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Zachary Klaassen: Hello, and thank you for joining us for this UroToday discussion, where tonight, we'll be discussing, Treatment Intensification in Metastatic castrate-sensitive Prostate cancer. My name is Zach Klaassen, I'm an Assistant Professor at the Medical College of Georgia. And joining me is Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto.

As most UroToday, readers and listeners will know, metastatic castrate-sensitive prostate cancer does have varying degrees of incidents across the globe. In the United States, the de novo metastatic prostate cancer incidents is roughly 3%. Across Europe is 6%. In Latin America is four to 10%. But even in countries in Asia Pacific, we see it as high as 60%.

There's been several papers out of the US, including out of the SEER registry, and this one was published in European Urology Oncology in 2018, that have looked at the incident rates of metastatic castrate-sensitive prostate cancer. And this study had follow-up to 2014, and we see a relatively stable cases per 100,000 population, up until around 2011, 2012, when we see an uptick continuing through 2014. And many have surmised that this has been secondary to the US PSTF grade D recommendation for prostate cancer screening around the same time period.

A more contemporary study, which was published earlier this year, again looking at SEER database, looked at trends in the incidents of metastatic prostate cancer, again among the US data. However, with more follow-up until 2018. And if we look at the top left as well as the top right, we see the derived SEER stage on the left, and the derived M1 stage on the right. And essentially, we see an uptick continuing through 2018, particularly in men over the age of 75, which are the orange line. This also corresponds somewhat to the uptick in N1 prostate cancer during this time period, with relatively stable rates, slightly increasing over the last couple of years, in patients with T3/T4 disease. So we see, particularly among older men, this continued increase in incidents of metastatic prostate cancer through 2018.

Of course, we know that the study for prostate cancer and the effect of androgen deprivation on prostate cancer control started with the classic Huggins and Hodges paper in 1941, which ultimately, led to the Nobel Prize in 1966. And we've seen, in particular over the last decade or so, an explosion of treatments, especially FDA approvals, in metastatic hormone sensitive prostate cancer.

So to briefly review, docetaxel has level one evidence, was not FDA approved in 2015/2016. We then had approval of abiraterone in February 2018, the approval of apalutamide in September 2019, the approval of enzalutamide in December 2019, as well as the approval of abiraterone plus docetaxel in 2022, as well as darolutamide plus docetaxel. So we've seen, in the last seven or eight years, the doublet therapy, as well as triplet therapy, on the landscape for metastatic hormone sensitive prostate cancer.

This is the most recent recommendations from the NCCN guidelines. This is version one from 2023, and we see that this is the following recommendations as of now. Essentially, we have ADT plus one of the following preferred regimens, which is either abiraterone, apalutamide or enzalutamide. Or, with the triplet therapy, ADT plus docetaxel plus either abiraterone or darolutamide.

In settings of primary tumor for low metastatic burden, we can treat with ADT plus external beam radiotherapy. Of note, what's interesting is that, ADT plus docetaxel alone is no longer a preferred regimen at this point in time, based on the most recent NCCN guidelines.

So of course, this is all from clinical trial data, but as we know, majority of patients will be treated in the real world setting. So the rest of this presentation will really focus on several studies that have been done in the United States, as well as across the globe, that have looked at real world utilization of ADT plus other agents in the mCSPC disease space.

This first study from Ryan and colleagues was done using two different databases from the United States, looking at 19,841 patients. This included the Optum Clinformatics Database, as well as Medicare/Medicaid. And this was patients diagnosed with metastatic castrate-sensitive prostate cancer between 2014 and 2019. And what they found was, in the Optum database, 38%, and in Medicare/Medicaid, 48% of patients received no treatment during a median follow-up of roughly 10 months. Roughly 45% and 46% of patients received only ADT monotherapy. And only 13% of patients in Optum, and 2% of patients in Medicare/Medicaid, received intensification of therapy.

This is a figure from this study, and you can see here this, the lighter blue scatter is from 2015 to 2017. And the darker blue scatter is from 2018 to 2019. And we can see that, roughly half of patients received ADT monotherapy alone, and very poor uptake, even in the more recent contemporary years, of other agents added to ADT, including first generation androgen signaling inhibitors, abiraterone and docetaxel.

The second study was from the VA data from Freedland and colleagues, and this was a cohort of roughly 1400 patients that were diagnosed with metastatic castrate-sensitive prostate cancer between 2013 and 2018. And you can see, this chart is on the right here, corresponding to ADT alone in blue, ADT plus NSAA in red, ADT plus abiraterone in green, and ADT plus docetaxel in orange.

Some of the key treatment observations; 63% of men had only ADT alone, 24% had ADT plus a first generation antiandrogen, 8% had ADT plus docetaxel, and only 5% had ADT plus abiraterone. And for the most part, we see that these lines are relatively stable with a slight uptake in abiraterone in the most recent years of analysis. Although, once again, these are still low absolute numbers, of only 5% of patients receiving ADT plus abiraterone.

Next, I'm going to hand it over to Chris, who's going to talk to us about the rest of these US studies, some of the global studies that have been published, as well as some concluding statements.

Christopher Wallis: Thanks so much, Zach. And so we move now to a recent presentation from Dr. George and colleagues that comes from ESMO this year. And it combined data from two of the data sets that we've already talked about, the Medicare sample and the VA, and looking at patients diagnosed between 2010 and 2019. And you can see in the figure on the left, the Medicare data, and on the right, the VA data.

