Matthew Smith: Our next and last speaker of the session is Andrew Armstrong. Andrew will talk about uptake of new treatment options in MHSPC.

Andrew Armstrong: All right. Thank you, [inaudible] and [inaudible], and the APCCC for a great first day. It's great to be with you here, live. And I'd also like to thank you for challenging me to put together a topic for everyone to consider the real world evidence of the hormone sensitive practice patterns. Making sure that we're focusing on our patients, both the diversity and the inclusion, and identifying those areas across the globe where there's gaps. These are my disclosures. So the outline of this talk, you've heard today, at length, the evidence for the life prolonging therapies but we'll be diving into what's actually happening in the real world up to the most recent geo symposium meeting. Including both USA and non-USA payers and countries. Looking at disparities and inclusion by race, disease characteristics, and payer patterns. We'll talk about global patterns of care and trends.

So I'll put in a plug for the IRONMAN registry and we'll finish with some unmet needs and evidence. So we've started off talking about synchronous metrachronous, but it's important to realize that men who present with metastatic disease do face that shortened and truncated natural history. And the prevalence of metastatic disease is really dynamic, depending on the parts of the world that you live. In parts of China and India, the prevalence can range from 50 to 70%. In the UK, it's presently around 20 to 30%. In the US, it's changed dramatically during the ebb and flow of PSA screening from three to 5% to presently around 10%. And we hope that that starts to go back down. These men still are treated with evidence-based practices to extend their lives and the key trials that have informed on this de novo population we've covered very well today. But really, ADT is no longer the standard of care.

And the goal is [inaudible], prolonged survival, improved quality of life, and clearly cost effectiveness, as you just heard. This is a list for all of you who were at the meeting today, and over the past year, I did not include piece one. That wasn't published when I submitted these slides, but I'll obviously add that tomorrow, but we have basically very successful potent therapies. The intensifying therapies, both with chemo hormonal therapies, potent AR inhibitors, and if you look on the right, the hazard ratios for overall survival are really phenomenal. They're all wins for our patients. They're all very similar to each other, right around 0.66 to 0.67, with significant delays in progression free or failure free survival. Now merging into triple therapy, as you've heard earlier. Really, the choice of these therapies is not going to be based on differential efficacy, largely, but based on patient characteristics; tolerability, frailty, as you heard from Alicia's elegant talk, as well as cost and availability.

A suggested treatment algorithm, as you go into your clinic practice, for men with hormone sensitive prostate cancer is going to be based on the patterns of spread or whether there has been spread. The volume of disease currently by conventional imaging, perhaps in the future by functional imaging, and the current evidence that we have that's constantly changing. Certainly in the high risk, very high risk setting, we're focused on curative intent therapies where it's very hard to measure qualities, but rather improving cures and stopping therapy early so men can live a normal life. ADT radiotherapy plus [inaudible] brachytherapy and intensification of therapy, or radical prostatectomy, lymph node dissection in early salvage. Based on disease volume, we talk about integrating treatment of the primary versus triple therapy in fit patients. Alicia showed you the NCCN guidelines, which, meeting actually on Monday to update.

Currently in the very high risk setting, you see abiraterone already mentioned. Docetaxel is probably starting to fade away in terms of current use, but in the M1 setting, as of the version from February, we have level one evidence for really all of these therapies. You see ASCO guidelines published last year, which have already fallen out of date a bit, but you see the integration of potent AR inhibition, even in non-metastatic settings, recommended by expert panels. I think what is important to realize and to question is whether all of these phase three studies have been representative of what we see globally. I will start at the top row, African ancestry has certainly been linked to poor prognosis presentation with more aggressive disease in a disproportionate impact at a population level. But the inclusion of men of African ancestry descent has been quite poor across all of our phase three trials, particularly the industry trials, and not reported in some of the trials that I could discern.

