Silke Gillessen: And we start with Alicia Morgans. I'm very, very happy that Alicia's here talking about treatment of frail patients with metastatic hormone sensitive disease. Thank you very much, Alicia.

Alicia Morgans: Thank you so much, wonderful opportunity to be here today. So as we start, I just wanted to take the moment to review the options that we have available for treatment of all patients. Of course, not just frail or older patients. We have multiple options for therapy as we've been discussing all day. And this is really quite an embarrassment of riches that allows us to tailor our therapy and have many options to do that for our patients. What we can say, though, from this guide is that it's very clear that combination therapy with ADT is a preferred category one recommendation for patients, and these recommendations do not come with asterisks that say only in younger patients at this point in time, as I think they probably should not. So importantly, these are for all patients and important to offer.

So I had the great opportunity to work with Dr. Beltran, earlier this year to review some data and write an editorial for JCO about androgen deprivation therapy in the hormone-sensitive space. And we were able to really review what are the cancer-related factors, the clinician related factors, the treatment-related factors, and most importantly, for this talk, the patient related factors that should be considered when we're trying to decide whether a patient is fit for something more than ADT alone. Importantly, at this point in time in the US, at least about 50% of patients are only getting ADT as a single agent when we have those category one recommendations. And so we need to think about things like life expectancy, comorbidities, et cetera. So is ADT enough if life expectancy and comorbidities are not in our favor? I would argue no for the majority of our patients, even in those where we have to support them in an extra way.

So let's consider how. So let's first define the vulnerable and frail phenotype so we understand who we're talking about. I think the classic consideration here is the older adult patient, and we know that we live in an aging world and we're fortunate for that. We can see by the shading on these maps, that the world will be aging. And is aging such that a greater proportion of individuals living around the world in most parts of the world will be older by the time we get to 2050, with a large proportion of this map, suggesting a large majority of patients being over 65 or a large proportion of patients being over 65. And this is our patient population because prostate cancer disproportionately affects older men. But importantly, too, we have to recognize and do recognize in our clinical practices, that chronologic age, the number on the patient's chart, the date of birth, and biologic age, the actual fitness of the patient, and the ability of that patient to support himself through treatment are completely different things.

The individuals in these pictures are the same age, 76. The man on the left clearly has a different physical fitness and a clearer younger biologic age than the man on the right, who may have multiple comorbidities and uses a cane to ambulate. So how does this actually work out in practice in our clinics? Well, this is an example of life expectancy tables, they're based on actuarial tables and how we consider patients in our clinic is usually done in this sort of a fashion. If we look at the difference between patients in the healthiest 25th percentile of their age group, versus those in the least healthy 25th percentile, we can see there's a dramatic difference. For example, at age 70 a life expectancy for the most fit 25% of that group is approximately 18 years. Whereas those individuals who are in the 25th percentile for the poorest health have a life expectancy of 6.7 years.

And this is the same across all ages, that these are different. So understanding the comorbidities is critical. Also, importantly, the International Society of Geriatric Oncology, also called SIOG, has helped us think through this fit versus frail concept, specifically in patients with prostate cancer. They suggest that we use basic criteria to try to evaluate our patients. And these are the mandatory initial step of the G8 assessment, which is a very brief geriatric screening tool of eight questions and a mini cog, which is a five minute assessment of mental function; just a quick screen. Both of these can be delivered by trained clinical staff within five minutes or less, and are a simple way to try to risk-stratify patients, even as they're checking in getting their vital signs. And we use this information to understand and categorize patients as fit, frail, or disabled with severe comorbidities.

And importantly, this G8 test can identify patients if they have a G8 that is greater than 14 as being fit for any treatment. And in the metastatic hormone-sensitive setting, this is going to be intensified therapy. In the middle we can see patients who are identified as having a G8 of less than or equal to 14, suggesting possible frailty who can be evaluated more thoroughly to understand the frailty. Are there reversible issues that we can support patients through physical therapy, through supportive services, through medication management, if they're dealing with polypharmacy or nutrition problems. Are there region or country specific supports that we can provide for patients that are unique to an individual who lives in a particular part of the world? And can we take that patient who through that assessment is identified as being frail and push that person into the fit category?

