Alicia Morgans: Hi, I'm so excited to be at ESMO 2022, where I have the opportunity to speak with Dr. Neal Shore. Neal, thank you so much for being here.

Neal Shore: Oh, great to see you.

Alicia Morgans: Wonderful. Great to see you too. And I wanted to get your perspective on some of the data we've been thinking about for the last few months. The ARASENS trial came out and I think has been certainly on our minds and sometimes in our clinical practice. What is your perspective on this data, which, of course, is data for patients with metastatic hormone-sensitive prostate cancer, who receive a triplet of ADT, docetaxel, and darolutamide. What is your perspective on that data and that benefit in your urologic clinical practice?

Neal Shore: Yeah, so I think it's great data, and this is the first FDA-approved triplet therapy. We had earlier very nice data from ESMO 2021, where there was the PEACE-1 data was presented. Similar construct, mCSPC patients, and getting a triplet with abiraterone, instead of darolutamide. But ARASENS, as you nicely summarize{d}, really clearly demonstrates the superiority, in terms of survival and numerous other secondary endpoints of triplet versus doublet therapy. I've always been a big proponent of triplet therapy, even before we saw the level one evidence. Why? Well, many of these patients, particularly the high volume patients, if we, say, have four or more bone lesions and/or visceral metastases, that's a very aggressive disease phenotype. And they tend to be younger. Their performance status is usually better than the CRPC patients. So my feeling has always been "hit these patients hard as you can with as many novel mechanisms of action."

A taxane microtubule inhibitor is clearly distinct and different from testosterone suppression, which is clearly distinct and different from an AR blocker. And so, the folks who designed the ARASENS trial did this back in 2017. It takes a while to see these results. The results are highly statistically significant. New England Paper plenary presentation at ASCO GU. So I think this is really, really important. We throw the word around "game-changing." It is game-changing. Now many have argued, "Well, but what about just ADT and darolutamide?" Sort of similar to what we saw, great results with ADT and enzalutamide with ARCHES and ENZAMET, ADT and apalutamide with TITAN, ADT and abiraterone with LATITUDE. And of course, all the STAMPEDE armed correlates, which have fantastic. There are two significant studies that are going{,} that are looking at ADT and darolutamide alone. I have the honor to be the PI of one, a large phase two study in the US called the ARASEC trial.

It's a phase two, 200-patient open-label single-arm. Our control arm, interestingly, is the monotherapy arm from the CHAARTED trial. And we're doing propensity match scoring, which is really kind of a fascinating way to do it. And so, I'm excited about that on a whole host of different issues. And then, a phase three trial just completed an enrollment outside the US called the ARANOTE, which is mCSPC ADT and daro versus ADT monotherapy. So this is great for our urologist and medical oncology colleagues, because we have more, as we say, the proverbial tools in the toolbox. And the clock's ticking on these patients. And we want to keep these patients living longer, living good quality of life, and avoiding complications of therapy. I like the idea of getting in the docetaxel early. It's only six cycles. Patients are typically a bit younger. They're fit. Of course, they have to be fit for chemotherapy.

Alicia Morgans: Absolutely. But I think it's interesting, the ARASENS trial did include any patient who was fit for chemotherapy. And there's been a lot of discussion about whether these patients should really be de novo, as they were in the PEACE-1 trial, or whether the patients that we should focus on for treatment should be those patients with high volume disease. And how do you think through that? Because these questions weren't answered exactly in the ARASENS trial, they did open to everyone, even though a majority of these patients did have de novo disease, at least at presentation.

Neal Shore: Yeah, that's a great point. 15% of the patients in ARASENS had recurrent disease, or what some people outside the US call metachronous de novo synchronous. I think I agree with the premise of your question. I think, for low volume, I'm not inclined to use triplet therapy, based upon the sort of traditional CHAARTED definition, that Chris Sweeney, to his credit, really started us thinking about. Of course, that was based on conventional imaging. So where does that put us now, as we start to use more PSMA PET technology? But I tend to favor couplet therapy for my low volume patients. Clearly, couplet therapy for patients who are chemo intolerable or ineligible. But again, I like to be a little bit more on the aggressive side and explain to patients not to get too panicked when they hear that we're going to add in chemotherapy, which I think just the word alone is frightening to many patients. I've actually been rather impressed with how well they tolerate the six cycles. But yeah, I'm going to almost invariably relegate it to high volume patients.

Alicia Morgans: Yeah, I think, in my practice, that's where I find the majority of my patients are as well. But it is nice to know the label doesn't have these restrictions. And so, it's important for us, as clinicians, to think about who is the right patient and make those decisions, as we're in practice with our patients. So very, very important there. So as you think about this data, and you mentioned the sort of game-changing addition of darolutamide to ADT and docetaxel. And now that we know that it's FDA-approved in this indication, what are next steps? And where do we go from here?

Neal Shore: Yeah. Well, first of all, I like the fact that you brought up that the label still leaves us to individualize, like a lot of things. In the nmCRPC population, they didn't include the PSA doubling time of less than 10 months. We can individualize and have that conversation with patients, which is very important, the shared decision-making. And that speaks to the art of medicine, which is fun and important and allows flexibility. And I think similarly, regarding triplet and couplet therapy, most importantly, monotherapy ADT for mCSPC needs to be highly discouraged, except for very, very small exceptions. So I think this leaves us at a very good point in time, in terms of our patients with advanced prostate cancer, as we kind of invariably call it, making it a chronic disease state.

So they don't succumb to the disease. I think it's also, from a health economic outcome reporting aspect and evaluation, very important to look at long term safety tolerability. ARASENS didn't show any particular discordance between the triplet versus the couplet arm. We know darolutamide from the ARAMIS trial, and now in ARASENS, is a very well tolerated drug. There are safety signals that need to be monitored, absolutely. And there are discussions that we all need to have with our patients, regarding that.

Alicia Morgans: Wonderful. Well, thank you again, as always, for going through all of this with us. We appreciate your expertise. Thank you.

Neal Shore: Thank you.