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Alicia Morgans: Hi, I'm so excited to be here with Dr. Matthew Smith, who is the director of GU Malignancies at Massachusetts General Hospital. Thank you so much for being here with me today.

Matthew Smith: Happy to be here.

Alicia Morgans: Wonderful. So, Matthew, you have really engaged and participated in the ARASENS Study, which is a study for patients with metastatic hormone sensitive prostate cancer that are eligible for chemotherapy treatment. It included high-volume and low-volume patients, patients with de novo metastatic disease, and recurrent metastatic disease.

Can you tell me a little bit about this study, which led to the approval of darolutamide in the metastatic hormone sensitive setting in combination with docetaxel chemotherapy?

Matthew Smith: Yeah, happy to do so. We designed ARASENS at a time soon after the first observations that docetaxel improved survival in patients with metastatic castration-sensitive prostate cancer, and elected to use the winning arm of the previous trial as the control group.

So all patients in the study received ADT and docetaxel, which would've been considered standard of care at that time, and were then randomized to darolutamide versus placebo. Important to note, patients started ADT and darolutamide, and then within six weeks began docetaxel. So it was really ADT darolutamide or placebo, followed by six treatments with docetaxel.

The primary endpoint for this study was overall survival. And again, at the time we designed the trial, we felt that in order to really move the needle to impact patient care, we needed to show an improvement in overall survival. There was a large statistically and clinically significant benefit in favor of overall survival, with more than 30% reduction in risk of death from prostate cancer, and significant improvements in a variety of other secondary endpoints, including time to pain progression, time to first skeletal-related event, and time to subsequent antineoplastic therapy. So really unequivocally substantial and clinically meaningful clinical benefit in patients receiving darolutamide.

Alicia Morgans: Wonderful. And I think really exciting that this is an approved combination used in clinics all over the world now. Very, very exciting.

So to really get down to what's important to patients, though, I know you and the team looked at some secondary endpoints that are really meaningful, including time to pain progression, skeletal-related event activities. Can you tell me a little bit about those?

Matthew Smith: Sure. I guess I'd first begin by saying I think overall survival's important to patients too. We can agree on that.

Alicia Morgans: Very much. Yes.

Matthew Smith: We can agree on that. But in terms of how a patient feels and functions, we try to understand that by looking at other endpoints including time to pain progression. Which is very important in prostate cancer, and particularly important in this high-risk group of patients.

You nicely pointed out that the study included a range of patients. De novo versus recurrent metastatic disease, high-volume, low-volume, high-risk, low-risk by other definitions. But it's worth noting most of the patients in the study had de novo metastatic disease, about 85%. And the majority of patients had high-volume and / or high-risk disease by those standard clinical trial definitions.

We were interested in understanding the benefit of darolutamide across that spectrum of subgroups. And it's important to note in previous reports, including by Maha Hussein at ASCO GU this year, published concurrently in JCO, we saw that the overall survival benefit was consistent across subgroups. Including high-volume versus low-volume, high-risk versus low-risk.

And at ASCO this year, we were interested in understanding the impact of darolutamide on pain progression, an important endpoint for patients. You wouldn't be surprised to know that patients with high-volume disease were more likely to have pain at baseline and had a shorter time to pain progression.

When we did these analyses that presented at ASCO this year, we showed that in the high-volume subgroup, the time to pain progression was significantly improved compared to placebo. It was also true in low-volume, although the magnitude of the benefit was more modest, as you might expect.

There were lots of questions from investigators and clinicians as well, about how much chemotherapy contributed to reduction in pain. So we did sensitivity analyses to sensor pain progression that occurred while patients were receiving chemotherapy. And again, in those analyses we saw clear, meaningful benefit in favor of darolutamide in that post-docetaxel analyses.

Alicia Morgans: Which is so important, because obviously both arms were getting docetaxel, one had darolutamide, so any difference would be attributed to the darolutamide. But great question from investigators, because in many cases we do like to use chemotherapy when patients are highly symptomatic and have a lot of pain.

So as you think about these primary endpoints that are so important to patients like survival, and all the secondary work analyses that you've done, what are your thoughts and how do you really use this data in your clinical practice?

Matthew Smith: I have to say that the way I approach this in the conversations I have with patients has changed over time. I like to think of it, we're interested in history, the history of the clinical trials and evidence and progression of treatment recommendations.

But patients are interested in the best treatment recommendation. And they don't really want to know historically we gave ADT alone and then we gave ADT in dose. That's all of historical interest, but really doesn't matter to the patient across the table from you.

So my approach is different. I tell them they need androgen deprivation therapy and an AR pathway inhibitor. And particularly for patients with de novo metastatic disease, we begin that at the first clinic visit when I'm meeting the patient.

And then really that decision about chemotherapy is a subsequent decision and that's where the patient selection... And in fact, that approach is exactly how we did it in ARASENS. Patients started ADT and darolutamide, and then subsequently began docetaxel.

So my narrative has completely changed. I think it's much easier for patients to accept and understand that the priority is getting ADT and an AR pathway and inhibitor to the patient. And then the subsequent decision is patient selection about appropriate candidates to add docetaxel.

Alicia Morgans: That's really interesting. I actually do the same thing, but I think that stepwise approach helps patients to conceptualize, which is really a lot of information, and really think about how do I get all of this done and not be overwhelmed with the entire process.

So I really use that too. It also, I think, helps with mitigation of side effects as they do occur when we start different therapies. So we can help say, "Well, this is related to this drug and this is related to that one," and we'll just take it step by step and not overwhelm someone.

Matthew Smith: Yeah, it's a good point. And I have to say, often with the other AR pathway inhibitors, I would be more inclined to take that stepwise approach, because of concerns about disentangling the side effects of ADT versus the AR pathway inhibitor.

But the favorable safety profile of darolutamide sort of emboldens me to just start them at the same time. Because candidly, the safety profile of daro is so favorable that it's a very rare event that you would need to either dose reduce or interrupt darolutamide.
A little bit different than some of the other agents where that does occur and there might be more of an inclination to do stepwise treatment. But I'm very comfortable starting ADT and darolutamide at the same time.

Alicia Morgans: Very good. Well, thank you so much for walking us through this new data from ASCO this year and the data that's come out, rolling in over time, related to the ARASENS trial.

And of course, also walking us through how you think about it with patients and those conversations that you have in clinics. So thank you so much for your time and for your expertise.

Matthew Smith: Happy to be here. Thank you.