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Alicia Morgans: Hi, I'm so excited to be here with Dr. Ravi Parikh, who's an assistant professor of medicine at the University of Pennsylvania, and a GU medical oncologist at the Philadelphia VA. Thank you so much for being here with me today.

Ravi Parikh: Thanks, Alicia. Great seeing you.

Alicia Morgans: Great seeing you too. And really great to talk to you about the fantastic education session that you gave at ASCO 2023. You talked about interventions to prevent or reduce frailty in our prostate cancer population. Can you tell me a little bit about it?

Ravi Parikh: Sure. So most of our prostate cancer patients that we treat, whether they be on active treatment or whether they be survivors, they tend to skew towards an older demographic. And so that becomes challenging at situations because oftentimes we're having to make decisions about how to address their own frailty if they are frail, and tailor our own treatment strategies in ways that aren't clearly evident from clinical trials that we base our treatment decisions are, which tend to skew towards younger, healthier populations. And so our education session as a whole, generally focused on ways of assessing frailty and other metrics of a comprehensive geriatric assessment and addressing strategies to address frailty which is the focus of my talk.

Alicia Morgans: Wonderful. So walk me through it a little bit. What, what are some of the interventions that you really focused on? 

Ravi Parikh: Sure. So when you think about the prostate cancer treatment spectrum, you're sort of ranging from diagnosis and treatment of localized disease and then addressing factors in advanced disease. And so the strategies that I talk about are really focused on strategies around the localized care setting, for example, prehabilitation to around the period of prostate cancer surgery for individuals undergoing prostatectomy to situations where we get into giving androgen deprivation therapy and addressing cardiometabolic factors and our other populations, and in particular, bone health along with other side effects of ADT. So those are sort of three areas where I give examples of interventions with proven, treatment benefit. And then but really highlighting there needs to be a broader evidence base for interventions to address frailty since we're kind of operating in the absence of evidence right now.

Alicia Morgans: Absolutely. And frailty is something that has been associated with increased mortality. Right. And can you talk a little bit about that and why it is so important that this is something that we consider?

Ravi Parikh: Yeah, so I think what it what you really have to start off with is defining a frailty phenotype. And so the first part of my talk really focused on that frailty phenotype. You know, trying to establish, well, what does it mean to call someone frail? It's not just age, there's plenty of healthier older individuals. It's really a phenotype that consists of things like sarcopenia, decreased mobility nutritional issues, and so we walk through that a little bit just to set the stage on what it means that, you know, what kinds of patients should be receiving these interventions and not just anyone over the age of 65 or 75, et cetera. When we think about frailty and prostate cancer, we really have to realize that many of our treatments that we think of as relatively benign, for example, androgen deprivation therapy, they have the potential to have outsized side effects among frail individuals, particularly because the mechanism of action of ADT is worsening a lot of the things that defines what makes someone frail, for example, decreasing muscle mass in a sarcopenic patient, or increasing visceral adiposity in individuals who are not having high mobility to begin with.

So that's why, integrating frailty assessment and, and integrating strategies at distinct components of the care continuum ends up being really important, but oftentimes forgotten.

Alicia Morgans: Well, tell me a bit about bone health. We have some proven strategies, at least in, in terms of increasing bone density and hopefully reducing fracture risk. Can you tell me about how frequently they're actually employed? Are we, are we doing what we need to do in that, in that setting? And, and how does bone health actually really come into play in the long-term outcomes of patients? Does it really matter if they have some thinning of their bones or a fracture here or there?

Ravi Parikh: So short story, no, we're not doing what we need to do, and bone health is extremely important. So our conventional strategies that are guideline based right now are to screen individuals who prior to undergoing androgen deprivation therapy and during the course of androgen deprivation therapy with DEXA scans to assess their bone density. And so from that DEXA scan, we can identify whether someone has osteoporosis or whether they have osteopenia that's high risk. And from those two designations, we can make decisions about whether to offer anti-resorptive therapy, which is one proven strategy to help prevent fracture risk. Now, fracture risk, before we go into some of the what we actually do let's just start with why fracture risk is important. You know approximately 20% of patients on ADT at a five to ten year mark will incur a clinically significant fracture, and the mortality risk from incurring that fracture increases by about four to five fold when you have it, not to mention the morbidity of having significant pain associated with the fracture and decreased mobility. I mean, this is what our prostate cancer survivors really want to preserve. And,  a fracture takes that away in a really, you know salient way. I would say screening for fracture is really important, but we only usually do it 30% of the time which makes it really challenging to address it when you don't screen for it. So that's a little bit about why fractures risk is important and how common it is in our sort of vulnerable population.

Alicia Morgans: Absolutely. And so using things like those bisphosphonates RANK ligand inhibitors, like denosumab, these are ways that we can, in appropriate patients, really try to improve their bone density and reduce the risk of fracture. So I'm sure that this is important in an older adult population.

