Early Aggressive Treatment Shows Promise for Prostate Cancer Recurrence - Stephen J. Freedland

June 22, 2023

In a conversation with Alicia Morgans, Stephen Freedland discusses a study he presented that analyzes Veterans Affairs’ data on men who had received either surgery or radiation therapy for prostate cancer and later developed a biochemical recurrence. The focus is on the 'doubling time' of PSA, a significant prognostic factor. According to the study, the majority of patients with a doubling time of less than nine months received secondary treatment within a year. Furthermore, the research indicates that early and aggressive secondary treatment might have a positive impact on the disease's natural course. In terms of future studies, Dr. Freedland suggests that we need a better understanding of tumor biology and the development of more precise metrics for tracking the progression and treatment of prostate cancer. Despite the encouraging results, more research is needed to determine the exact timing for aggressive treatment.


Stephen J. Freedland, MD, Urologist, Cedars-Sinari, Los Angeles, CA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Stephen Freedland, who is a professor of urology at Cedar-Sinai. I'm so excited to talk to you today.

Stephen Freedland: It's great to see you, Alicia.

Alicia Morgans: Great to see you too. And you know, I really am thrilled to discuss the podium presentation that you gave at AUA, really thinking about hormone-sensitive, biochemical, recurrent patients, a high risk, and maybe even some intermediate risk patients in that population. Can you tell me a little bit about it?

Stephen Freedland: Yeah, no, absolutely. I mean, we're, we're hearing a lot more about BCR. We've had some recent trial data in that space. Yes. So it's a very interesting space. So basically this was analysis of VA data looking VA wide, and men who had received either surgery or radiation. So primary therapy and developed a biochemical recurrence all too often of an event. Unfortunately, and we know from prior data that PSA doubling time is very prognostic. And particularly those with doubling times above 15 months have really good outcomes. We, we know that. So we, we kind of eliminated those patients said, look, we know they're gonna do well. The question is among those with doubling times less than 15 months, what is going on in the real world and how does doubling time predict outcomes? And we certainly know from Hopkins data from years ago that if you delay hormonal therapy, we know the natural history from prior papers from myself and Pound and others. We know doubling time is very prognostic, but in the real world, most patients don't delay hormones until the time of metastases. So in a more real world, how quickly are patients being treated and how prognostic is doubling time? Those were essentially the questions we were asking in the study.

Alicia Morgans: Well, and so important to your, to your point that many patients are actually getting treated pretty early. Absolutely. So tell me, what did you find? What are we doing in the real world, at least in the VA?

Stephen Freedland: Yeah, so it's interesting. So if you look at men with doubling times less than nine months, which was enrollment criteria from EMBARK, Hopkins, data says is the high risk they're being treated aggressively in the real world. The median time from biochemical recurrence to secondary treatment, which was generally hormonal therapy, was 11 months. So the majority of these patients are actually getting secondary treatment within a year. They're not waiting until metastasis. Yeah. If you look at the doubling time between nine and 15 months, median time to secondary treatment was just over two years. So it's, it's still not the long natural history, but it is longer than those with doubling times less than nine months. We are in the real world, as you say, in the VA. And I think the practice patterns probably are similar outside the VA. We're being pretty aggressive with these patients.

Alicia Morgans: So do you happen to know the median PSA when this is, when this is happening? Because within 11 months we might think that many of these patients are going to have relatively low PSAs if they're getting treated within 11 months of their biochemical recurrence. I mean, is this doubling from 0.01 to 0.02? Or is this doubling from something higher that would be potentially more meaningful as a doubling time?

Stephen Freedland: Yeah, no, it is a great question. As the median PSA was about one somewhere in there, which reflects surgical patients where the definition is 0.2 and radiation patients where it's nadir plus two. So you have some patients where it's two, some it's 0.2, the median comes out to a little over one. So you can imagine if you're doubling time is six months, just pick some arbitrary low number. 11 months later you've doubled twice. You've gone from one to two to four. So you know, I think most of these patients are not necessarily getting hormonal therapy with the PSAs below one. But certainly from the majority of them, just based on the math, would be less than 10, certainly way before metastases.

Alicia Morgans: Okay. And that, and I think that also makes sense. So it does sound like clinicians are thinking about PSA doubling time and using that information to make their clinical decisions.