We see some uptake, particularly of the novel hormonal therapies in the later years, 2017, 2018, and 2019, with our absolute percentages are still well under a third of patients. But what's interesting and suggests the real potential for population benefit to be derived here, is that we've seen improvements in overall survival among these patients newly diagnosed in metastatic castration-sensitive disease in this most recent epoch, dating from 2015 to 2019, compared to historical patients treated when there weren't treatment intensification options. And so this really suggests that the diffusion, even though slow, of these agents, is having a population level of survival effect. And if we can get a better uptake of them, we can likely see even greater benefit.

We now move to this data, which is again, from the same study, and just highlights that point even more, that you can see that as time goes on, we're seeing improvements in overall survival, and this is likely driven by increased utilization of life prolonging therapies, although this study really did this as an ecologic kind of analysis.

Our last piece of data from the US comes from the Flatiron Database, which includes patients treated in both academic centers, as well as community oncology practices, and this dates from 2011 to 2019. And we see a few key observations. First, more than half of patients are still receiving ADT alone, although we do see a decreasing trend in this cohort. We see increases over time in treatment intensification approaches, including abiraterone, docetaxel, as well as enzalutamide. And so, we're seeing here, approaching half of patients, by the most recent time period, receiving some form of treatment intensification, and these are the first treatments after metastatic diagnosis.

And then we can consider more global data. And so, the first data set we'll look at here comes from Leith and colleagues, who looked at the Adelphi Prostate Cancer Disease Specific Programme, or DSP, which surveyed physicians from the US, Europe and Japan, regarding their treatment approaches.

Key observations include the fact that ADT monotherapy remains the most commonly proposed treatment paradigm. And this is notable, as in a survey situation, we would expect respondents to give more socially desirable responses. I potentially overestimate the amount that they treatment intensify, and yet, ADT monotherapy remains most commonly recommended.

Novel hormonal therapy is next, at approximately one third of patients. And chemotherapy is relatively infrequently recommended as the primary treatment approach.

You can see from this figure here, that when we look across jurisdictions, there's considerable geographic variation. Certainly, the uptake of docetaxel varies quite dramatically, up to 40% in the UK, and essentially, negligible use in Japan. And so, this variation is quite marked.

The other thing we see from these data is, variation in the rationale for treatment suitability. And so these are physician reported reasons for treatment choice, and treatment intensification is seen most commonly, as you see on the left side here, where NHA bars are tallest, among physicians whose goals are to maintain or improve quality of life, in patients where we have the top priority of maximizing progression-free survival or overall survival. And among patients who have a high disease burden with a relatively good performance status.

When you're looking at the chemotherapy patients, those green bars, it's really those where the feelings that are prioritizing overall survival, and having a good performance status, are marked features. And also, where those who are rapid onset of action is required.

We can now move to other sources of data from around the world. And these data come from Ontario. This is approximately 3,500 patients accrued in a truly population based manner, looking at de novo metastatic prostate cancer diagnoses between 2014 and 2019.

The authors here divided their analysis into the period from the start of cohort accrual till early June 2017, and that's the post-CHAARTED but pre-LATITUDE data, and then after 2017, the post-LATITUDE data. And we see, that in this population, most patients received ADT alone, between 77 and 80%. And while the utilization of androgen deprivation therapy with abiraterone increased following the publication of LATITUDE, it was met with a decrease in the utilization of docetaxel, such that, there was a trade off, and overall intensification rates didn't really improve.

So then, we need to consider, who's receiving the intensification? We can look from both US based data and Ontario based data. And we see that in general, it's those younger patients with lower comorbidity levels, higher PSA, and higher metastatic burden, suggesting a fitter, healthier patient, with more aggressive disease. And these are the ones who are really getting treatment intensification. And in particular, that applies to those who are receiving docetaxel.

The abiraterone treated patients, relative to the docetaxel patients, who are a bit older, will tend to have lower cardiovascular disease, and a higher visceral disease burden, compared to those who receive ADT alone. Interestingly, in US based data, black men are less likely than white men to receive intensified therapy, and this fits with what's previously been identified, in terms of disparities in access to guideline concordant care.

So recent work, presented at ASCO this year, by Freedland and colleagues, looked at barriers to treatment intensification. This is based on a survey of oncologists and urologists, that was linked to a retrospective chart review across numerous US based practices.

In this cohort, ADT was the predominant treatment approach, with nearly 70% of patients receiving ADT alone. And NHT based intensification, predominantly abiraterone, was employed in about a quarter, and docetaxel was used in less than 5%.

What you can see here is that, there's multiple reasons that the treating physicians cite as reasons not to prescribe treatment intensification with a novel hormonal therapy. This includes, what I would say, are some misconceptions regarding the data, including concerns regarding tolerability, or lack of clinical trial evidence of survival improvements. As well as more logistic concerns, including issues regarding reimbursement, and treatment sequencing, as well as financial toxicity for patients.

So moving forward, we know that treatment intensification, with either a novel hormonal agent, or docetaxel in addition to ADT, or the combination of both of these, has been shown to improve both overall survival and quality of life, in patients with metastatic castrate-sensitive prostate cancer. This treatment intensified approach is now guideline recommended, and should be considered standard of care.

However, population based data, from numerous jurisdictions, and different reimbursement environments, show that the majority of patients receive ADT alone. Thus, better understanding, both patient and clinician level barriers to intensification is critical, to improve the care of patients with mCSPC, and really ensure that all patients are receiving the best available treatment.

Thank you for joining us in this UroToday discussion, and we hope that this presentation has been of interest, and hopefully, educational for you.