Rana McKay: Oh, it's such a pleasure. It was really an exciting conference and great to be with you today.
All right, so we're going to dive right in talking about how to treat older patients with high-risk and locally advanced prostate cancer. And as we know, these are the different clinical states for prostate cancer with a recent evolution in terminology. So you're going to start to see these terms, androgen pathway modulation sensitive, APMR and APMS from the new Prostate Cancer Working Group for criteria. But to say that the bulk of patients who present with prostate cancer actually present with a localized disease and about 15% of those individuals who have localized disease actually have high-risk disease, where there is an opportunity, of course, to cure and many people receive curative-intent therapy. So that's what we're going to be talking about today.
So first I'm going to step back and highlight the epidemiologic imperative. The median age of men diagnosed with prostate cancer is 66 years. However, 60% of those individuals are diagnosed greater than the age of 65 and 20% are diagnosed greater than the age of 75. And really men at greater than 70 years of age carry the highest incidence rates and this has been rising since 2014. And additionally, we're seeing an increase in distant-stage disease that's increasing at about 6% per year among men who are older than 70 years of age.
When we look at the distribution of developing prostate cancer by age and race, we see that the risk of developing prostate cancer increases sharply with age across all racial groups, with men aged 70 to 79 facing the highest decade-specific risk of developing prostate cancer that's here highlighted right in the middle. And additionally, when we look at the projected prostate cancer new cases and deaths by age, the burden of death actually sifts dramatically, probably as you would expect to older men, with 80% of the projected deaths occurring in individuals that are greater than 70 years of age.
And there's been, again, increasing trends across the board. When we look at those individuals in the US being diagnosed, you can see that steep curve in purple at the top for those individuals being diagnosed with prostate cancer greater than the age of 70. And we're seeing this epidemiologic trend.
All right. So why age alone? I think the considerations, hopefully, I've identified for you that there's a epidemiologic need for why we need to be focusing on the older adults, but age alone is not enough. Chronologic age is not biologic age and frailty is not comorbidity, is not disability. And ECOG/KPS is really inadequate for assessing frailty or fitness for therapy in older adults. So how do we define frailty? I think this is a really important paradigm. Like I said, comorbidities are just coexisting chronic diseases that does not define frailty. Disability is actually when somebody has dependence on something for their activities of daily living, they're not able to independently do their activities of daily living.
Frailty is really reduced physiologic reserve and vulnerability to different stressors that can ultimately lead to poor patient outcomes. And on this slide, I really want to highlight a paradigm approach when assessing patients in the clinic, assessing older adults, and also in general, just assessing many of the patients that we see as doing a life expectancy calculation. There's many life expectancy calculators that are out there to help inform decision-making. There are geriatric screening tools to assess for vulnerabilities. And based off of whether somebody has an abnormal geriatric screening tool doing an in-depth comprehensive geriatric assessment that takes a look at cognition, comorbidities, nutritional status, functional status, mental health, polypharmacy, and then actually segueing that into how can we optimize a patient-specific treatment plan that integrates the patient's goals, their social support, what we know about the disease biology and all of those factors.
And what I want to highlight here is that there are actually many frailty screening instruments. I've highlighted the oncology-specific instruments. There's actually instruments that also integrate a physical metric such as grip strength and gait speed or a walk test. There's also EMR-based frailty assessments that are now using the totality of data within the EMR to give a frailty screening score. The ASCO guidelines and many agencies actually recommend using the G8 as the first screen line for older adults with cancer. And just as a point of reference, this is the Geriatric 8 Screening Tool. It's a very simple test. It takes about four to five minutes to go through that has eight different items focusing around nutrition, weight loss, BMI, mobility, neuropsychosocial status, polypharmacy, self-rated health and age. And then if somebody scores 14 or less, that's an abnormal score and should really trigger a comprehensive geriatric assessment. And so I think these are tools that could potentially be deployed in the clinic. And as I've alluded to, these are the different elements for a comprehensive geriatric assessment.
So as we went through, we've talked about the EpiRisk. We've talked about, well, how do you assess for frailty in this vulnerable population? And the next decision point is actually how does that impact the complexity of treatment decisions for patients with locally advanced disease or localized disease and I think the different things that I think about are what's the choice of local therapy, surgery, radiation, or no treatment? What's the choice of ADT? Do you use ADT or not and if so, what agent? What's the choice of ADT intensity? Do you need to add an RP or not? And of course, duration, six months, 12 months, 18 months. And so we're not going to have the time to go through all of these elements, but I think this is the complexity of the treatment decision that's had.
And here are some data around the prevalence of frailty differing by choice of therapy and the potential impact on outcomes. I think obviously there's some bias in some of these data, but choice of therapy can impact frailty. And then the different things to consider. It's not to say that radical prostatectomy is out of the realm of possibilities. Certainly these are things that can be considered, but what are the preferences around radiation therapy. It tends to be well tolerated across the age groups. Hypofractionation SBRT certainly can reduce treatment burden. And the GI and GU tox has in data series, and I'd love to hear your thoughts on this, Leslie, it has really not been an age-dependent factor. And the ADT certainly is a consideration here and can be age-specific.
And then I think there's been some 12-year data from the ProtecT trial. They did an age-stratified analysis, and really across the board the main difference was really around urinary incontinence being worse with RP when they did this age-stratified analysis based off of choice of therapy.
