Read the Full Video Transcript

Daniel George: Hi, I'm Dr. Dan George, your host for this session for UroToday at GU ASCO 24. And it's my pleasure to introduce Dr. Alicia Morgans, my friend and colleague from Dana-Farber, a GU oncologist, who has a poster here, a presentation that, with a number of our colleagues, presents a real large meta-analysis on the 14 trials that have been conducted so far, large phase three trials, at least with patients with metastatic hormone-sensitive prostate cancer using treatment intensifications, chemotherapies, or hormonal therapies. And you've done some really interesting post-hoc analysis. Help us understand which patients might be benefiting maybe more than others. Alicia, walk us through your study.

Alicia Morgans: Sure. Well, thank you so much. I have to really give credit to Dan Spratt, who really brought the group together and raised the questions and helped really drive the analyses. He's incredible in so many ways. And also wonderful analysis. So this was really a meta-analysis that was meant to understand whether there might be differences in the effectiveness of treatment combinations for patients who are overall versus those patients who are older adults and patients who may be younger. And I think it's really important in our population in particular, given the median age of diagnosis of prostate cancer at 67, that we do have a fair number of patients who are older adults.

So one important thing in this analysis as we looked at all of these studies and tried to understand the effect and where differences may be, is that there were two different ages of older adult used, and that was based on the data available in the different trials. Because not every trial has a breakdown of patients by age. For some studies, actually a majority of studies, this was 70. For others, it was 65. And again, we really just tried to look at the differential effect of these intensified therapies for metastatic hormone-sensitive disease.

Daniel George: Got it. So focusing your hypothesis that hey, these older patients might have a different tolerance and benefit profile associated with these treatment intensifications than the younger patients.

Alicia Morgans: Yes.

Daniel George: What did you actually find?

Alicia Morgans: Well, we did find that older patients seem to have less extreme benefit than the younger patients. And this, I think, was, as you said, a hypothesis initially, but really striking to see in numbers in this analysis. And certainly, there are many reasons why this could be the case. As we get older, we experience more competing risks from other causes of mortality, and we also, of course, have more comorbidities. There are more drug-drug interactions. So there are a lot of reasons why this may be the case, but I do think it was pretty striking to see this pretty much across the board in this analysis.

Daniel George: So now I'd like to dive into numbers a little bit here because it's important to recognize just these are all proportional. How much of a difference was there in terms of the benefit in the younger patients versus the benefit in the older patients?

Alicia Morgans: Sure. So the hazard ratio for benefit for the older patients was about 0.8 versus the younger patients 0.65. And I really want to emphasize that this does not suggest that older patients do not get a benefit from intensified therapy. That is absolutely not the message. I think what we're trying to understand is whether there may be a differential benefit, but of course, acknowledge that there still is a benefit. And certainly, we still treat patients who are older adults with these intensified therapies in our clinics every day.

Daniel George: That's great. And I think that's a really important point because we don't want to send the message here, we're not going to want to treat those patients. But if they're having difficulty with the therapies, because these do increase the toxicity on patients and maybe there's a little bit higher toxicity in some older patients. So recognizing that with a less absolute benefit, those are patients maybe more willing to compromise on dose and schedule and whatnot.

Alicia Morgans: Absolutely. And the other thing is that we as individual clinicians don't have a crystal ball to understand which patients are going to actually have a mortality event from some other illness. And so I think this also reflects our lack of knowing this patient's going to have a heart attack in six months or a year or whatever that competing cause of morbidity is or mortality is. We can't be expected to know those things. And so we do have to approach each patient when we see them with the best therapy for their prostate cancer and of course, support their comorbid illnesses through collaborating with their other physicians. Because until we can tell the future, we can't say, "Well, your hazard ratio for you as an individual is only this because you're actually going to have another event."

Daniel George: And that's a great point because this is population data and even meta-analysis population data. So really broad. And what we're doing is making treatment decisions on an individual basis because some of our patients age, it's just a number. Some of them are physiologically healthier than their stated age. Some of them are worse. How do you take that into account in your practice?

