Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU Medical Oncologist at the Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today Dr. Matthew Smith, who's a Professor of Medicine and the Director of GU Malignancies at Massachusetts General Hospital, also in Boston. Thank you so much for being here with me today, Matthew.

Matthew Smith: Happy to be here.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about a phenomenal presentation that you gave at GU ASCO 2022 on the ARASENS trial. Can you tell us a little bit about the trial, who was included in this trial, and what you found?

Matthew Smith: Sure. So we designed ARASENS in 2015, 2016, where there was really just very new information that the addition of docetaxel to ADT improved overall survival, and that was reported by both CHAARTED and, subsequently, STAMPEDE. We really had confirmation that that should be best standard of care in patients with metastatic hormone-sensitive prostate cancer. At the time the study was designed, there was really a lack of clarity about where the benefit resided. High risk, low risk, which has sort of now become generally accepted, was not at that time because we didn't have sufficient follow-up from CHAARTED in particular. We elected to make ADT and docetaxel the standard of care, the control arm in our trial. It was a placebo-controlled trial with darolutamide, and we included patients with metastatic hormone-sensitive prostate cancer who had a good performance status and who were candidates for treatment with ADT and docetaxel.

They all had to have metastatic disease, and as you might expect, the investigators enrolled patients who they thought would benefit from at least the control arm, which included docetaxel. So between 2016 to 2018, the study accrued 1,306 patients at 286 centers in 23 countries, so a big undertaking. Patients were randomized within 12 weeks of starting ADT to either darolutamide or placebo, and then patients in both groups were treated with docetaxel for six cycles starting six weeks after randomization. So it was darolutamide concurrently with docetaxel, and then darolutamide or placebo continued thereafter. To make the study easily understandable, we designed it sort of boldly, I think, with a primary endpoint of overall survival. We looked at a number of other key efficacy endpoints, but did not include RPFS because we really didn't feel like improving RPFS alone would be sufficient to move the needle now, since there had been a demonstrated OS benefit for the addition of docetaxel to ADT. We thought that was sort of the necessary standard to change the standard of care in this disease state.

Alicia Morgans: Absolutely. I think you were very right in doing that, and we appreciate your patience in waiting for that endpoint. Obviously it took longer. So what did you find? What was the difference there?

Matthew Smith: So the primary analysis for overall survival was pre-specified and event-driven. There was no interim analysis. It occurred after 533 deaths were observed, and we saw a big benefit. There was a 32% reduction in risk of death in favor of darolutamide. The hazard ratio was 0.68, highly statistically significant. These were a group of poor prognosis patients. The median overall survival in the placebo group was 48.9 months. Big improvement with darolutamide, so not yet reached. And the four year overall survival rates were 50.4% in the placebo group, and improved to 62.7% with darolutamide.

Alicia Morgans: That's phenomenal. From a patient perspective to think about these timelines, I think it's really a hopeful thing. What I think is also quite hopeful is that the studies seem to meet multiple secondary endpoints as well. Can you tell us a little bit about that?

Matthew Smith: Sure. So as you might expect with a large improvement in overall survival, we met a variety of key secondary endpoints, including time to castration-resistant prostate cancer, which is probably a reasonable surrogate for RPFS because those are tightly linked outcomes, but we didn't formally measure RPFS in the study. Time to pain progression, time to symptomatic skeletal event, these are, I think most of us would readily accept, is additional evidence of patient benefit.

Alicia Morgans: Absolutely, and can you tell me a little bit about the adverse events in toxicity, because I think darolutamide has been thought of as perhaps having lower toxicity than other approaches to treatment. How did the toxicity profile look?

Matthew Smith: Certainly from the prior experience in ARAMIS, darolutamide has a favorable safety profile and it's exactly what we saw here. The rates of treatment-emergent adverse events, serious adverse events, adverse events leading to treatment discontinuation were similar between the daro and placebo groups. Grade three and four adverse events were mostly attributable to docetaxel treatment in both arms, and those rates were not altered by addition of darolutamide. We talk about these adverse events of special interest, but they're adverse events of special interest for the drug class. But when you really look at daro versus placebo, there's no meaningful difference in any of those AEs of special interests once you adjust for drug exposure. And even the unadjusted rates for nearly all of those so-called AEs of special interests were similar between the darolutamide and placebo groups.

Alicia Morgans: So when you think about this data, clear overall survival benefit. And really not a substantial difference in toxicity when we think about patients receiving continued ADT versus ADT and darolutamide, which is what they had after, of course, that docetaxel. It seems to be pretty positive in terms of that conversation you might have with patients, as you think about encouraging them. "Let's do some chemotherapy, and then take a maintenance therapy for years." What do you envision that those conversations might be like? Obviously not approved in that setting yet, but how do you see this data being implemented?

Matthew Smith: I think the other point I wanted to make is just the generalizability of the data. So one of the concerns in all of these sort of early intensification type trials is what happened with the control group. So is your benefit because you provided access to a drug or class of drugs that some of the patients were never going to receive in other parts of the world? That really was not the case here, so the OS benefit that was observed was seen, despite a high rate of subsequent life prolonging therapy in the placebo group. 75% of patients, the placebo group, received one or more subsequent life prolonging therapies, and two-thirds of them received a subsequent AR pathway inhibitor, so while not formally a sequencing trial, it's sort of a defacto sequencing trial. So the argument that, "Well, you can just wait and give that later," really doesn't hold true here, as is also the case in some of the other mHSPC trials.

I think the conversation, the way I think about it, is that there's just clear and compelling data that the addition of an AR pathway inhibitor should almost be foundational therapy, right? There are fewer and fewer patients who should be receiving ADT alone. I would argue across almost the entire spectrum of prostate cancer. The earlier disease states perhaps to be determined, but for metastatic hormone-sensitive disease, non-metastatic CRPC, metastatic CRPC, we have really compelling overall survival data from across a number of trials, and including in ARASENS, where these are a particularly poor prognosis group of patients.

I think for me, the conversation's going to be, "Why wouldn't I add an AR pathway inhibitor to ADT in this patient?" Then you're going to choose which drug. I think based on the collective information we have now about darolutamide, one could make a case that it is perhaps best in class. Strong efficacy data is good or better than the other trials in the similar disease states, and arguably better safety, as best you can tell from between trial comparisons. And then the other conversation's going to be, "Who should receive docetaxel?" In some ways, that's almost the harder question now, right? This study, nor PEACE-1, was designed to specifically address that question. It'll be interesting to see how the community incorporates that data.

Alicia Morgans: It will be, and that decision is going to be a challenge as we move forward. I look forward to figuring out how to best make that decision. So if you had to summarize your presentation, this study, and of course the New England Journal of Medicine Publication that was published simultaneously, what would your message be?

Matthew Smith: I think that clearly in the United States and elsewhere, we need to improve care of patients with metastatic hormone-sensitive prostate cancer. There is consistent and compelling data that ADT alone is no longer the standard of care. ADT plus an AR pathway inhibitor is appropriate for most patients with mHSPC and for selected patients, I believe the three-drug regimen of ADT, docetaxel and an AR pathway inhibitor is really the way to go. I would submit that the strongest data to date supporting the latter is the ARASENS data.

Alicia Morgans: Wonderful. Well, thank you so much for sharing your time and your expertise today.

Matthew Smith: Thank you.