Now with regards to therapy escalation, I think around therapy escalation with abiraterone, the best that we can gleam is the subset analysis from STAMPEDE. When we look at those patients that are less than or greater than 70 years of age, we see that the hazard ratios are very similar, 0.52, 0.55, telling me that for these very high-risk individuals, actually therapy escalation does seem to continue to benefit outcomes. And interestingly, when we looked at ENZARAD, we know that ENZARAD was overall a negative study, had a different definition for high-risk disease. You can see the criteria there that are vastly different, I think, from the STAMPEDE high-risk. And when you look at the age analysis, actually for those older adults, the hazard ratio is at 1.07. For those less than 70, it's at 0.69. So really calling into question dose escalation strategies with regards to Enza in this population.
And the last that I'm going to share is the data around the optimal duration, and this was an individual patient-level meta-analysis of 13 randomized phase-3 trials, including over 10,000 patients. Median age was 70. They don't actually show the age subset analysis in this, but it was an interesting analysis demonstrating that the prostate cancer-specific mortality benefit in the context of ADT duration was non-linear and that most of the benefits seemed to be derived within that first nine to 12 months and then the benefit appears to flatten out.
I think this is very provocative and calls into question, what is the actual optimal duration of therapy for a high-risk individual, a very high-risk individual? I don't think we have the right answer, but I think for those individuals that have risk factors in clinic, I know that always comes up like, "How long do I need to stay on this, doc? I'm a year in and I'm feeling terrible." And I will say that the bulk of benefit is probably in the first 12 months rather than the latter 12 months. And at the end of the day, it's obviously shared decision-making. It's bidirectional, patient-centered view where we seek the patient's participation, understand what their goals and values are and come to a decision around treatment, really aligning with the patient's goals and values.
So that's really a summative review of the presentation I gave at APCCC. And I think this is something that's critically important given the aging population, the push towards treatment intensification in these patients, but the need to balance with frailty, comorbidities, and quality of life.
Leslie Ballas: Thank you so much for presenting your talk to us and going over some of the different elements to taking care of men who are 70 and older, it seems. It is always interesting to me to think about what is an elderly population when the median age is 66 years. And with heart disease being the leading cause of death in American men, I'm always intrigued to hear about choice of ADT, especially given some, and especially with ARPI, given the cardiac comorbidities. And while the studies that you presented certainly do have some data breaking things down by age, they don't have it broken down by cardiac risk factors. And I think that that's something that always ... I kind of have a hard time coming to terms within the clinic. How do you deal with the cardiac component?
Rana McKay: That's a very, very good point. And I think that there have been some old analyses like SEER analyses and real-world analyses that have looked at cardiovascular risk and ADT. And I think actually Paul Nguyen has led some of those works almost like a decade ago. And what I glean from some of that data is, at least how I approach it in the clinic, the people that are most at risk are those individuals that have had a recent cardiovascular event within six months of them starting ADT and you starting them on ADT, they're at risk of having a second event when they're on ADT. I think the data around cardiac mortality with ADT and people with various risk factors has been pretty mixed. In the literature, it's been mixed. But if you actually look at having another cardiac event, the risk is highest in those individuals with a recent event.
So I am very leery about putting an older adult who's had a recent MI or recent stent placement on ADT without a very elaborate discussion with their cardiologist. But I think the data around mortality or having a cardiac event that results in mortality has been pretty mixed when you start ADT.
Leslie Ballas: Yeah, I think ADT, certainly there's a lot of mixed data as you're commenting on. It's actually like the more recent JAMA paper on ARPIs and the increased risk of grade 3 or higher cardiac events, that is where I get worried in these locally advanced patients where we're seeing, now that we have PSMA PET and we are seeing more clinically node-positive disease, and then we're putting people on ARPIs, that's where I start to be like, I don't know how to weigh an individual's cardiac risk, especially in an older person who, as you mentioned, has polypharmacy on board.
Rana McKay: Yeah, yeah. No, absolutely. It's a good point. And I didn't go into it in this talk because Dana reviewed it in her talk on how to manage individuals with metastatic hormone-sensitive disease who are older, but of course the STOPCAP analysis that looked at ABI and the older patients with mHSPCs.
Leslie Ballas: Got it. Okay. Thank you. And for the people who are listening to us chat about this today, what would be your take-home? Should frailty assessments be done on every patient in the clinic that you see that's over a certain age or that expresses concerns about their own frailty? Where is your point at which you assess and intervene?
Rana McKay: Yeah, I think we need to do a better job of doing these assessments. I think a lot of us are like, oh, we do the eyeball test. My frailty assessment is the eyeball test. But I think there's a lot underneath the surface beyond that. And I think there's information that a patient may or may not disclose, especially when they're there in the visit with their doctor. And I think now there are a lot of easy ways that patients can do this, whether they're just waiting in an exam room and you just get flagged. They fill out a questionnaire in the waiting room or something and you get flagged with the score. I think there's ways to implement it in a seamless kind of manner, but I think it's having that awareness.
I don't necessarily think that we need to blanket roll out for every ... I think these are things that are difficult to operationalize because it's one thing to roll it out, but then you also have to have the network to do the referral for a comprehensive geriatric assessment. All that comes with, okay, if I identify like on whose shoulders is the burden to ... you've got to do the nutrition assessment, maybe see neurology, psychology, whoever it is that needs to help with those elements. Geriatricians, we know that there's a huge shortage of these individuals. So I think it's to step back and have a more comprehensive approach as we think about these individuals in the clinic. I think we over treat a lot of patients with high-risk localized disease.
Leslie Ballas: Yeah. Well, thank you so much for joining us and for reviewing this very important topic. It was truly a pleasure, Dr. McKay.
Rana McKay: Thank you so much. Appreciate it.