Alicia Morgans: Hi. I'm so excited to be here with Professor Fred Saad, who is joining us to talk today about a recently published network meta-analysis on treatments for patients with metastatic hormone-sensitive prostate cancer. Thank you so much for being here with me today, Fred.

Fred Saad: Always a pleasure, Alicia.

Alicia Morgans: It's always a pleasure to talk with you. And I love that you have your hand in so many areas of research, and especially, have become interested and pioneering in this metastatic hormone-sensitive setting, where we find a lot of controversy around what actually that treatment should be for patients with newly diagnosed disease, whether it's de novo, whether it's recurrent, high volume, low volume, all of these things whirling around. And you and your team tried to put together a network meta-analysis to help us bring some of that data just into a spectrum that we could really understand. So can you tell us a little bit about what you did?

Fred Saad: Yeah, sure. So I think a lot of people, including ourselves, are wondering what's the best approach for patients with metastatic hormone-sensitive, and clearly, ADT alone is out the window. I mean, you have to almost justify why you would give ADT alone to any patient today with everything that we know. Now, the question comes to, we've always had to decide, ARAT, or novel hormonal therapy, like Apalutamide, Enzalutamide, Abiraterone, or Docetaxel. We could never give all of it together. And for a long time, when I saw the data of Docetaxel and the data from the novel hormonal therapies, and I was saying, the data always points to earlier being better, and that's clearly the case for novel hormonal therapy. But we've always known that patients fail. We don't cure really any of these patients, and when they fail, and we give them Docetaxel, they really don't do very well. They've developed really resistant clones, because they've been exposed to ADT plus a novel hormonal.

And so, the idea is, we have to hit all the clones early and as well as we can with what we have available. And so this network meta-analysis, and we're a group of people that were working on this, right? And some are strong believers that Docetaxel doesn't add anything. And let's be honest, I mean, that's what we keep hearing. What does Docetaxel actually add to ADT and novel hormonal? So this was an attempt to try to figure out the best we could with the data that's available, looking at overall survival in patients with ADT and novel hormonal, versus patients with ADT and Docetaxel, and then with the new data that's coming out with ADT, Docetaxel, and a novel hormonal therapy, and seeing what comes out just looking at the network meta-analysis across the board on overall survival.

Alicia Morgans: And I just wanted to say, really, I think the group did a phenomenal job bringing together 11 randomized controlled trials, many thousands of patients, to try to answer that question. And you've compared all of these survival benefits here against ADT and a novel androgen receptor targeted agent, an ARAT, rather than against ADT alone, because to your point, ADT alone we know is suboptimal, so why do we keep comparing things to it? It is always going to lose. It's always going to be the wrong choice if we're choosing a treatment for patients.

Fred Saad: Exactly. And that's, so we took the common knowledge and practice today that ADT plus an ARAT or novel hormonal therapy should be the standard care. And clearly, when you use ADT compared to that, it's clearly worse survival. You harm patients in terms of overall survival and early mortality. Then the question comes, what about ADT plus Docetaxel compared to ADT and ARAT? And clearly, it looks like from this analysis that it does less well. It's not significantly different, but trending towards worse survival if you used ADT and Docetaxel alone. And the clinical trials have shown that in ARASENS and PEACE-1 that the control arms were ADT and Docetaxel, and when you added a novel hormonal therapy, you did better. And so this was an attempt at the triplet.

And with the limitations of a network meta-analysis is that you see that the best outcomes, even though it's not statistically significant with all the limitations, comes from triplet therapy. And clearly, some of the limitations are, we didn't do it patient-by-patient analysis. So we didn't account for tumor volume, that patients were in the clinical trials with an ARAT, and for patients on Docetaxel, and you would assume that there were probably higher tumor volumes in patients that were getting Docetaxel, whether it was in triplet or in ADT plus Docetaxel alone. So even with those limitations, and taking into account the fact that a lot of patients are asynchronous when you're giving the novel hormonal therapy, which is not the case that we saw in the trials, both in PEACE-1 and ARASENS where almost all the patients were de novo metastatic patients.

