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Maria De Santis: My topic, "Frail Patients with mHSPC." These are my disclosures. And I would like to start my agenda with the definition of frailty and looking into the life expectancy. So it is well known, but maybe underappreciated, that age itself does not necessarily come with geriatric conditions or frailty. However, we are treating with a frail man. And frailty most likely comes with age. So we are talking about a decrease in physiological reserves of multiple systems, which increase vulnerability to stressors.

So the definition of frailty is based on five components, including nutrition with unintended weight loss, energy, physical activity that can be self-reported or measured with grip strength and slow walking speed, physical strength, difficulty in lifting bags weighing 5 kilo, for example, and mobility difficulty in walking up and down stairs. When the patient meets three or more of these five components, the definition of frailty is met. If it is only one or two, the patient is pre-frail, and this makes a huge difference in the life expectancy.

As you can see here, depending on the databases and the literature, the median life expectancy of a frail man—and I say man because it is more in women—but frail men, 1.2 years. But pre-frailty brings a life expectancy of six years, so a huge difference. And we should keep that in mind.

There are more sophisticated tools. And I made the exercise of putting three frailty points and some comorbidities into the UCSF e-prognosis calculator, a mixture of Schonberg and Lee index. I don't go into details here. But the Lee index told me that this patient would have a life expectancy of 3.8 to 5 years with three frailty points and some comorbidities. So it makes sense to look into some detail before taking treatment decisions.

So how do we achieve the diagnosis of frailty? So this is a graph out of an educational booklet of ASCO last year led by Alicia Morgans. A great graph showing that we start with a geriatric screening tool. The G8 tool is recommended by the EAU guidelines. If we find abnormalities, the cutoff is 14 points here.

We should, I think, look into our resources. I would not have the resource for going into comprehensive geriatric assessment. However, if we find intervenable areas, we should intervene and treat them if possible. If there are non-intervenable areas and the patient is diagnosed as frail, we should look into non-cancer life expectancy, as I have shown you before. And of course, the goals of the patient, they should all be patient-centered. And most importantly, early integration of palliative care is not only recommended by the ASCO clinical practice guidelines, it is a mainstay of our treatment in these patients.

So my clinical perspective here. My personal view is that even though frailty is regarded as a potentially reversible condition, in mHSPC management, I think we don't have time to wait, putting patients on waiting lists for assessments, and then wait if those measures would help or not. We need to take our treatment decisions now.

So what about the efficacy of treatments in frail patients? We don't have data. The EAU guidelines tell us that we should offer ADT monotherapy only in patients that have a life expectancy of one year or less. All the others should be offered a combination therapy.

So you have seen this curve, I think, 12 times already in this meeting. Sorry for that. ADT alone is effective, but it is not that effective in de novo high volume disease, for example, with 3.5 years life expectancy. It is much more up to eight years in other patient groups. Maybe this is not the endpoint, OS endpoint, that we need so much in this patient population.

But in the same paper, we find the time to CRPC, maybe reflecting the time the patient is stable in a certain state on treatment. And here, we see that ADT alone only allows 12 months of time to CRPC. And this is two years in the low volume metachronous patient population. So this is maybe not so much if a patient has a life expectancy of three to four years, for example, even though he is frail.

Efficacy of treatments. We have data on younger age and older age. Docetaxel is working very well in both age groups. But of course, we would never think of using docetaxel in a frail patient. Looking into an ARPI-based combination, systemic therapies, we find that younger age patients are benefiting a lot. Older age patients are benefiting also, but maybe to a lesser extent. But this is not data in frail patients, admittedly.

So how can we achieve the individual patient's goals? How can we select appropriate treatment and treatment intensity? So a given patient, 84 years, frail with three of five points, with mHSPC de novo, high volume, and mild symptoms. He has a natural life expectancy of 3 to 4.5 years, seven con-meds, including clopidogrel for atrial fibrillation and stroke in the past, hypertension, some mild diabetes.

So what I want to point out is that frailty rarely comes without polypharmacy and drug-drug interactions. And the intake of five to nine medications brings along a 50% chance of an adverse drug interaction. So drug interactions are a problem for our patients, I think. So drug-drug interactions are frequent and potentially also harmful and might be life-threatening. Clopidogrel, together with a strong inducer, might make the drug ineffective and cause another stroke maybe. So in such a situation, abiraterone/prednisone would be a preferred option over enzalutamide, apalutamide, or darolutamide, for example.

But what are the patient's goals? The patient tells me he wants to have the symptoms improved, yes, no deterioration over time, and maintaining quality of life. Can we achieve that? Well, the options are pretty obvious. We can give ADT, of course, and with a life expectancy of three years add an ARPI, abi, pre, apa, enza. And of course, we should never forget about palliative radiation to bone, or prostate, or whatever indicated.

My last point is interventions. We should not leave the patient alone with a shot of Lupron. We need interventions to improve the tolerance of treatment and quality of life. And this starts with the first shot of ADT. We need to look into bone health management and also in frail patients that start on ADT, indications for bone antiresorptive therapy along with vitamin D and calcium.

The risk of falls is an important topic. We should consider physical therapy referral, and on strength training also for patients only on ADT. If we consider combination, abiraterone or darolutamide might be preferred in lieu of apalutamide or enzalutamide when it comes to risk of falls, for example. And when the focus is on cardiovascular health, we might consider the use of LHRH antagonists in lieu of LHRH agonists, for example, together with optimizing cardiovascular risk factors.

So in summary, we should explore the frailty status and the life expectancy of the patient to start with and, of course, the goals of the patient. ADT alone in patients with a life expectancy of below one year is fine but with continuous supporting interventions that are crucial—physical training, osteoporosis prophylaxis, LHRH antagonists if cardiovascular health is a priority. We should consider the addition of an ARPI in other patients that have a longer life expectancy. The selection is dependent, of course, on the side effect profile of the individual drugs, which you all know, the risk of falls, and potential drug-drug interactions. And we should never forget about early palliative care involvement. Thank you very much.