Ravi Parikh: Right? Absolutely mean when you think about it. Just generally take, take away prostate cancer, approximately 20 to 30% of men will meet criteria from an osteoporosis perspective or a high risk osteopenia per perspective to receive anti-resorptive therapy like bisphosphonates or denosumab. That number is certainly elevated when you add a high risk medication like ADT. And we don't have a lot of knowledge right now about what some of our novel treatments like androgen receptor signaling inhibitors, actually, whether they augment that risk or, or take away from it. So identifying individuals to receive early anti-resorptive therapy is critically important to mitigate that high fracture risk that, that prostate cancer, many prostate cancer patients are already coming in with. Now, when we think about clinical guidelines around this, what we've realized is that for individuals in the castration sensitive setting, whether they be metastatic or non-metastatic routine administration of anti-resorptive therapy is not indicated. It hasn't been shown to necessarily improve outcomes or even reduce fracture risk in some in some cases. And so we take a risk stratified approach, at least here in the United States that's based on someone's DEXA scan. And so when people aren't getting screened, that ends up being a challenge.

Alicia Morgans: Absolutely. And it's interesting, as you said in the US that's what we do, but that's different in Europe, in the UK. So there are, there are some interesting differences that, that we as a field, I think are still trying to work out.

Ravi Parikh: Absolutely. And I mean there's certainly, you know, in talking to individuals in the UK just about, you know, what's the rationale for some of this strategy, for some of these strategies, there is some evidence that suggests not only you know, some amelioration of fracture risk, but also some cancer specific effects in terms of mitigating risk of progression for prostate cancer that's associated with anti-resorptive. The challenge is that one anti-resorptive therapy, early anti-resorptive therapy doesn't necessarily mitigate risk for everybody. Two it tends to be it's not a benign intervention. You know, people need to be screened for by a dentist beforehand to mitigate risk of osteonecrosis, for example. There are some potential renal effects and then there's cost of these medications as well. So alongside with an unclear evidence base of the clear treatment benefit, that's one of the rationales as to why there's variability in practice. And we really, you know, one great idea for a study that might come out of this is actually comparing what are the long term effects for having a routine administration strategy like is done outside the US versus a risk targeted strategy on overall downstream outcomes.

Alicia Morgans: Absolutely. So I'll have to keep up on where you go with all of that. I know you do a lot of research in this space, so looking forward to seeing where that work goes. I wonder if you could take a few moments to comment on cardiovascular health, which is something else you mentioned earlier, and certainly is something that is commonly a problem for our patients with prostate cancer.

Ravi Parikh: Absolutely. So androgen deprivation therapy and even some of the novel prostate cancer therapies, they increase someone's risk of incurring a cardiovascular event, both because of factors like increasing circulating lipids and increasing risk of hypercholesterolemia but also by leading to factors such as early insulin intolerance and, and diabetes. And so the priority for early screening and mitigation of some of these factors, even in some individuals who say may not have, diabetes or hyperlipidemia coming into their ADT, but may incur it during the course of therapy is actually really important. Now, we've done some work, and we previously discussed this on UroToday, that's around just how prevalent is hypercholesterolemia and hyperlipidemia and hyper and diabetes screening in the prostate cancer population during ADT.

And it's certainly not a hundred percent. In fact it's more also on the order in terms of routine screening in the oncology care setting of somewhere in the order of 60 to 70%, which means that 30% of our patients, where we're assuming as their oncologist oftentimes their primary care, we're not doing the recommended screening to assess for cardiovascular risk that honestly is gonna be the major contributor to their risk of mortality. And so that ends up being a gap that we need to fix through routine screening and, and making it easier for people to be screened either through routine reminders to the clinician or better integration with primary care who are more used to screening for these type of things.

Alicia Morgans: Absolutely. And collaboration, as you said with that multidisciplinary team, the primary care doctors, the cardiologists, the cardio oncologists raising awareness across all of these players in the, in the care of, of this patient or these patients.

Ravi Parikh: Absolutely. And, I'm really happy to see that we've realized this risk and are thinking about treatment strategies to help address it. So with the recognition of major adverse cardiovascular events being primary endpoints for novel treatments like Relugolix and thinking, and now that we have an option that can help to mitigate cardiovascular risk and certain high risk populations, I think that ends up being hopefully a flavor of research as in developing treatment strategies as we move forward cuz we don't have to commit our men that we see to high risks of fracture, high risk of cardiovascular events, high risks of becoming frail, there's strategies to help deal with it. And whether that be, you know, your treatment selection and your initial prostate cancer treatment selection or integration of other specialists intervention strategies during the course of ADT. I think hopefully we'll get to a better place than we currently are in the next five to 10 years.

Alicia Morgans: Absolutely. So if you had to sum up your recommendations and really the message from your talk from ASCO 2023, what would that be?

Ravi Parikh: So probably three things. First screen for elements of frailty and try to integrate routine, comprehensive geriatric assessment into your practice or collaborate with others who do would be one major component recognize that there are proven strategies to help address frailty and, and the frailty that's incurred in the localized treatment setting through strategies like prehabilitation and collaborating with some of our experts in physical medicine and rehabilitation, for example. And then in the more high risk or advanced setting realized that routine cardiovascular and bone health screening is a part of routine care for individuals receiving ADT. And so integrating those reminders or interior routine, you know, care checklist along with things like routine surveillance with PSAs and imaging for example, is really, really important and can help to reduce the risk of something that may end up being quite morbid for a patient.

Alicia Morgans: Absolutely. At the end of the day, all of these things are competing risks for mortality. And so I think if we can support the whole patient by addressing the rest of these factors and addition to their prostate cancer itself, we can really do better for the patient. So absolutely. Thank you so much for your time and for your expertise. I appreciate your conversation today.

Ravi Parikh: Thanks so much, Alicia.