We've been good about reporting and characterizing patients by de novo disease, by relapse disease, by the patterns of spread, by symptoms, and functional status, but we need to do better. When we've looked globally and nationally, and across industry versus federal versus academic studies, we see a lack of representation of disproportionately impacted minorities, particularly in US prostate cancer trials. So Black men in blue, white men in red, Hispanic, Native American men in orange, and we have Asian and Pacific Islanders in green. And if you look at the prostate cancer group, you see an over representation of white men and an under representation of Black men in our clinical trials. This is ameliorated in federally funded studies, but is more disproportionate in industry studies. And even in academic studies, we need to do much better. You can see the relative inclusion or representation as a quotient by what should be expected.

We see that the impact of lethal prostate cancer, however, is largely in Sub-Saharan Africa, in South America, and the Caribbean. And that's not where our clinical trials are happening to try to save the lives of men with metastatic prostate cancer. So again, we need to do better. We see US treatment trends slowly starting to emerge with treatment intensifications. You can see the green line is ADT alone. We're pretty much stuck at 60 to 70% of men, up through about 2018, receiving ADT alone, despite a diagnosis of metastatic castrate sensitive prostate cancer. One of the major risk factors for being treated with ADT alone is race and ethnicity, with an under representation of minority and disproportionately affected men receiving ADT alone. More recent trends suggest that we are doing better, that docetaxel and a potent AR inhibitor is being increasingly offered, particularly as of maybe three years ago, four years ago, datasets. Particularly in men with bone metastases, visceral patterns of spread, and outcomes are incrementally getting better as we follow the national trends.

The most recent trend was published by Pedro Barata at the GU Symposium just a few months ago. And you see that, still, 45% of men, as of 2020, were not receiving treatment intensification. But you see a big bump up in the use of novel hormonal therapies, from about 23 to 49%, and a major reduction in the use of older anti-androgens like bicalutamide and flutamide. And certainly we're starting to see a reduction in docetaxel as well. There are other trends that overlie these efforts and these go into how men are presenting. Screening leads to the earlier diagnosis of localized disease and can reduce metastatic disease. But we are seeing, at least in the United States, a reduction in the proportion of men getting a PSA test, being diagnosed with prostate cancer, and we're starting to see an uptake five to 10 years later in the diagnosis of M1 disease.

So we do worry that this is going to be exacerbating the problem of now having a group of men who are going to be facing a non-curative setting. And certainly the COVID-19 '20 and '21 and '22 pandemics are exacerbating these. The COVID-19 impact during 2020 has been particularly notable and this is published in BJUI just a few weeks ago, you can see that the number of radical prostatectomies, diagnoses of men with localized disease, really took a dip during the peak of the pandemic and really has not caught up. In the UK, national level data initially found that about 13% of men would present with M1 disease, but during the COVID pandemic since April of 2020, that number has risen to about 21%. There's been a 54% reduction in the number of patients newly diagnosed with any type of prostate cancer during that peak, followed by an increase thereafter, but not catching up to pre-pandemic levels.

And for M1 disease, the treatment trends, as published here, has shown a clear reduction in the use of docetaxel and an increase in the use of drugs like enzalutamide with its avoidance of steroids and immune suppression. Perhaps because of concerns over the vaccine rollout or immune suppression. We're no longer winning the war on prostate cancer, we have stopped some of our informed decision making and our screening as primary care doctors. We're essentially taking a break from screening. We've seen leveling out of lethal prostate cancer and an uptick in some geographic regions. In our institution, we've instituted a broad primary care screening program that largely follows NCCN and involves a risk adapted algorithm that's both PSA and age based. We've implemented this across the 50,000 patients in the primary care clinics across North Carolina, 21% of whom are African American.

And when we implemented an electronic health record prompt, simply to notify the doctor that it was time to do the PSA screening, this led to a improved implementation of rational screening, following this algorithm, from 49 to 68%. And this increased across all races and ethnicities, suggesting that simply screening may reduce the metastatic hormone sensitive disease burden more than anything that we could do. When men are included in clinical trials, across race and ethnicity, we see from this SEER database that, across the country, Black men are disproportionately dying of prostate cancer. But when included, and when included in a shared equal access program or in a clinical trial, men of African ancestry tend to do well, if not better, than other races and ancestries. So testifying to the importance of inclusion. And those are the hazard ratios. We also see, in the mCRPC setting, again, a lack of inclusion. Again, these are global trials, but largely being conducted in parts of the world where there's less of a proportionate impact.

