Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so delighted to have here with me today, two friends and colleagues. One, Dr. Scott Tagawa, who is a Professor of Medicine and Urology at Weill Cornell Medicine and an Attending Physician and GU medical oncologist at New York Presbyterian in New York. I also have here with me today, Dr. Stephen Freedland, who's the Director of The Center for Integrative Research in Cancer and Lifestyle, as well as a Professor of Urology at Cedars-Sinai and a Staff Physician at the Durham VA Medical Center. Thank you both so much for being here with me today.

Stephen Freedland: Thanks for having us.

Scott Tagawa: Absolutely.

Alicia Morgans: Wonderful. So I wanted to talk with you both about the importance of real-world data and how that really affects your practice. And then to look a little bit more in-depth at a presentation that you have this year at GU ASCO 2021. So, let's start with the importance and utility of real-world data. Scott, can you tell us a little bit about real-world data, what it is? What it isn't and how you think it best fits into clinical practice decision-making?

Scott Tagawa: Sure. So, I think that there are strengths and weaknesses of multiple different data sets. Those data sets that generally lead to drug approval are prospective clinical trials, sometimes randomized, and there's great strength about that with homogeneity and inclusion-exclusion criteria, et cetera. And I think that's important to address one or two specific questions in terms of efficacy and safety. However, not all patients would qualify for a clinical trial. So, I think it's important to have additional data sets. And some data sets that have what we call real-world data, have the strength of including all patients within a particular population, regardless of age or performance status, or comorbidities. And generally, we also have larger numbers and those strengths come in terms of numbers.

One of the things that I'll let Dr. Freedland talk about is this particular data set that includes the VA population. One of the issues we have with some of the modern drugs today is cost, and that includes out-of-pocket costs for some oral drugs. That is one of the advantages of the VA data sets in that generally speaking, those medications are provided. So that's one factor that doesn't come into play.

Alicia Morgans: Absolutely. And now that you mentioned it, I think it's great to turn it over to Steve and ask him a little bit about the specific work that the two of you are presenting as a poster at a GU ASCO this year, "Survival Outcomes in Patients with Metastatic Castration-Sensitive Prostate Cancer". This is a real-world evidence study that I think was performed in a VA data set. Is that right, Dr. Freedland?

Stephen Freedland: Yeah, it's correct. And I'll go through it in a second. I think just to echo what Scott said is, the value of real-world data is not only to look kind of what we see in clinical trials, but also in standard practice patterns. We do this clinical trial, we see drug A leads to better outcomes than drug B, does it actually diffuse out into the community, and actually are our physicians using those agents? So, that's another one of the key questions we are trying to ask here is what are the practice patterns of people where we have some data suggesting again, treatment A is better than B. Is that being done? And so to address that, we actually pull data over about a five-year span from the VA health system.

The nice thing about the VA, it's an integrated health system. It actually captures about 6% of all prostate cancer patients in the entire country who are diagnosed within the VA. And there are the people diagnosed outside the VA that come into the VA at various points in time. So it's actually a huge data set. And to speak into that in our five-year span, we identified almost 370,000 patients with prostate cancer during that five-year span. So huge numbers. Once you start whittling it down to really metastatic castrate-sensitive disease, which is what we were focused on. And when you're doing that huge number, you need to rely on claims. You need to have a claim for metastatic disease, we know in practice we don't always use those claims, so a lot of people get dropped out that had mets, but weren't able to be included. And we were looking at newly diagnosed metastatic disease. So it could be recurrence that developed mets, but castrate-sensitive mets and newly starting hormonal therapy.

And we ultimately got down to about 1,400 men. One of the first questions we asked is just what treatments are they receiving? And so we looked at practice patterns of ADT alone, ADT plus anti-androgens your traditional bicalutamide, what we used to call combined androgen blockade, maximum androgen blockade back in the day, or ADT plus abiraterone, or ADT plus docetaxel. And, what we found is that the majority of men were treated with ADT alone. And you say it's about a five-year span from 2014 to the early part of 2018, you say "Okay, well, CHAARTED didn't come along, LATITUDE until the later parts". So let's look at just the most recent period, 2017. We had the LATITUDE data, we had CHAARTED data, and even in that setting, we look at ADT and ADT plus antiandrogens, which was three-quarters of the patients were receiving that.

