Alicia Morgans: Hi, I'm so excited to be here today with Professor Maria De Santis, who's joining me from Berlin, Germany, and who also joined me in Lugano, Switzerland for APCCC 2024, where she gave a really wonderfully detailed and thoughtful talk on how we deal with patients who are older or perhaps have developed some frailty. Thank you so much for being here with me today, Maria.

Maria De Santis: Well, thank you for inviting me. It's a real pleasure to talk with you about my topic, and I'm excited to have an interview with you.

Alicia Morgans: Wonderful.

Maria De Santis: So I'm happy to share with you some of my thoughts about the management of frail patients with metastatic hormone-sensitive prostate cancer. Summary of the talk I gave at the APCCC meeting in Lugano recently. So my agenda included the frailty definition and life expectancy. And I think this is pretty important because many don't really know what frailty means and it is important to point out that older age does not necessarily include geriatric conditions of frailty, but nonetheless, frailty mostly comes with age. So looking into a definition of frailty, the usual definition includes five points starting with nutrition, so unintended weight loss, energy, and issue with a positive answer to the questions, do you feel weak now, then there is physical activity, a low level of activity, and this can be checked with a self-report instead of measures of grip strength and low walking speed, for example.

Then physical strength, difficulty in lifting a bag weighing five kilograms and mobility, a difficulty in walking up and down stairs. So three or more of the five points would meet the definition of frailty. If it is only one or two of the five components, we would consider these patients to be pre-frail, and this makes a huge difference in the life expectancy. So if we have to establish a frailty status, we need to start with some evaluations, and usually we start with a geriatric screening tool. There is the G8 screening tool, which is very simple and quick.

If we find some abnormality with this G8 screening, we should, if possible, look into more testing if we have the resources. So if we find an intervenable area, then we should try to do some interventions to improve the status of the patient. If there are non-intervenable areas and the patient is regarded as being frail, the next step should actually be to look into the non-cancer life expectancy, and of course have a thorough conversation with the patient about the patient's goals and values. It is also crucial to integrate palliative care early on before any treatment decisions are taken because these patients need support, need early support, and palliative care in their condition.

So there is actually no real data about the treatment of mHSPC in frail patients. However, the EAU guidelines give a recommendation with regards to life expectancy. And here, EAU guidelines tell us not to offer ADT monotherapy in a patient with a life expectancy of more than a year, and who is willing to accept the increased risk of side effects with additional treatment. So this recommendation is kind of helpful I think. The treatment options we have are I think well known. Androgen deprivation therapy is the basis of our treatments for mHSPC. I think we all agree that chemotherapy in the sense of triplet therapy will not be the right option for a frail patient because this frail patient would not have any resilience and resources to face new challenges in his life. But if the life expectancy is regarded to be more than a year, and it is true that quite some patients that are regarded frail do have a life expectancy of about three years, then we should consider adding an ARPI, an androgen receptor pathway inhibitor, as they are called now.

And this would include the choice between abiraterone/prednisolone, apalutamide, or enzalutamide. Most importantly, we should not forget about palliative radiotherapy to bone or prostate or whatever is needed as part of best supportive care or palliative treatment of these patients. Another point is that frailty rarely comes without polypharmacy and the drug-drug interactions. The intake of five to nine medications means a 50% chance of an adverse drug interaction. And this actually causes challenges for our elderly and frail patients. So drug-drug interactions are frequent and potentially harmful and may also be life-threatening when it comes to stronger CYP3A4 inducers or inhibitors. And here, for example, anticoagulants can be inactive when a strong inducer is combined with. And in such cases, we might rather choose abiraterone/prednisolone over enzalutamide or apalutamide with regards to drug-drug interactions.

However, we should not leave the patient alone with just a shot of LHRH agonists or antagonists. We need to support the patients right away. We should look into their bone health, into indications for bone antiresorptive therapy along with vitamin D and calcium, osteoporosis prophylaxis for example. Many of these patients are also at risk of falls and ADT by itself can increase the risk of falls. We should never forget about that. Patients will benefit from physical therapy and or strength training and support the androgen deprivation therapy better. If we consider a combination therapy with regard to the risk of falls, we would rather consider abiraterone or darolutamide in lieu of apalutamide or enzalutamide in this respect. And finally, if there is a focus on cardiovascular health in a patient, we might consider LHRH antagonists like the oral relugolix in lieu of LHRH agonists in such patients alongside cardiovascular risk factor optimization and so on.

So in summary, we need to explore the frailty status of the patient and the patient's life expectancy, which we can do with tools like e-prognosis. There are several e-tools like the UCSF tools, and we should also consider the goals of the patient. ADT alone is considered for a patient with a life expectancy below one year. Nonetheless, the patient needs continuous supporting interventions like physical therapy training, osteoporosis prophylaxis, and LHRH antagonists should be considered if cardiovascular health is a priority. If we consider the addition of an ARPI, the selection should be dependent on side effect profiles, the risk of falls, and potential drug-drug interactions. And finally, earlier palliative care involvement is really important for these patients. Thank you very much for your attention, and I'm looking forward to our discussion.