Stephen Freedland: Yeah, and I mean, on the one hand I agree with you, on the other hand, the shorter the doubling time, the quicker you're gonna hit some arbitrary PSA number. So whether they're really saying, look, I'm gonna start therapy when your PSA is five and your doubling time determines how long until you get five, or I'm gonna do it because you have a short doubling time. Always hard to know what's going on in the mind of the clinician. Yes, because the two are, are so intimately related.

Alicia Morgans: That's a great point. And in claims data we don't have the backstory, we don't have the information, we just have the numbers and the data.

Stephen Freedland: Correct.

Alicia Morgans: Yeah, that sounds So what else did you find?

Stephen Freedland: So what we found, which was really interesting, is if we look at time to metastasis, which we know from the Pound series, if we look at all comers and keep in mind in the Pound's, so the Pound was the Hopkins series delayed hormonal therapy until the time of metastasis. A lot of the guys had longer doubling times indolent, more indolent disease. Yeah. Some bad disease as well. A mix median time to metastasis, there was eight years. So when we look at our cohort of patients where the median doubling time was less than nine months, we took the worst players, median time to metastasis was about eight and a half, nine years. So we could actually take the worst players, treat them early and aggressively, and actually find outcomes on par with all comers. So, which is pretty interesting, you know, I mean, we certainly need to do follow up in terms of overall survival and, and different things, but it certainly provides some evidence that this early aggressive secondary treatments may be having an impact on the natural history, which is pretty interesting.

Alicia Morgans: That is interesting because in biochemical recurrence until the EMBARK data which was recently reported, came out, we didn't necessarily have a sense that we could change the trajectory of the cancer by starting earlier rather than later, at least in the hormone sensitive BCR setting. Correct. So how do you think the EMBARK data will affect what we might see when you do this study again in five or seven years?

Stephen Freedland: I would love to say we're gonna see a lot of patients treated one, the decision to start hormones, that they'll be treated with intensified hormonal therapy and EMBARK as, as you know. But for the audience you know, with biochemical recurrence doubling time less than nine months standard ADT,  ADT plus enzalutamide or enzalutamide monotherapy, and both the enzalutamide therapies significantly clinically and statistically delayed metastases free survival. I'd like to think we're gonna see a lot of patients treated that way. I have concerns when we look at the metastatic castrate sensitive space, where the uptake there, despite many, many phase three trials, is a lot lower than we'd like it to be. So I have some concerns that something similar is gonna happen in the BCR space. But I'm hopeful, you know, that we'll see it. And I think, you know, related to this question, you know, I think we're seeing data now that early secondary treatment can make a difference.

Stephen Freedland: If you're gonna treat more aggressive treatment is better. The exact timing of treatment is still not exactly clear. I think increasingly for these really bad players, we don't wanna wait super long, but do we need to be super early or is early good enough? How does PSMA metastases directed therapy fit into all this? I mean, there's so many unanswered questions and that's what makes it challenging to treat these patients as, as you know, well, but that's what makes it fun is as a researcher, a clinician who wants to improve care, there's so many unanswered questions.

Alicia Morgans: Absolutely. And really understanding the heterogeneity of disease across the spectrum of prostate cancer is a challenge that I know we both enjoy tackling.

Stephen Freedland: Yeah. No, and I think, you know, as I look to the future, I mean the, the, the metrics that we are currently using are relatively crude. I mean, we are there four or more bone METs or less than four. Is the doubling time short or long? If the doubling time short, it means the tumor's growing fast. But it doesn't tell me really anything about the biology of the tumor, except it's growing fast. It's probably bad disease. I need to be aggressive, but am I aggressive with pathway A or B or C or A plus C? You know, it doesn't really tell us the biology and that's, that's where we need to go. We're not there yet in prostate, but that's the great hope that we will get there sooner rather than later.

Alicia Morgans: Absolutely. So if you had to give a final word on the work that you presented at AUA 2023, what would that be?

Stephen Freedland: Yeah, what I would say is we're seeing in the real world that patients with bad disease are being treated more aggressively than historical data. And when we do that, the outcomes seem to be better than what we've observed. So I think it supports you know, early aggressive secondary treatment and exactly when is still an unanswered question.

Alicia Morgans: Well, many questions remain, but so interesting to have this mirror held up to us as a community, at least within the VA population, which as you said, I think does reflect what we're doing across practice. I think it does such in informative work that you're doing. So thank you so much. Well.

Stephen Freedland: Thanks for having me.