Alicia Morgans: Well, I think that's one of the most important things that we as a community interested in older adults have been trying to educate on and think about for the last few years. There's absolutely a difference. Even if you look at actuarial tables in people of any given age, when we look at the healthiest 25% of that population versus maybe the 25% of the population that has the most comorbidities or other reasons to be more frail or other things. And that difference at each age can be six years, eight years, ten years of survival difference, even though each of those patients may be 70 years old. So when I see an individual patient, I'm thinking about not only what is the performance status of this individual, but what other medical comorbidities might the patient have? Are there issues related to polypharmacy? Does this patient have physical limitations that may impair their overall ability to care for themselves?

Mental changes, whether they're depression, anxiety, or perhaps early dementia or cognitive change or even more advanced. So we have to think about the patient in his totality as we're really trying to understand how intensified should the therapy be. I mean, at the end of the day though, it's really difficult to know which of the competing things that any individual is dealing with will be the thing that's most dangerous. And we're responsible for prostate cancer, and so we have to make those choices around the prostate cancer while also acknowledging that we have to work together with our multidisciplinary teams and other providers to support all the other aspects of their health.

Daniel George: It's a lot, isn't it? I mean, we're oncologists and now we're also geriatricians in assessing these things.

Alicia Morgans: Absolutely.

Daniel George: Now, there was a second part to your abstract that also thought was, well, your team's aspect, that I also thought was really interesting. And that was the breakdown between the type of intensification, whether that was an androgen receptor inhibitor, say like enzalutamide or apalutamide or darolutamide, or abiraterone, which is sometimes lumped together in the same class, but it's really a different mechanism. And it looked like you saw different results depending on which class, AR inhibitor or androgen synthesis inhibitor, if you will, patients were put on. Tell us a little bit about that.

Alicia Morgans: Yes, so we did see that difference. Again, we would still expect a benefit from intensification, but the benefit seemed to be most pronounced with the AR signaling inhibitors or the antagonists, I should say. Just to be very, very clear, the AR antagonists, so apalutamide, enzalutamide, darolutamide as compared to abiraterone, as you said, a synthesis inhibitor. The reasons for this, absolutely not things that we can pull from the data, but we can imagine that there's something perhaps about inhibiting the adrenal function, inhibiting the production of the testosterone, the ligand rather than directly blocking the receptor. That may just either not be as effective, or when we're talking about inhibiting adrenal function, may cause challenges for some patients, particularly patients with certain comorbid illnesses. So this, I think, is thought-provoking. It doesn't prove anything, but is a really thought-provoking finding that came out of this data.

Daniel George: It is really important because we don't really have any head-to-head data between these classes of drugs now. And so sometimes these retrospective analyses or real-world evidence is all we have to base this on, but it does at least raise the possibility that these are not equivalent drugs. And it's important because sometimes we think in these older patients that, gosh, these drugs that might make them dizzy or cognitively impaired might be worse, and maybe abiraterone is a safer drug. But from what you're describing, we need to maybe question that thinking, and here abiraterone, still as a generic, something we're using frequently. So how do you put that together in your practice?

Alicia Morgans: Well, I think the number one message is that treatment intensification in metastatic hormone-sensitive disease is still beneficial for patients. And none of this analysis really refutes that. But when we are making decisions with patients who are younger versus patients who are older, we do have to think about the magnitude of benefit and how we counsel and support our patients as they're working with us to make decisions about intensification and how we intensify. So those conversations really can include more than just, "Do you want to intensify with chemo or with an AR signaling inhibitor?" And maybe we need to think about which of our approaches, antagonist versus synthesis inhibitor, we want to use, particularly in our older adults. But to your point, I think prospective head-to-head data is the only way to really definitively answer this question, but certainly hypothesis-generating and something that I'll think about or I will think about when I'm in clinic next time.

Daniel George: Fantastic. Well, Alicia, as always, super great to have you on the program today. Thank you so much for this thought-provoking work and I think practice-informing data, and hope you enjoy the rest of GU ASCO.

Alicia Morgans: Thank you so much for taking the time to talk.