Read the Full Video Transcript

Alicia Morgans: Hi. I'm so excited to be here talking with Dr. Ben Maughan of the Huntsman Cancer Institute at the University of Utah. Well, we're here to talk about a recently published network of meta-analysis that included 11 RCTs, randomized control trials, of patients who were treated for metastatic hormone-sensitive prostate cancer. This network, meta-analysis, was published in European Urology Oncology in July of 2022, and really raised quite a firestorm on Twitter. And so, I'm really excited to talk to Ben as someone who participated in some of that conversation and had some really nice comments about the pros and cons of this approach, and how we might think about interpreting this data. Just to set the stage, and you can see that there is a reference listed here, I think it's important for us to recognize that treatment of metastatic hormone-sensitive prostate cancer has really evolved in the last number of years, with ADT alone really not being the standard approach to treatment any longer as we know that that's inferior, which of course was pointed out in this network meta-analysis.

But the goal of this study was, really, to help understand whether triplet therapy was really superior to other approaches perhaps, and whether ADT plus docetaxel and ADT plus an AR-targeted therapy might be good alternatives, or whether we should be pushing patients in the direction of triplet therapy. Of course, always limitations on any approach, especially one that's not a head to head randomized analysis, but really a place to start and a way for us to think through all of the abundance of data that we have available to us. So, thank you for being here with me today, Dr. Maughan.

Benjamin Maughan: Alicia, it's always a pleasure to visit with you. Thank you so much for the invitation to talk about this study today.

Alicia Morgans: Wonderful. So, I'd love to hear your thoughts, and maybe if you're able to lay out your perspectives on the comparison of all of these options, triplet and ADT plus docetaxel versus ADT alone against ADT plus an AR-targeted agent, because that was the reference standard in this particular meta-analysis.

Benjamin Maughan: So, the issue with this treatment is that it's rooted in an area of complexity. So, prior to these focused triplet therapy clinical trials being published of PEACE-1 and ARASENS, respectively, there were two therapeutic strategies that you could use for intensified therapy, either ADT plus docetaxel or ADT plus a novel hormonal therapy. For instance, apalutamide or enzalutamide or abiraterone. These two focused clinical trials looking at triplet versus doublet therapy, though, only compared the standard of care that they used as their comparison, again, in both trials was ADT plus docetaxel. So, what we're really lacking is triplet therapy versus an ADT plus novel hormonal therapy doublet. And therein lies a lot of the contentious discussion about this topic of triplet versus doublet therapy.

And the other piece that layers into this complexity is based on some of the data. There's many investigators that think ADT plus a novel hormonal therapy, in general, is a more effective doublet than ADT plus docetaxel. And you can see that played out in terms of prescribing patterns nationally. ADT plus docetaxel is much less commonly used. It still is, but it's much less commonly used than ADT plus a novel hormonal therapy. Thereby, bringing up the question of, was this an inferior comparison arm?

Alicia Morgans: Absolutely. And especially when we also think about toxicity, people say, "Well, if I am going to add chemotherapy, I have to be sure that the toxicity is going to be worth it." So, really, really important there. And that's why I think in this network meta-analysis, ADT plus one of those AR targeted agents as you referred to was really the standard of care. Of course, not a randomized comparison, but one that they tried to make in this analysis. So, what did they find? And what is your take on the data?

Benjamin Maughan: Yeah. So, I'll go out on limb and say never. Because we're never going to have a prospective randomized control trial, at least there's none being designed to my knowledge so far, looking at a triplet therapy against the doublet of ADT plus novel hormonal therapy because that trial's not going to happen. There's other research tools that have been employed to try and answer that question. Again, they're not as robust as a phase three clinical trial, but in the absence of that happening, these are appropriate questions to ask. And a network meta-analysis is one way to try and approach that question. So, in this particular study that was done, they compared ADT plus docetaxel versus ADT plus a novel hormonal therapy versus ADT plus, actually, the triplet ADT plus docetaxel plus a novel hormonal therapy. And they did include data from these two prospective studies in ARASENS, but they also included data from patients on other clinical trials because in some of these other clinical trials, like TITAN, for instance, or ENZAMET, patients were allowed, they weren't required, but they were allowed to receive docetaxel.

So, some of those patients did receive triplet therapy. So, they amalgamated the data across all of these trials to try and make these different comparisons. And so, in their study, what they found in this network meta-analysis is that the triplet therapy seemed to outperform the other treatments in terms of some of these, what we think of, softer endpoints, like progression free survival. It didn't meet statistical significance in terms of what we still to this day consider the defining hard endpoint of overall survival. But it did seem to outperform ADT plus NHT or ADT plus docetaxel in those other categories.

And consistent with data from the Stampede group, the ADT plus NHT combination, or doublet, seemed to outperform the ADT plus docetaxel in terms of things like progression free survival or response rates. So, overall it seemed to be better. Now, part of the contention here is that if the doublet, we know that the triplet offers significant more toxicity because you're adding in docetaxel. And so, if it doesn't seem to improve overall survival, then it might not be worth it to... The added toxicity. So, therein lies a lot of the controversy about the results of this network meta-analysis.