Alicia Morgans: Yeah. I think it's really important to emphasize that. So the patient populations when we bring all of these trials together are going to be a little bit heterogeneous, not quite really the same populations. PEACE-1 and ARASENS both included a majority of patients that were de novo metastatic. PEACE-1 was all de novo metastatic.

Fred Saad: Exactly.

Alicia Morgans: And many of these patients in both of these studies were high volume, though, of course, the specifics of that in the ARASENS trial have not yet really been reported at this point in time. So when we put those patients and those higher volume patients, or those at least de novo metastatic for the majority of those patients, that they have a poorer prognosis, more aggressive disease biology, and we're mixing them all together with patients who were on some of these ADT and ARAT populations or these studies. It's just going to be an interesting comparison.

Despite that, there really did seem to be this trend to the improvement in overall survival with the triplet, and really only a trend that ADT and Docetaxel is perhaps less effective than an ADT and AR-targeted agent. So if we pick out those patients who are potentially most benefiting from chemotherapy, and really that might be a de novo metastatic population, a high volume metastatic population, it's really plausible to think that if we really pick out those patients, we could see a bigger difference in the benefits there, which is what we expect, at least from the initial trial data that we have.

Fred Saad: Absolutely. Absolutely. But we wanted to be as transparent and as inclusive as possible. And, in fact, the ADT plus ARAT could have turned out to be actually better than triplet, because of that selection. The fact that the triplet turned out to be superior really forces us to consider triplet therapy in patients that will be needing Docetaxel sooner or later. And I think we've talked about this in the past. If you're going to give it sooner or later, probably is going to be more effective sooner when patients are younger, healthier, and at a lower hormone insensitive clonal population where you can hit them and hope to get them at that holy grail that now we've put 0.2 or lower as being in our new objective. And whether you give ADT and ARAT alone, or ADT and Docetaxel alone, you clearly are far from getting all patients down to below 0.2. So you really need to keep that in mind when we start these therapies.

Alicia Morgans: Yeah, I think that's great. And I love the work that you're doing. To your point about trying to get to the lowest burden of disease, we do this in other diseases, and for ovarian cancer, for example, in kidney cancer, we try to get rid of all of that metastatic burden that we possibly can. So it does make sense, biologic plausibility, that if we can get down to the lowest number of clones, there will be the smallest opportunity for the development of metastatic or resistance mechanisms, and then the lowest possibility that these resistance mechanisms can be shared among these clonal populations. So really, at least, biologic plausibility. And so interesting and important that you and your team put together this meta-analysis so we could look at the clinical outcome data and try to make some decisions. So as you put all this together, and as you think about it now, what would your summary be, or your message to the listeners?

Fred Saad: Well clearly, there are a few key messages. ADT alone, no longer an option. Second, ADT plus ARAT should be the minimum that you would offer all patients. And then the question of Docetaxel really should be individualized, but the triplet therapy should be considered in every patient with high volume, high-risk disease. And then even in some patients that have lower risk, lower volume disease, especially if they're younger, healthier patients where you're not looking at 5-year survivals, you'd like to get them to the very longest survival. You say 5 years is great for cancer, but it's patients that are young, 5 years is far from enough, and we'd like to keep them in remission for as long as possible. And I think that's something that we really need to consider in every patient we see with hormone-sensitive metastatic disease.

Alicia Morgans: Yeah. I think that's a great message. Hitting them hard at the beginning, if they can handle it, really does, I think, give us the best shot at trying to get control of this disease when we have our best and the greatest opportunity. And I so appreciate you and your team for putting together this network meta-analysis, and giving us the opportunity to try to look at some of these trials and compare them, even though we're always told we never compare across trials unless we do some of the adjustments that you did in this work, and of course, consider the limitations. So thank you so much for your time and your expertise.

Fred Saad: Thanks, Alicia. Always a pleasure.