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Alicia Morgans: Hi, I'm so happy to be here with Dr. Matthew Smith, who's joining me to talk about the ARASENS data and the recent updates in terms of volume status, risk status. So thank you for being here. Dr. Smith, can you tell me a little bit about the ARASENS study, just to sort of set the stage and then we will kind of dig into that data update?

Matthew Smith: Yeah, happy to do so. So ARASENS is a randomized controlled trial that looked at the addition of darolutamide to androgen deprivation therapy and docetaxel in patients with metastatic hormone sensitive prostate cancer. The study was positive, it showed a significant improvement in overall survival, and those results supported the regulatory approval of darolutamide as part of triplet therapy in men with mHSPC.

Alicia Morgans: Wonderful. So why was there a need to look into this volume data or risk data? What was really the impetus for this update?

Matthew Smith: Yeah, so at the time we designed the trial, there was really no consensus on sort of best way to assess prognosis or stratify risk within a prospective clinical trial. We opted to use straightforward and I think important characteristic, which is recurrent versus de novo metastatic disease. Subsequent to our design of the trial, there were other prognostic considerations that became commonly considered that include high volume versus low volume, and then high risk versus low risk. So after the results of the ARASENS study, primary results were reported, including the pre-specified subgroup analysis by de novo versus recurrent. There was a lot of interest in looking at subgroup analysis, looking at other prognostic groups.

Alicia Morgans: Which is important I think, as we're making those clinical choices. And did you find that there was a difference in terms of the benefit of adding darolutamide to ADT docetaxel by any of these risk groups?

Matthew Smith: The short answer is no. So in first, I should comment on our pre-specified subgroup analysis. There was similar hazard ratios for both recurrent and de novo, sort of making the argument that there's benefit of adding darolutamide regardless of prognostic group, at least among enrolled patients. And then when this was looked at further using alternative definitions in these exploratory analyses, high volume versus low volume and high risk versus low risk, there was just consistent benefits seen in all of the subgroup analyses.

Alicia Morgans: That's very interesting, I think supportive of the data at least being applied to clinical practice. Does this actually change your practice, though, every day? Because it doesn't answer any questions about docetaxel, obviously, but really is focused on understanding the benefit of darolutamide?

Matthew Smith: Yeah, I think the big takeaway is this further highlights the fact that ADT alone is no longer an appropriate standard of care for the vast majority of patients with metastatic prostate cancer. And sort of provides further confirmation that the benefits of an AR pathway inhibitor are observed across a wide spectrum of prognostic groups. What our study and no other study can answer at the present though, is whether docetaxel is necessary. So that would require other research.

Alicia Morgans: So I think there was some other updated data, safety analyses by volume, did you find anything unexpected there or anything of interest?

Matthew Smith: So no surprises. The favorable safety profile of darolutamide was confirmed in the updated analyses.

Alicia Morgans: Which is great. Good to know. And not that we would expect anything by volume in that situation-

Matthew Smith: Agreed.

Alicia Morgans: Necessarily anyway. And so as you think about this, what would your kind of overarching message be on this update?

Matthew Smith: So I think it's an important reinforcement of the need to intensify systemic treatment in patients with metastatic prostate cancer. ADT alone is no longer an appropriate standard of care, with very few exceptions, perhaps older, frailer patients or patients who have a particularly good prognosis disease. But for the vast majority of the remaining patients, they should get more than ADT. Nearly everyone should receive ADT and an AR pathway inhibitor and selected patients should receive triplet therapy.

Alicia Morgans: Great. Well, thank you so much for your expertise and of course, congratulations to you and your team for some additional data on the ARASENS trial. We appreciate your time.

Matthew Smith: Happy to do it. Thank you.