So less than a quarter of patients were receiving one of these newer agents that we know from clinical trials. So the next question was, how was the survival based upon... ultimately that was the title of the abstract: what was the survival? And so we didn't have enough patients in the ADT plus abi or the ADT plus docetaxel groups to look at. So it's really ADT versus ADT plus anti-androgens. And what you saw is if you looked at it that overall that the time to metastatic disease as well as overall survival was similar, if anything, slightly worse in the group adding anti-androgens. But that's the group intuitively we give a little bit... We're more worried about them, they're a little bit more aggressive disease. So once we did our statistical analysis and actually some fancy adjustments in terms of IPTW waiting and different things to really try and match the groups, we saw no difference in outcomes between the groups and the median time to metastatic disease was about 22 months, which is kind of on par with what we look at some of the new trials from the ADT alone group.

So what we do think we are kind of replicating the natural history here of ADT alone, we don't see significant benefits from adding anti-androgens. And we know historically that there were some data suggesting that adding bicalutamide that combined androgen blockade did give a little bit of a survival advantage. We're not seeing that in the modern era, we have limitations it's claim space when we were not able to adjust for everything, but it's possible alternatively, with all the new effective therapies we have for mCRPC any modest benefit from adding anti-androgens upfront is completely lost. So I think it shows that there's a gap in terms of our treatment patterns, there are opportunities for improvement. And at least given the limitations we have adding that anti-androgen upfront is really probably not doing a lot for the patients.

Alicia Morgans: So let's just make sure that we clarify too, though, what you mean by adding anti-androgen. I would assume you don't mean anti-androgen at the beginning of a GnRH agonist therapy, that induction period where we see testosterone flare. And sometimes we do a few weeks to a month of overlap. You mean combined antigen blockade with an anti-androgen, and this is one of the first-generation anti-androgens I assume that's going to span the duration of ADT for that patient before they move on to the next therapy. Is that right? Am I understanding that properly?

Stephen Freedland: Yeah, that's actually a great point. And thank you for pointing that out. So, we often will give bicalutamide to block the flare for a few weeks, a month, or two. So adding the antiandrogen, our definition was you had to be on it more than three months. So you started with ADT, you're on it for more than three months, and most of these patients did ultimately stay on that until they showed progression and went on to something else. So this is not kind of that blocking the flare. And it was looking at bicalutamide, flutamide, nilutamide not this kind of second generation, if you will, enza, and apalutamide and darolutamide, which during the study period, weren't approved for metastatic hormone-sensitive disease. That's why we didn't look at those.

Alicia Morgans: And that makes a lot of sense. I think, in normal practice, I hope we strive to really use these newer generation androgen receptor-directed therapies, or perhaps chemotherapy in that intensification period where we had that strategy available to us. Importantly and nd interestingly in the VA setting, as you alluded to, Scott, these patients should have access to all of those agents. Now, as you both have mentioned, this is not during a time period where that would be possible, but Scott, as a medical oncologist who sees these patients, do you find this useful as you think about patients who might be getting combined androgen blockade or think about getting combined androgen blockade with these first-generation anti-androgens in this initial treatment period?

Scott Tagawa: Yeah. I think that it's quite useful to see, one of the advantages of looking at that, Dr. Freedland brought up of looking at data like this art to look at practice patterns, and it's disappointing to be honest. So this, just to kind of clarify the years, this started more or less at the time of the CHAARTED presentation and then overlapped STAMPEDE for abiraterone. So, but that was towards the tail. And we did see, as Steve mentioned, an increase in the use of docetaxel and abiraterone, but still, it really maxed out at about a quarter, and not everyone is appropriate for that, but in my mind, clearly more than a quarter are appropriate for that given the major differences in overall survival with the long-term M1 STAMPEDE data from ESMO, almost a three-year difference in overall survival, despite even adding late abiraterone.

So in this case, I find that a little troubling, I do find it helpful to look at the overall practice patterns. And one of the things that Steve also pointed out is that, you know, despite the older, mid-analysis of a very minor survival advantage for a drug like bicalutamide for the duration of the treatment for metastatic castration-sensitive disease, that washed out in this data set, probably because of the later availability in either early with CSPC or for castration-resistant disease and the data to show that that novel anti-androgen therapy with abiraterone bicalutamide, et cetera, where the most commonly used once the patient transitioned to castration-resistant disease. So in this era, there's no real use, I would say for those drugs, for the vast majority of patients, other than perhaps to block that initial flare.

Alicia Morgans: Yeah. Really, important. And I wonder too, Steve, not that this is the practice pattern we want to take up and to sort of carry forward, given the lack of benefit in this real-world population. But you also sort of alluded to the fact that maybe these are patients that we were a little more worried about, these patients getting that combined androgen blockade. Were there differences in the clinical characteristics or in the disease characteristics of patients who seem to be more likely to get combined androgen blockade than single-agent generic GnRH agonist?

