Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Northwestern University and an Associate Professor of Medicine there. I am so excited to have here with me today, Dr. Stephen Freedland, who is a Professor of Urology at Cedar Sinai in LA, and a Staff Physician at the Durham VA. Thank you so much for being here with us today, Dr. Freedland.

Stephen Freedland:  No, thank you, Alicia. It's great to be here again talking to you about another exciting project that we had.

Alicia Morgans:  Yes, I agree. It's wonderful that you do so much work in this space, in health economics and really help us, I think, as a cancer community, put the treatments that we have into a context that helps us understand this benefit-risk ratio a little bit better. Not just in terms of cancer outcomes, but in terms of the other things that affect patients.

And that's why I wanted to talk with you about a recently published paper in Urologic Oncology: "Seminars and Original Investigations", where you did a study of veterans and looked at their survival, their healthcare resource utilization, in that non-metastatic castration-resistant prostate cancer population.

And before we really dig into what you found, because I think that was interesting. Can you tell us a little bit about why this kind of work is important?

Stephen Freedland:  Absolutely. So, non-metastatic castrate-resistant prostate cancer means castration-resistant, PSA's rising despite hormones, but non-metastatic disease. So bone scan, CT, shows no evidence of metastases.

And so the question is, what should we be doing for those patients? They are asymptomatic. They have no metastases. We now know there are three different agents that all can delay time to metastasis-free survival. And now with updated followup, all three improve overall survival. So the question is which of the patients that are right for those agents. And ultimately if they're treated with those agents, what are we preventing?

We are preventing metastasis, prolonging survival, which clearly is very important. But as you said, there are other metrics.  There are costs, there's healthcare resource utilization, how many times does a person have to go into the emergency room? And so, understanding all of that and how that changes once you develop metastatic disease, it's very important to put those agents into the appropriate context.

Alicia Morgans:  I agree, and I think particularly in the non-metastatic CRPC setting. As you mentioned, this is an asymptomatic population, and so as we have conversations with colleagues and in our community, I am not infrequently met with the comment that these patients don't need any more treatment, until they become metastatic, for example. And I think that the overall survival data and the metastasis-free survival data is actually quite compelling. But, if we're trying to round out the picture, this is exactly what could be helpful, this healthcare resource utilization.

So, in this trial, you had over 12,000 patients, in the VA Health System, who were included. Can you tell us a little bit about what you assessed and what you found?

Stephen Freedland:  Yeah, absolutely. So working with Janssen, that was the sponsor of the study... And I should say, I'm a consultant for Janssen, as well as, also a consultant for Astellas, Pfizer, and Bayer, which makes the competitor drugs in this space here in non-metastatic CRPC, as well as other companies I work with. We accessed the entire VA system.

So the VA system, for the last 20 years, has data on over one million prostate cancer patients. And from that, using various algorithms based on claims, PSA, we were able to identify this cohort of men who had no evidence of metastasis, so no codes for metastasis. We didn't obviously review every single chart individually, but had no evidence of metastasis, had not received drugs that are typically given for metastatic CRPC, but yet appeared to have castration-resistant disease, so kind of this non-metastatic CRPC.

And the question was; looking at how quickly the PSA was going up, calculators of PSA doubling time, how did that correlate with the risk of developing metastasis? And once you develop metastasis, what were the costs and healthcare resource utilization?

And I don't think it's a great surprise, but still very nice to document, is that the quicker the PSA was going up, the shorter the PSA doubling time, the more likely men were to develop metastases. But very importantly, once men develop metastases, the cost of care went up dramatically.  And these are not just the agents used to treat men with metastatic CRPC, but imaging, the number of hospital visits, the number of ER visits, inpatient stays, all of that went up. Arguing, that preventing metastases not only has a human impact, in terms of the psychology on the patient of having metastasis and overall survival but actually has an economic impact in terms of, can we reduce costs, keep them out of the ER, keep them out of the hospital, if we can prevent those metastases.

Alicia Morgans:  Yeah, I completely agree. And it was actually kind of striking to see these numbers really quantified, and this is the kind of work that can do that. I think we all think that, at least in our practices, we'll have more of a burden, for example, going from the non-metastatic castration-resistant setting to the metastatic castration-resistant setting. But I thought it was just pretty striking that there were large increases for inpatient costs in that transition, as you said, emergency room costs, and pharmacy costs, all increased by, sometimes, tens of thousands of dollars in some of these situations. Really just going from the non-metastatic to the metastatic setting.

And it is interesting to think about if we have a drug that can delay that progression, delay that time to metastatic disease, we can really save quite a bit of money in addition to, of course, improving the quality of life and maintaining function for our patients.

Stephen Freedland:  Yeah, I think that's key. And it's always challenging to take a human life, and quality of life, and some of the things that are important, and distill it down to dollars, but dollars are money spent somewhere. And if they're spent in the emergency room, that's a visit when someone is trying to lead their life and live it to their fullest. And all of a sudden needs to make an unplanned visit to the emergency room, or become an inpatient in the hospital, and the anxiety and, the stress.

And unfortunately, with claims-based data, we can't quantify that, but just the impact on the quality of life, needing to spend more time in the hospital, more time in the emergency room, the anxiety, the stress that it creates, that's huge. And as you say, it's not all the pharmacy costs of the drugs for mCRPC, though, that's a part of it, but there's a human toll here. And I think that's important.

I think that... The flip side of the analysis, if you looked at the outcomes for men with really long doubling times, they actually do pretty well. And so when we start to think about who to treat, it's really the guys with the shorter doubling times, less than 10 months, maybe less than 12. But we see some patients with 24 month doubling times, really long doubling times, that do quite well for years.

Alicia Morgans:  Yeah, I agree. I think that patient selection in the non-metastatic CRPC setting is going to be key, as we try to actually get the most that we can out of these treatments, but also avoid treatment when it's not necessary. And I know, I am always in support of that. And so are you, which is why you even do those kinds of breakdowns in this work.

So as you think about this particular publication and the work that you and the team did, what would your bottom line message be for this paper?

Stephen Freedland:  So I would say the bottom line is, that for those men with the shorter doubling time, whether we define that as less than nine, less than 10, less than 12, somewhere in that range, for those men, they're at significantly increased risk of developing metastasis. When they do develop metastasis, they're at significantly increased risk of increased costs, increased inpatient hospital stays, increased ER visits. There's a huge personal and economic toll on those patients.

And on the flip side, for those with longer doubling times, they normally tend to do pretty well without any significant therapy in this space and can be watched for sometimes years.

So one final thought is, this study looked at the cost to the health system, which obviously is very important, but there are patient costs, there's lost time from work, lost time with their family, lost productivity. So when we put that into the context, which we can't quantify in claims data, the economic impact of developing metastasis would be even far greater than what we're able to quantify in this study.

Alicia Morgans:  I really appreciate that you brought that up. These indirect costs, these things that we don't measure within the healthcare system, are things that are even harder to put a number on. But they certainly impact our patients, and they do impact our broader economy, and people's lives. So, important that those are out there, not yet included in analyses like these, but things that we absolutely need to think about.

So thank you so much for this work, for helping us put things into perspective. And for helping us understand that even in different patient populations, and this is another example of the way that PSA doubling time can really be associated with things like MFS and OS, and even healthcare costs, helping us to choose our patients wisely as we move forward with our care. Thank you again for your time today.

Stephen Freedland:  No, thank you for the interest. Great to talk with you, Alicia.