The percent African ancestry has ranged from two to about 5% across these trials. And again, Dan Spratt wrote a nice editorial in JCO suggesting we need to do better. And perhaps say, as the FDA is currently suggesting in a draft, perhaps we need a mandate to have a minimum allocation of disproportionately affected minorities in our cancer trials. We've tried to do this at Duke through a Department of Defense consortium trial, where we mandated equal allocation to abiraterone by men of self-reported race. We enrolled 50 white men, 50 Black men, who were treated with abiraterone prospectively. There was some suggestive data from the Cougar 302 trial that there may be differences in PSA outcomes and progression free survival. What we've learned from this inclusive study, and we call it the AbiRace study published in Cancer last year, is that the overall survival was no difference. But that Black men, when they're treated with abiraterone, tend to progress simultaneously with PSA and radiographic imaging, while white men tend to progress first with a PSA followed by radiographic imaging.

So you do see a discordance in the PSA outcomes, but not the radiographic outcomes. Another outcome was PSA responses. We saw greater PSA declines in men who were self-reported African ancestry. Important in this trial, we saw differences in toxicity, and if we're not inclusive in our trials, we'll never learn these things, that men of self-reported African ancestry had a differential fatigue. Differences in hyperemia, hyperglycemia, headache. And some of these were grade three and four, suggesting that comorbidities and other factors, other medications, may play a role that's important to capture. We also identified ancestry-based genotypes that were associated with some of these efficacy differences. We wrote an editorial in JCO when we were covering the [inaudible] and latitude stampede, updated quality of life data suggesting, just like Alicia said in her editorial, that there's a balance of making treatment decisions across the world.

It's based on efficacy, but also effectiveness in large populations. It's based on the safety and the comorbidities that a patient may bring, and the individual patient factors and preferences, but also the financial cost both to the individual. Sometimes the co-pay is the major driver rather than to the healthcare system. And obviously the quality of life. Some of the gray areas for discussion when we've conducted our voting that you'll hear soon is, and you've heard all day, is the role of imaging. How do we redefine volume of disease to inform treatment decisions? How should we treat the primary in the face of novel PET imaging? Should we treat oligometastatic sites like little primaries that could continually seed a distant sites? And what volume of disease justifies that? Can we actually stop systemic therapy if you achieve a complete remission and all disease has been treated? That may be more cost effective. What are the biomarkers to choose between an AR inhibitor versus docetaxel versus triple therapy?

How could we save money by giving less abiraterone? Perhaps with food? How can we integrate docetaxel chemotherapy and sequential therapy without creating a financial major impact on our populations with real world data? And how do we follow patients to maximize their survivorship? I'll just put in a plug for the IRONMAN Registry, this is now a 2,500 patient registry across the world. Including sites, both in South America and Sub-Saharan Africa, the Bahamas. It's attempting to become a very large representative study. Got the cowbell. And the goal is 5,000 men to answer some of the questions, as men transition from the metastatic hormone sensitive setting, all the way to the castration resistance setting. So just to finish with questions, what are some of the major unmet needs? I think I covered this. There's obviously studies on cost effectiveness of using alternative doses or schedules or food effects.

There's an Alliance Cooperative group study that's being planned to study intermittent potent androgen deprivation therapy with an AR inhibitor in men achieving a response and thus a risk adapted approach. Reductions in the long term systemic therapy needs, obviously if we can get more men screened and early detected so that we don't see as much metastatic disease, that will ultimately be more cost effective. And if we can improve our cure of intent therapies, even in these high and very high risk patients, where they can stop therapy, not have to take these agents for the rest of their lives. I would point out the FDA draft guidance on required representation in the clinical trials, which is available for download there. Thank you, guys.