Alicia Morgans: Maria, that was wonderful. Thank you so much for running through that. One of the things that I think about a lot and have had questions on, and I think this was discussed a little bit at APCCC also, is how we best navigate and manage these supports and these assessments for patients when we have constrained resources or limited time in our clinics. Do you have advice for clinics that are trying to offer these supports, these assessments, and interventions, but really are running very busy practices and need to figure out how to carve out the time and the support?

Maria De Santis: Well, I think this is a crucial question for every one of us. I think that the G8 tool is really quick and easy and it takes three or four minutes. It is doable. And besides that, very often I think we don't have the time with those patients to do interventions and wait for things to improve or not. So we need to make our decisions in the present situation of the patient, but we should implement some additional support for the patient while we start the treatment. And I think this is different from other clinical situations, but metastatic hormone-sensitive patients usually need the treatment right away and not after two months or so. This is the first aspect here. And then of course, we need to look into the resources of the individual patient, of the health insurance and what they offer, what can be implemented.

But I think awareness is important. And some patients could also do some training at home together with their relatives, and they need to be aware that being active and remaining active is crucial for also the success of the treatment while they are on ADT, for example, or on a combination therapy with ARPIs. So it is of course time-consuming in a way, but on the other hand, it could be pretty easy. Just try to find out what the patient wants, establish treatment, and then while this treatment is starting, evaluate the options. Because if there are no options, of course, we cannot do a lot. But I think we can always do something.

Alicia Morgans: I think that's great advice. And I always think about drawing on the resources of the multidisciplinary team, including the nursing team and the social work team, and others in the United States. We have nurse practitioners or physician's assistants sometimes who can also help. And as you said, the G8 and some of the screening is actually so brief and in some clinics is even administered by the medical assistants, the team members who are getting the vital signs and things. So there are many ways that this can be deployed and it can save time and certainly save patients over time if we are able to identify those areas and provide the supports that really help improve the patient outcomes and really their holistic type experience. So really, really, really helpful. As you think about the conversations that happened at the APCCC, was there consensus that this is an important aspect of care that we need to devote our time and resources to? Or is this still something that is more controversial? What are your thoughts there?

Maria De Santis: Well, I think that everyone appreciates the thoughts about this patient population. On the other hand, it is not as sexy as looking into different treatment options and more intensified treatments and active clinical trials because these patients are not fit enough to be included in prospective clinical trials. And this is why we don't have data. So I think there is a general consensus that it is important to deal with these patients and evaluate them properly. On the other hand, I think the enthusiasm about the treatment of frail patients is kind of limited, unfortunately. But it is a fact. We do have these patients and I think they deserve our attention and the best possible treatment in their frail situation.

Alicia Morgans: Yeah, actually that's such a wonderful point to make, Maria, because we all agree that this is important, but we often may be distracted by shiny PET scans and new targeted radiation approaches and all of the things which are highly exciting. But when it really comes to taking care of our patients, I'm glad to know that we're dedicated, and I agree with you, we can all be more dedicated and more interested in ongoing research to understand how to best support these patients and to provide them life-prolonging treatments that also improve quality of life and maintain their function rather than increasing their frailty. So more work to be done. And I appreciate that you call us out on that and encourage us to continue that process. So, as you think about the treatment of these patients and the talk that you gave, what would your summary or message be to clinicians who are trying to figure out how to approach this patient population in the clinic tomorrow?

Maria De Santis: Well, I think the first bit is to evaluate the life expectancy. And for me, this is the basis of treatment decisions. If we find out that the patient has a life expectancy, so putting the data into an e-prognosis tool, for example, and finding out that the patient has a life expectancy most likely of three years, then I think it is fair to offer the patient what we have and combination therapy and the appropriate support. If the life expectancy is probably one year or below, then we would rather advise the patient not to do too much because the patient might not benefit from additional time to a CRPC in this situation. And the second thing is that I think we should try to at least generate data like real-world data by registries or getting information on what is happening with those patients and maybe do a little work into that. Prospective studies, this will never happen, but retrospective surveys on how these patients are doing on our also novel maybe combination treatments.

Alicia Morgans: Wonderful. And I know that the EORTC is also doing some work, I think, to support other studies that might de-escalate and really support our more frail patients as well. I think certainly there is interest and more work to be done. Thank you so much for providing your expertise and sharing your time with us today as well as at the APCCC. We really appreciate it.

Maria De Santis: Thank you. It's a real pleasure talking to you.