Treatment Advances in Non-Metastatic Castration-Resistant Prostate Cancer - Evan Yu

Evan Yu joins Alicia Morgans to discuss treatment advances in the non-metastatic castration-resistant prostate cancer space, focusing on the data and clinical implications of the ARAMIS trial.


Evan Yu, MD, Medical oncologist, treats prostate, bladder, and testicular cancer, and is passionate about providing a personalized medical approach to a selection of novel therapies, as well as understanding biologic mechanism of drug sensitivity and resistance. Professor, Department of Medical Oncology, University of Washington School of Medicine and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so happy to have here with me today, a friend and colleague, Dr. Evan Yu who's a Professor of Medicine at the University of Washington where he's also a GU medical oncologist. Thanks so much for joining me today, Evan.

Evan Yu: Thanks for having me on again.

Alicia Morgans: Great. So I wanted to talk with you a little bit about patients who have nonmetastatic castration-resistant prostate cancer and some of the advances that we've seen in this setting, particularly as they relate to the ARAMIS trial.

Evan Yu: Yeah, I think it's really timely to talk about the ARAMIS trial. As you mentioned, there are multiple trials in this disease state for nonmetastatic, or M0 CRPC. Different people call it different things. But the ARAMIS trial was the last trial to read out and for there to be results. As we know, the primary data from the ARAMIS trial showed in about 1500 patients with a PSA doubling time less than 10 months, they were randomized in a two to one ratio and they received darolutamide, a pure androgen receptor antagonist, 600 milligrams PO BID versus placebo, and they showed a significant metastasis-free survival of benefit and that was the primary endpoint. The median metastasis-free survival was like 40 months versus 18 months for the control placebo arm; very significant hazard ratio, I think it was around 0.4. P-value, very, very significant.

The one nice thing I think about this study is that there were very few adverse events. If you really look at it across the board, the adverse events between the darolutamide arm versus the control placebo arm were quite similar for adverse events across the board. There might've been a little bit more fatigue, a little bit more rash, but it wasn't dramatic. I think it was like 3% rash rate in this study. The one other interesting thing about this study is that because biochemically darolutamide is dissimilar from some of the other AR antagonists out there, darolutamide is felt to really not have as much crossing of the blood-brain barrier, neurocognitive effects, and potential seizure risks. So one unique thing to this trial is just that they did allow patients with a seizure history or seizure risk, whereas other trials did exclude those patients. So I think that's a unique thing to think about and to point out.

I would just say the last key point is that soon after the trial was presented for this primary endpoint and published for the primary endpoint in the New England Journal, the secondary endpoint of overall survival was press-released to be positive as well for overall survival. Now, we haven't seen all the nuts and bolts of that data yet. We were going to see it at ASCO. I'm sure we still will see it in some sort of a virtual presentation. At least the slides will be available or the poster will be available for download, but we certainly look forward to seeing the nuts and bolts of the overall survival benefit in that study.

Alicia Morgans: Absolutely. I think that gets to one of the points that I wanted to talk with you about. When we first heard about these AR antagonists and the use of these drugs in the nonmetastatic or M0 CRPC space, some people said, "Well, really this is an iatrogenically induced space." This is a space that we have created by treating biochemical recurrent patients with hormonal therapies and systemic generate jaggedness or antagonist therapies and we have really created this patient population and it's not meaningful. This metastasis-free survival, even though it's two years longer almost for these studies, it's not meaningful. But the overall survival data suggests that the earlier treatment actually is meaningfully bending the curve for these patients, and I'm just curious what your thoughts are on that. 

Evan Yu: Yeah, I think that it is a reasonable point that people make about the fact that we created this issue because we treated biochemical recurrence with androgen deprivation therapy. But I would ask the question; how many of those individuals that might be critical of that fact put in the situation where you've, let's say undergone radical prostatectomy or localized external beam radiation or maybe both, and you still have a rising PSA, certainly not one that's just kind of moving along very slowly, but some patients have a very short PSA doubling time and a rapid rise in their PSA and we know that the prognosis is much worse for those patients. How many of those critiques, or maybe they might really alter if they were in that situation and that's what we're faced as providers on a day to day basis.

We're faced with making tough decisions on risk-benefit ratio, looking at safety, looking at toxicity, potential adverse events versus the benefit, and you can easily criticize it by saying, "There's no definitive data that shows that early introduction of androgen deprivation for biochemical recurrence or intermittent androgen deprivation therapy...", let's say in that setting, "... even shows definitive survival benefit." But for a patient sitting there with the rapidly rising PSA, how many people really say they have bone pain, let's say before you start androgen deprivation therapy. I think these patients exist and I might be part of the contribution to it.