Alicia Morgans: Yeah, I thank you for laying that out so clearly. I mean, there was a pretty consistent trend there that the triplet appeared to suggest a benefit. But there are differences in the populations that may have been in the different studies. And so, of course, this could also influence that trend in one way or another, and this was not powered to make that comparison. And we probably will never have a study that actually looks at these comparisons, triplet versus doublet, to understand the contribution of chemotherapy. I think generally, though, there was a suggestion pretty clearly that ADT alone is inferior to these combinations, which is also really important to remind everyone.
n
And when we're trying to make these decisions about triplet versus doublet, I think conversations with patients, shared decision making, also assessing whether the patients fit for chemotherapy, are all really, really important, as are probably the subgroups that we think about that we're really enrolled either solely, like in PEACE-1, these were all De Novo metastatic patients. Or preferentially, like in ARASENS, there was a preferential enrollment of over 85% of patients who had de Novo metastatic disease. What are your take homes from this work and from the studies in general when you're thinking about making these choices with patients in clinic?

Benjamin Maughan: Yeah, Alicia. The way that I think about these results is that... Well, I guess as a starting point, I think back to those progression free survival curves and those hormone therapy doublet trials, like TITAN, for instance, or ENZAMET. If you look at the progression free survival curves, there are some patients that immediately are progressing within just a few months, certainly within 12. There's a significant minority of patients that are having an inferior response to a pure hormone therapy treatment. And so, what that tells me is that there is a subset of patients, there's a population out there of patients, that have prostate cancer that's, from the very beginning, relatively, not completely, but relatively resistant to hormone therapy. And so, what we really need is some new treatment for them. So, clearly there are patients who really deserve or need chemotherapy. And we've known that for a while.

We're starting... Well, I shouldn't say starting. We're very much understanding some of those clinical characteristics now. Patients that have liver metastases. Patients that have, as you mentioned, that have De Novo metastatic disease, or that have high volume disease, or that have this discordance. This is a clinical judgment piece, but a large volume to a small PSA, right? These are the patients that overwhelmingly have a shorter than average response to hormone therapies. What we're starting to better understand is what are the genomic characteristics of those patients. And so, I think, over time, as we better understand the genomic characteristics, we'll be able to identify these patients better. But the way that I approach this data in clinic is those patients who have the clinical characteristics like we described, again, De Novo metastatic disease, high volume disease, liver metastases, these are the patients that from my experience, and based on the data, seem to have a better response to a chemotherapy-based treatment as opposed to a pure hormone therapy-based treatment.

And so, the data is very clear from PEACE-1 and from ARASENS that if you're going to be using a chemotherapy, doublet type foundational treatment, they do even better with triplet therapy. And I think the reason that the network meta-analyses don't show us clear of a positive or helpful trend with the triplet therapy, as we see individually with the ARASENS and with PEACE-1, is very much what you were highlighting. The patients are, on average, much more aggressive. The biology... I shouldn't say that patients are. But the patient's disease is much more aggressive in those trials than we see with TITAN, for instance.

And so, I really approach it as, "Does the patient's biology of prostate cancer suggest they really should have chemotherapy?" And if the answer to that question is yes, then I think about a triplet therapy. If the answer to that is no, right? So, they have a small volume of disease. They have lymph node only metastases or a few isolated bone mets. They've got low volume disease. They've got metachronous disease. Then, the answer to that question for me is no. And so, I think of a doublet as a very appropriate way to balance efficacy and toxicity for them.

Alicia Morgans: That makes a lot of sense, and thank you for talking us through that. Now, one thing that I thought you did very nicely on this Twitter conversation that arose around this paper was to remind all of us of some of the limitations that we can see or must consider when we interpret these types of studies. And I wonder if you're able to highlight some of those.

Benjamin Maughan: Yeah, absolutely. So, as we have been of talking around just now, part of the limitation is that the network of meta-analysis is not a prospective study. And in particular, these network meta-analyses do not use patient level data. They use trial level data, which means we're not getting the granularity that you would need to be more confident in the results. So, those are a couple of limitations of it. Additionally, we are including patients from a number of different trials, and those each have different eligibility criteria and enroll different types of patients. And so, as we're comparing data that's not similar, it starts creating more uncertainty in the results that we make.

So, there is some uncertainty about the results of these network meta-analyses that have come out and opinions that have been written about it in editorials, et cetera. So, there are some of those limitations, as well. And ultimately, again, we are better understanding today that the biology drives the prognosis. And so, we don't have data about the patients that have enrolled in any of these trials about what their biologic characteristics, the genomic and transcriptomic analyses of their cancers are. And that's ultimately going to factor into the responses that we're seeing with these different agents.

Alicia Morgans: I agree. Well, thank you for talking us through that and helping us think through some of this data. I think, particularly, as we think about these more complex ways of considering compilations of different studies, network meta-analyses being one of those complex ways, it's really, really helpful to think through not only what the paper says, what the data says, but how we consider that in our clinical practice, and how we consider the limitations of these kinds of papers as we really consider how heavily do we weigh this data or this assessment of the data as we make those clinical decisions with our patients. So, thank you so much for walking us through the way that you perceive this data, the way you in incorporate it into practice, and the ways that you're cautious about interpreting things with any study, including a network meta-analysis. I really appreciate your time and your expertise.

Benjamin Maughan: Well, thanks. It was a pleasure visiting with you, again, today on this topic.