Stephen Freedland: Yeah, no, I mean, they did have slightly more aggressive disease. It wasn't overwhelming, we do see certainly the patients that got chemotherapy had more visceral disease and tended to be younger, healthier, kind of that chemo fit. So when looking at the data, a lot of it intuitively made sense. The guy that you're a little bit more worried about got the combined androgen blockade, really visceral young, healthy with getting more chemo. So I think the practice patterns fit what we think. And, the one caveat I would put is, when we look across the spectrum in terms of care at the VA and various quality metrics and care received, in general, it's on par or better than what we see outside the VA.

And these data haven't been as well published from other data sets, but some preliminary analysis showed that this seems to be a common practice issue. So I don't think these are, you know, it's often easy as someone who's spent a career focused on VA data. We often hear, "Oh, that's the VA doesn't apply to the real world". I think these data are very relevant to the practice patterns we are seeing out there in the real world, unfortunately, and room for improvements.

Alicia Morgans: Absolutely. I mean, one thing that the VA does exceptionally well is really trying to standardize their practices across all of their VA sites, and to the extent that they even have trainings around things, they have pop-ups reminders. I mean, I think I would echo that one hundred percent that the VA really strives to be, I think, a beacon for what prostate cancer care should be and can be. So I would not discount this and say that it doesn't reflect the rest of the population.

So as the two of you think about this and congratulations on this work, I think that this needs to be updated. I'm excited to see the next generation in the next few years so that we can understand whether intensifying therapies, which are more recently available, may do better than this combined androgen blockade. But what would your message be to the folks who are listening, who are trying to make these decisions with their patients in clinics on a day-to-day basis? Why don't we start with you, Dr. Tagawa?

Scott Tagawa: Most doctors that are treating men with advanced prostate cancer, are not like the three of us that are talking that focus really on prostate cancer. So they have, particularly in the medical oncology world, they have breast cancer, lung cancer, et cetera. So I think it's important that they realize that treatment is not the same today for any of those diseases like it was 10 years ago. And I think every patient deserves the opportunity to get the latest and greatest, basically. And I would point out that two of the drugs that lead to major survival advantages are available generically.

So it's not just a kind of a cost issue. These are now in all of the updated guidelines, including ASCO guidelines. They are only a week or two old. I think there is a small percentage of patients that perhaps aren't right. So a lot of comorbidities with maybe minimal disease burden, that's not the average patient. So, I think that because of multiple reasons, whether it's chemo, whether it's a generic oral, or whether it's a commercial oral agent, I think that everyone deserves the right to consider those drugs and then receive them if appropriate.

Alicia Morgans: I completely agree with that. And we'll give Dr. Freedland the last word. What would your message be?

Stephen Freedland: I would agree completely with Scott and I think, thinking about... It's interesting... Scott's thought is, well, the medical oncologists treat lots of cancer... not just urologists think about all the urologist who, yes treats prostate cancer knows how to give hormones, but doesn't give the newer agents. And it's the same type of thing you need to be aware of it, make sure that they're getting the care from the right physician who can do it. And I've heard this argument, well, let me just start hormones and see how they do, if they do well, then all is great, and the answer is, we don't know... I mean, that's not how the studies were done. So we don't know that a person who does well on ADT won't do even better on ADT plus novel hormonal agents or chemotherapy.

So just because they got a good response to ADT doesn't mean that's enough. We don't know that's not how it was studied. And, if you're not comfortable giving one of these drugs for metastatic prostate cancer, that's fine. You got to interact with a urologist or a medical oncologist who is, it's the right thing for the patients. And, I agree with you, Alicia, it will be very interesting as time goes on, we now have data you could argue from STAMPEDE that abiraterone was for all M1, but focused on LATITUDE, that was high risk. But now we have data from low risk if you will, metastatic treated with novel hormonal agents have benefit. We have multiple agents, there's a lot more marketing behind it. It'll be interesting to see how these change over time. Hopefully, it improves.

Alicia Morgans: Well. I think we all hope the same. We all hope that outcomes continue to improve for men with prostate cancer. And I commend the two of you for helping us understand the difference between efficacy in a clinical trial and effectiveness when we get into the clinic, because at the end of the day, it's the effectiveness in our patients that really matters to them. And I'm sure, man, it matters to us as well. So thank you for all of your efforts and for explaining this to us today, we appreciate your time.

Stephen Freedland: Thanks for having us.

Alicia Morgans: Thanks a lot.