Alicia Morgans: Well, and I don't know that it's necessarily a problem because I would argue that... I do the same, but I would say that you probably do what I do, which is selecting those patients with, as you just described, a rapidly rising PSA, so a really short PSA doubling time and these are the patients that we know are actually going to develop metastatic disease and potentially die ultimately from metastatic prostate cancer. We're not talking about, or at least when I treat patients with hormone-sensitive biochemical recurrence, I'm not talking about the patient who has a PSA doubling time of two years.

Evan Yu: Yeah, absolutely not. I want those patients. 

Alicia Morgans: Yes, of course. I think we all do because we're trying to responsibly balance the risks of treatment against the risk of the disease. In this setting, the ARAMIS trial was designed to include patients who had a PSA doubling time of less than or equal to 10 months. That's not what the label is and I think it's important to mention that as well because the FDA even has stated that they did not want to box providers into a situation where we were not able to access medications that could help our patients. I appreciate that they said that. When I apply the data, I actually typically do look for that shorter PSA doubling time, but we don't have to if we don't want to. Because these things can change rapidly and can be defined slightly differently depending on how you're measuring the PSA or how often, it's nice to not have that restriction. I don't know what your thoughts are on that.

Evan Yu: I agree. I think it's nice to not have that restriction. I will say in my own personal practice, I tend to only treat people that have shorter PSA doubling times. If you look at the trial, the ARAMIS trial, probably about 70% of the patients had a PSA doubling time less than around six months. So it was a really aggressive patient population. I definitely am going to treat those patients in that situation.

But if somebody has a really long PSA doubling time, whether it's for hormone-sensitive, biochemical recurrence, or for M0 castration-resistant prostate cancer, I'll often observe those patients. Now, we have to take everything into account. If a patient has a lot of comorbidities, is of great advanced age, it's much easier to observe them. If your patient's 45-50 years old and maybe their PSA doubling time is 11 or 12 months, not quite 10 months or less, I'm going to take into account that they're not going to pass away of natural causes anytime soon and that's a situation where I like the flexibility that the FDA has given by not putting that little tag on there saying, "10 months or less."

Alicia Morgans: I totally agree and I definitely, as you said, watch those patients for the longer PSA doubling time, whether it's nonmetastatic or M0 CRPC or hormone-sensitive biochemical recurrence. So it sounds like we really align on a lot of these principles, again, just trying to balance the risk of treatment versus the risk of disease. One of the other things that I appreciated about the ARAMIS trial is that the investigators have released some of the quality of life information as well and it does suggest that quality of life is better to improve. It was interesting that the specific domains of improvement were really around bowel and bladder function.

I remember thinking, "Gosh, that's really interesting because these patients should have had a treated primary," but not all patients had a treated primary and it wasn't necessarily local recurrences that were causing the problem, but it was just interesting that those are the domains that really significantly appeared to be better in the quality of life assessments. But I think it's always nice if we're going to treat a patient population that for the most part is asymptomatic to know that we'll potentially improve their quality of life, but at least not make it worse and that seemed pretty consistent within the trial.

Evan Yu: Yeah, absolutely. If you look at the spectrum of agents that are FDA approved or big randomized Phase III trials in prostate cancer, this is an agent that really has minimal side effects and toxicity. It's really hard to glean out what the key side effects are and I think that's pretty impressive for an agent that, I was impressed that they had an overall survival benefit so quickly on after they presented their metastasis-free survival benefit data. So you see this kind of efficacy. Usually, people expect some sort of adverse events and it's rare to see this kind of efficacy and see very minimal toxicities. I think the quality of life data helps, but it's not surprising to me that that's what they found.

Alicia Morgans: Right. So it's nice we do have consistency across this across the nonmetastatic or M0 CRPC landscape, a lot of consistency with AR antagonists, improving MFS and certainly, darolutamide is improving overall survival as well. More data to come from all of these agents and this ARAMIS data will be coming out we hope in the near future so that we can all investigate that for ourselves a little more closely, but a nice option to have as we think about trying to help patients in this setting. So any overarching messages or final thoughts regarding the nonmetastatic CRPC population and the ARAMIS trial?

Evan Yu: I would just say that this is a patient population that these patients do develop morbidity and mortality. I think it's very clear that yes, these patients will have some time, maybe a year or two years or so before they develop metastases and there are newer, better treatments for metastatic castration-resistant prostate cancer. But the likelihood that this patient population dies of natural causes or other comorbidities is still not as likely as them dying of prostate cancer. I would say when these M0 CRPC patients are identified, I think this data and others really support "you ought to treat".

Alicia Morgans: Great. Well, thank you so much for taking the time to talk this through with me, and I always appreciate it, always learn.

Evan Yu: Thanks so much for having me again. Take care.