If not, this is not to say that we should not still treat these patients, but perhaps use the therapies that we should use for all patients, perhaps with a dose reduction or a step-wise approach to intensifying therapy that recognizes their potential frailty and supports them through it. This is the G8 screening tool. And I just want to point out the categories that are included so that we're aware of these. We can see that nutrition is certainly top of mind, mobility as well, neuropsychological problems, which are also being evaluated through the mini cog, as well as polypharmacy taking more than three medications a day, age and patient perceived health status. For individuals who have a G8 of less than 14, they actually have a poor overall survival and some prospective analyses that included many cancer patients, but a specific portion of about 10% of those being prostate cancer patients.

So this correlates with survival. So to take all of that understanding and assessment of our patients, I think, and put it into the context of our clinically available therapies is the next most important step in metastatic hormone-sensitive disease. So let's consider the disease control outcomes and how we should consider our patients fit, and frail with these outcomes. What is clear from these trials, and we'll start with Abiraterone Acetate trials first, is that very importantly, from my perspective, the benefit of ADT plus intensified therapy in this setting ADT plus Abiraterone versus ADT alone occurs very early. Here we see in the latitude trial that it's approximately six months that we already see a survival benefit branching in this trial, and in the stampede trial, we're approximately 12 months. This is a survival benefit, other important outcomes like progression-free survival and others occur even earlier. Enzamet and Titan keep up the same theme.

Enzamet approximately 15 months in the non-docetaxel group. And in Titan, we see it's just under 12 months, somewhere around 10 months. So these curves separate early for survival, which is important. If we look specifically by age, and I would say that there's a paucity of data specifically by age in this population. And if we really want to comment on how to best treat patients who are vulnerable and frail, we should do the specific studies. But if we look in some of the data that does exist, we can see that Enzalutamide was assessed in this way in Arches, great job, Dr. Armstrong. And we could see that this assessment suggests a similar benefit across ages. So these patients younger, or over 65, both seeming to benefit. Latitude also has some subgroup analyses that inform us. Here, we can see again, similar benefit, not statistically different when we look by age.

Titan also, similar benefit when assessed by age. And even Docetaxel similar benefit when assessed by age in a chemo-fit population. So maybe not for all patients, actually, of course, not for all patients, but important to consider for chemo fit patients. And finally, if we need to think of an option, but feel uncomfortable with a systemic therapy intensification approach, some may consider that radiation for low volume metastatic hormone-sensitive disease may be an option that provides some survival benefit without the toxicity expected with intensified systemic therapy, though, of course, this can be toxic for some patients as we should always acknowledge. So the second in terms of aspects to consider with intensification in frail patients is quality of life. Here we can see in the latitude trial, not analyzed by age, but important quality of life data that shows that Abiraterone plus ADT maintained quality of life versus ADT alone. So we see early disease control benefit, and quality of life that was maintained. Enzalutamide, this is an assessment of quality of life by age difference, but in an mCRPC patient population also showed a similar quality of life preservation.

Interesting, one assessment that was secondary analysis in a population of mCRPC patients, randomized to Abiraterone or Enzalutamide. A phase two study did suggest that there may be some differences in quality of life when we randomized patients to Enzalutamide versus Abiraterone and assess the fact P which is an assessment of overall quality of life for patients who are over 75, but no difference for patients under 75. So there may still be differences that we as a field need to figure out in terms of quality of life. But in general, these agents don't seem to impair quality of life and seem to be associated with at least a maintenance and quality of life, particularly when compared to ADT alone, which generally shows a decline in quality of life over time. Adverse events slightly increased when we saw patients treated with ADT and Docetaxel in older adults, but this was certainly not substantially different across all adverse events was most notable for Neutropenia was not notable as substantially for Febrile Neutropenia necessarily.

So something to consider and again, only in a chemo-fit population. So in summary, the standard of care treatment for all patients fit, vulnerable, frail, or fully functional and healthy is intensified therapy. Chronologic and biologic age are not the same, but we can use geriatric assessments to identify areas of reversible decline and need and support frail patients so that they can get the treatment that they need. Disease control, outcomes, and quality of life outcomes suggest that there are similar benefits, young, old alike, and the curves for disease control separate early. So if we get the patients the treatments they need, they may be able to benefit. So I believe that we should not use older age or frailty as an excuse to use ADT alone. We should evaluate each patient on his own and determine if that's best for him or not. But always consider combinations first, unless a patient has an extremely limited life expectancy, comorbid contraindications, financial toxicity, or strong personal preferences to limit treatment to ADT alone. All men deserve intensified treatment for metastatic hormone-sensitive disease. Thank you.