Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist at Dana-Farber Cancer Institute in Boston, in the US. I'm so excited to have here with me today, a good friend and colleague, Dr. Cora Sternberg, who's a Professor of Medicine and the Clinical Director of the Englander Institute for Precision Medicine at Weill Cornell in New York, New York. Thank you so much for being here with me today, Cora

Cora Sternberg: It's always a pleasure to be here with you, Alicia, and you know that.

Alicia Morgans: Oh, well, wonderful. It is always good to talk to you too. And today, I wanted to talk to you about the ARASENS trial, which was, of course, presented at GU ASCO 2022, also published in the New England Journal, and you were an author on this paper and participated in this study.

So first, can you set the trial up for us? Just remind us, at a high level, what the ARASENS trial was.

Cora Sternberg: ARASENS is a trial for patients with metastatic hormone-sensitive prostate cancer. Patients were randomized between receiving androgen deprivation and docetaxel plus darolutamide, a new androgen receptor inhibitor, or androgen deprivation therapy and docetaxel with placebo.

The patients were stratified according to their extent of disease, whether or not they had lymph node only disease, or lymph node in bone or visceral disease, and according to alkaline phosphatase. 86% of the patients, in both arms, presented with metachronous hormone-sensitive prostate cancer, which we know, is a more serious disease than those patients who have had radical prostatectomy in the past, and then slowly creep up, and have a metastatic disease. So it's a more aggressive presentation.

And what they were looking at, docetaxel was in both arms, as was done, as has always been used quite frequently in Europe, more so than in the United States. And they were looking at the difference between adding an androgen receptor inhibitor, as compared to placebo, with the docetaxel, which was given for six cycles. It wasn't a question of whether or not docetaxel should or should not be used, because docetaxel was in both arms.

And in fact, the trial was extremely positive. There was a 32.5% reduction in the risk of death, in favor of those patients who received darolutamide. Now we know about darolutamide. It could be like, you could say, it's the new kid on the block, after enzalutamide and abiraterone. We know it from the non-metastatic CRPC trials. It has a low level of toxicity, it doesn't cross the blood brain barrier. And in those non-metastatic CRPC trials, it showed it could really increase metastasis-free survival by some two years, and a 31% reduction in the risk of death. So there was good evidence to put this drug, which is fairly non-toxic, together with the docetaxel in the metastatic hormone-sensitive space.

Now, we have a precedent for doing this, a triplet therapy, in the PEACE-1 trial, that was presented by Fizazi, at the last ESMO meeting, where they used docetaxel, ADT, and abiraterone and prednisone, versus docetaxel and ADT. And there two, the triplet therapy was better than a doublet therapy.

Now, in the United States, and I would say worldwide, patients with hormone-sensitive disease are not receiving triplet therapy, which is new. They're not even receiving doublet therapy, which we've been talking about for ages. They're mainly receiving just ADT. And so I think there's a lot to do with education in the community, to make people understand, that at least, doublet therapy with an androgen receptor antagonist, is better, or, with docetaxel is better. But now we have the triplet therapy, and we need to understand, who are the patients that really are going to be eligible for the triplet therapy? Who, when you see in your practice, will you give triplet therapy to? Probably not the 90 year old that you see, but maybe someone younger, who's sicker. And as I said, many of these patients, 86% in both arms, did present with metachronous disease. So these are patients that are presenting with widespread disease, rather than the patient who's just creeping up with a low PSA, after having a radical prostatectomy.

Alicia Morgans: Absolutely. And I think it's interesting too, that certainly, they have not yet reported data by disease volume yet. Because at the time when the study was designed, as you said, they were really using, I think, the AJCC classification to describe patients by the extent of lymph node or bone metastases, rather than that high/low volume designation, which makes sense, I think, given the time that the study was designed. But we do look forward to that analysis too, because that may help us understand which patients were those that were included, in large part, in this trial.

Cora Sternberg: Yeah. These trials were designed in like, 2015, 2016, before we even had results from the CHAARTED trial, and we talked about high volume and low volume, or the LATITUDE trial. That was the way it was done back then. But they not only decreased the risk of death, it decreased the time to developing of CRPC, it decreased the time to pain, it decreased the time for skeletal events, it decreased the time to needing secondary other therapies. So, there were very many benefits.

In Europe, docetaxel is used more frequently than in the United States, partly because of the cost. It costs less, and it's just generic, rather than the new androgen receptor inhibitors. So that, was kind of a standard there. So adding on something like darolutamide, is something very new for Europe. And yet, we also have to consider, obviously, the financial toxicity of putting a triplet regimen together for people anywhere.

Alicia Morgans: Yes. Agreed on that. And just the ongoing taking a pill each day. Which in the past, we've been able to say to patients, "Take your ADT and docetaxel. You won't have to take a continuing medication." But as you said, this was resoundingly positive, not just for overall survival, but for all of those other endpoints.

Cora Sternberg: Yep.

Alicia Morgans: So I think, it makes a compelling case to use the triplet in patients, who are fit for, and eligible for, in the eyes of the treating physician, docetaxel chemotherapy, at least, that ADT/docetaxel doublet.

Cora Sternberg: I absolutely agree with you. Having data now, that's showing an important improvement, a 32.5% decrease in the risk of death, with ARASENS, was really quite important. And I think that we can't ignore these data. We'll have to understand, who are the patients who actually are eligible for triplet therapy? And we also have a backup in the PEACE-1 study, that had been reported with docetaxel/abiraterone and ADT, back in September.

So I think, when we'll be in our clinics the next weeks, we'll have to think about which, who are the patients that are young enough, and fit enough, for chemotherapy, and to receive one of these, and to receive darolutamide.

The toxicity was mainly related, in the first six cycles, with the docetaxel, not particularly with the darolutamide, which is, I think, important to notice, that darolutamide did not create extra toxicity.

Alicia Morgans: Absolutely. Especially if you're going to continue a maintenance pill over that period of time. I think the toxicity is incredibly important to consider. So as you reflect on the ARASENS trial, and of course, remember the PEACE-1 information, what would your message be to the community, as they're trying to think about how to incorporate these findings into their clinical practices?

Cora Sternberg: I think that it's very important that the community learns that we shouldn't be giving ADT alone, that that is inadequate therapy. And that whether they added androgen receptor antagonists, or six cycles of docetaxel, which may be less expensive, and many patients can tolerate those six cycles, one or the other, at least, the doublet should be used, because we've improved overall survival in that way.

But in those patients who are young with aggressive disease, I certainly would think about going for triplet therapy. I think that will become the new standard for those patients who are fit enough to undergo triplet therapy, and those who present with aggressive disease. The man who comes to the emergency room with spinal cord compression, is really different than, the man who we've been following for years, and years, and years, and just has a rising PSA, and some small oligometastatic disease, for instance.

Alicia Morgans: I agree. I really appreciate you giving your reflections on the ARASENS trial, and also helping us to think through, how and what this means for us in our clinical practice. Thank you so much for your time and your expertise.

Cora Sternberg: My pleasure.