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Alicia Morgans: Hi, I'm so delighted to talk today with Dr. Evan Yu who is a professor of medicine at the University of Washington and the Fred Hutchinson Cancer Center in Seattle, Washington. Thank you so much for talking with me today, Evan.

Evan Yu: Thanks for having me today. It's a pleasure to be here.

Alicia Morgans: It's always a pleasure to talk to you. And I want to talk to you about one of the more pressing and somewhat controversial things that has come up since GU ASCO and some recent publications. Of course, we're waiting for more data as well. We've heard some early data on triplet therapy from the ARASENS trial. We have some not entirely mature data from PEACE-1 and ENZAMET with triplet therapy thinking about overall survival outcomes. And I think the question that everyone's thinking about now is how do we actually consider integrating these approaches into our clinical practices, especially around the use of chemotherapy in these populations as people ask, is AR targeted intensification with ADT enough?

So a big topic, but I knew you'd be the right person to take it on. What do you think?

Evan Yu: Well, I think it's a good question. But personally, I don't think it's all that controversial. I'm pretty impressed by the data. And what I would say is this, is that, although I'm impressed by the data, I also have to recognize that this is not all patients with metastatic prostate cancer. This is a subset of patients with metastatic prostate cancer. So one of the key points from these studies is the fact that most of these patients had de novo metastatic disease. If you look at the PEACE1 trial, that was mandated for inclusion onto the study, that patients had to have de novo metastatic disease, meaning they presented with metastatic disease. And we think that that might have a different biology than patients who have local therapy, let's say surgery or radiation of prostate, and then present with relapse later. We think it might have a much more aggressive biology.

When you look at the ARASENS trial, 86% of the patients had de novo metastatic disease. So again, although I think the data is unquestionably positive for triple therapy, it's unquestionably positive for a patient population that has very aggressive risk characteristics. And I think that this is probably a treatment for some, but not for all.

Alicia Morgans: Yeah. I would completely agree with that. And I think that makes it, I guess, an easy conversation. Of course, all these patients were also chemo fit and we don't always see chemo fit patients as the ones that are walking through the door in clinic. But, when I think about it from my perspective, and I'd like to hear yours. If a patient is chemo fit, especially if that patient has de novo metastatic, high volume, hormone sensitive disease, I would think in most every case, unless again, the patient really expresses without me prompting him that he doesn't want chemotherapy. I would present chemotherapy and triplet therapy as really a standard for the patient to refuse. So offering it to that patient as an option and giving that patient the opportunity to say no, I really think the benefit is so strong that I would rather offer it and have the patient have an educated discussion and decision and decline, rather than not offer it at all. What are your thoughts?

Evan Yu: Absolutely. I agree with all that. The one thing that I'll state is that we just don't know the contribution of the CHAARTED criteria, high volume versus low volume, because we haven't seen those subsets yet from these studies. But, I know that they're going to do them and we're going to see these subset analyses. And I think it'll be probably reassuring, meaning that most of these patients that were chemo eligible and had de novo metastatic disease probably had high volume disease as well. And I think eventually when we see that it'll probably be reassuring. Of course, you never know. You've got to see the data. But I would guess that will be the case and then it'll offer reassurance. But I definitely offer chemo to those with de novo metastatic disease. And I talk to them about this data and let them tell me what they think.

I don't think it's wrong to not incorporate chemotherapy. I don't think it's wrong to just use ADT and abiraterone or enzalutamide and apalutamide, and I don't think it's wrong to just do ADT and docetaxel. I just think it needs to be an active conversation with the patient presenting the data that exists and recognizing the gaps in the knowledge. Because there are gaps that we don't quite understand exactly who those best patients are that will respond very well and get the most benefit. But I will say, emphasize again, I think this data is really quite indisputable for the patients that were accrued to the study.

But, I will point out that at this point in time, we had a lot of data already and I'm going to guess that most investigators were highly selective about who they put onto these studies. They probably put patients who have more aggressive risk characteristics that you could just see and smell from the door and those with the lower volume disease, more indent risk characteristics. They probably just gave them a novel hormonal therapy treatment for intensification rather than offering them this more aggressive regimen.

Alicia Morgans: Well, I can say as one investigator because I was, that was absolutely the thought process that I had. I was absolutely considering patients with the de novo metastatic disease as being fantastic candidates, but really the volume status is something I did think about. But to your point, first of all has not been reported out in ARASENS. The data is immature in the low volume group in piece one.

Evan Yu: Right.

Alicia Morgans: Of course we haven't seen what's going to be shown in ENZAMET. And I think that there is some potential risk in relying on subgroup analyses that are, in the case of ARASENS, not pre-specified and certainly defined in a post study analysis, which will be very interesting. But is, I think, something that we would potentially use to the exclusion of the overall data to our peril. So it's important for us to recognize that the primary endpoint is very positive and that these subgroups may be useful in some thought processes, but aren't necessarily what needs to drive our decision making.

Evan Yu: Absolutely. I think I used the term reassuring, which means that, it shouldn't be your primary decision maker, but it might make you feel better about the decision you made. Yeah, absolutely. Not to get off topic too much, but the one thing that's not answered by these studies is we know that if you have somebody with de novo metastatic disease, these high risk characteristics, and they receive ADT and docetaxel that you need the darolutamide. It offers benefit over not having the darolutamide.

What we don't know is do you need the docetaxel? So if you give somebody ADT and abiraterone, let's say, do you need the docetaxel on top? And that hasn't been done. And so I'm a little doubtful it'll be done, but, it could be done in certain settings, I think. Perhaps the NCTN cooperative group setting would be willing to take on a study like that. I'm not sure what the appetite would be, but that question's unanswered, so we're thinking about.

Alicia Morgans: Agreed. And it's the question that everyone's asking. So maybe it is going to be something that we should answer. I know Alliance actually talked about it a few years ago and I'll give credit to Alan Bryce who brought that up and kept kind of hammering it home. And no one's appetite was really wetted for pursuing it. But really an interesting question to be had, of course. So if you had a final word, a final message to folks who are thinking about triplet therapy, which by triplet, I mean ADT, docetaxel, and either darolutamide or abiraterone acetate, or potentially even enzalutamide. Though first that data remains immature too. What would your message be?

Evan Yu: Yeah. I think the key message is that really take every opportunity you can to present this data to your patients, for those that you think are chemotherapy fit and for who might meet the potential eligibility criteria for these studies. I think all too often, when we look at a regimen it's easy to say, oh, that's a pretty intense regimen. Or, oh, this patient, they might have some comorbidities, might be a more advanced age. Maybe we take it easy. But I think that's an active discussion and we need to give our patients the benefit of the doubt and present all the data to them and work with them to decide. Is that something that they want to take on or is that something that they don't want to take on? I think it really should be shared decision making and not something that we make the decision for the patient. I really think that we need to discuss that and make a decision together with the patient.

Alicia Morgans: I think that's a great message. And you never know, your patient may just surprise you. It's happened to me more than once. And the other thing I always think of is that a treatment plan is never a contract that needs to be fulfilled. It's evaluated with each cycle. Each time a patient comes in and there is always the opportunity to make a change. So thank you so much for your time and for your expertise today.

Evan Yu: Well, thanks for having me again at UroToday.