival, so really cementing it as an option as what appears to be additive, very clearly, to ADT and docetaxel, that standard of care, which was used as the backbone and control arm. My question for you is really, I think, about implementation as a urologist in Germany, as you're seeing patients in the clinic, how do you choose the right patient to use this approach, knowing the effectiveness of darolutamide in this setting?

Jan Philipp Radtke: I think most important is that you start with propedeutics and this is when you're treating patients. What do you have to know in this status of disease? First, you have to know, okay, is this the noble or is this recurrent disease? Meaning, at least two measurements, both PSA increase over 0.2 after radical prostatectomy, or at least two measurements over two nanogram per milliliter after radiotherapy, so you have to compare the De novo versus recurrent disease. We're talking about in a minute, why this is important and the second is even more important is metastatic burden. On the one hand, we are talking about volume, depending on CHAARTED criteria, so is this high volume with four bone metastasis, including one outside of the vertebra column or the spine, or do we have visceral metastasis or do we do not have? And the second is the risk, according to latitude.

So, over two risk factors. Three bone metastasis, [inaudible 00:08:41] or ISO grade group four or greater. And this is pretty important, because when you have an overview of the study designs within this trials we have, in this registration studies. In most studies, we have the De Novo metastasized patients. 96% in the STAMPEDE arm for docetaxel, 94% in the stem STAMPEDE arm for [inaudible 00:09:09], a hundred percent in latitude trial and so on, and for Apalutamide, in the TITAN study, where 83% are De novo metastasized patients. And when you were having a look at this overall survival benefits sub-stratified in De novo versus recurrent disease for the ARASENS trial, you have nearly the same picture, so we have 86% of men who were included into the ARASENS trial, had De novo metastasis hormone-sensitive prostate cancer, 86%. And here you have a hazard ratio of 0.71, which is clearly statistically significant. On the other hand, if you have recurrent disease, only 14% within the ARASENS trial had recurrent disease.

And even if you have a hazard ratio here, which is of 0.61, which is very, very good, this didn't reach statistically significance, so, meaning, this crosses the one... And there are less patients, and this is in the moment a problem, so we can tell, okay, and we can see there is a trend towards adding darolutamide, also helpful and beneficial for recurrent disease patients, but in the end, didn't reach the statistically significance, because in fact, the study is not powered for this. This is pretty important. And second question is which patients really benefit. Do all subgroups benefit from adding darolutamide and what you can see here is that most patients who were included in the ARASENS trial were those who have high metastatic burden and high risk. Even these groups were not called according to risk, according to latitude and were not called volume, according to CHAARTED this is a problem.

In fact, a problem we have to talk when we're talking about ARASENS trial, so we have some trends in, an example, most were M1 metastatic disease at initial diagnosis and here we can see there is a statistically significant benefit for adding darolutamide. If they had visceral metastasis or bone metastasis in effect, bone metastasis here is pretty clear that adding darolutamide is beneficial. The same is when you have alkalic phosphatase as a surrogate parameter and if this alkalic phosphatase was above the upper limit, the patient was... So, darolutamide was in favor for those patients, so you can construct a little bit, some factors that show pretty clear that darolutamide is helpful, but we do not have to subgroup analysis that we know from Chartered or latitude.

Alicia Morgans: I think that's all fair and a really nice analysis, so thank you so much for walking us through that. I'm always cautious with subgroup analysis, especially, as you mentioned, they're not powered, but certainly can help us understand as a hypothesis-generating exercise, whether there might be opportunities at least to investigate more in certain populations to understand the clear benefit and so important to really dig down in the patient population, which was of course, a chemo fit population that could enroll in this trial, so as we wind up, I'd love to hear what your final message was for the audience at EAU 2022, as you reviewed this data and really dug into it from a clinical perspective.

Jan Philipp Radtke: Thank you, Alicia. And in fact, this matters. This subgroup in analysis, even if they're powered or not, they matter. In example, in Germany, you won't get a cover for some novel hormonal treatments by your insurance, in terms of adding abiraterone to ADT, if you are not on high risk. And in fact, adding docetaxel to ADT, if you're not high volume, according to CHAARTED, so it really does matter if it's power or not, and I think this is pretty important also for clinicians, not only in Germany.

Alicia Morgans: That makes a lot of sense. And I really appreciate you walking us through that, because insurance, of course, matters to get drug to patients, but as clinicians, these subgroups are always going to matter to us so that we can maximize benefit in our patients and really minimize toxicity and settings, where we don't expect the benefit to be substantially enough, so if you had to define who are the patients where you're really going to use this data, what would that definition be? Who are those patients?

Jan Philipp Radtke: Thank you. And what I want to empathize is a little bit which patient fits most for this, so even if we are not having data on volume or risk, what we can say is if we have patient with higher tumor burden, and if we have a patient who is fit for chemotherapy, or you think who is fit for chemotherapy and will benefit, and unless we do not have aranote data available until 2024 or 25, so if you want to give your patient chemotherapy, then ARASENS might teach us to add darolutamide to those patients. I think this is beside the more general question, whether to give a triplet versus a duplet, maybe for sequence purposes or for side effects. If you simply want to answer this question, if you want to give chemotherapy, then according to ARASENS, you should give or add darolutamide.

Alicia Morgans: That's a great message. And I think it's so important too, as you said, understanding where these drugs may work most effectively and ways in which we can maximize the benefit for patients and really reduce risk in settings where we might not have as much benefit, is important for clinicians regardless of insurance coverage, so I so appreciate you walking us through this and sharing your expertise and your unique perspective from Germany. We so appreciate your time.

Jan Philipp Radtke: Thank you.