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Sandhya Srinivas, MD: Hello. I am Sandy Srinivas and I'm the host of the Medscape InDiscussion podcast series on prostate cancer. Today we want to talk about bone health and survivorship with androgen deprivation therapy (ADT). Bone health is an extremely important topic in men with prostate cancer for two reasons. One, inherently, patients develop metastases to the bone about 85% of the time. Second, ADT causes osteoporosis and really puts our patients' bone at additional risk. With the increasing use of ADT intensification with some of our novel hormonal therapy, this topic becomes even more relevant. Let me introduce my guest, Dr Rana McKay. Dr McKay is an associate professor of medicine and urology at UC San Diego. She specializes in treating patients with urogenital cancers. Dr McKay co-leads a multidisciplinary genitourinary oncology team and is an associate director of translational sciences at the Morse Cancer Center. She's also a member of our National Comprehensive Cancer Network panel on prostate cancer and has done remarkable work in addressing bone health for men with prostate cancer, has been a lead primary investigator on many investigational trials, and it's really my pleasure to welcome her today.
Rana R. McKay, MD: Thank you so much for that kind introduction, Dr Srinivas.
Srinivas: Before we dive into the topic Rana, I'd love to learn a little bit about your journey. What led you into medical oncology and specifically urologic oncology, a field so dominated by men?
McKay: Very good question. I honestly think it all comes down to the right environment and the right mentors. I knew I always wanted to do oncology when I was completing my fellowship training at the Dana-Farber Cancer Institute and rotating through the different specialty clinics. I really fell in love with caring for patients with genitourinary malignancies, particularly individuals with prostate cancer, and had great mentors with Dr Mary-Ellen Taplin, Dr Phil Kantoff, Dr Toni Choueiri, who actually helped me see just how unique of a specialty and a unique group that genitourinary medical oncologists are. It's been great. I've never looked back since.
Srinivas: That's awesome. All the people you mentioned are great investigators who have contributed so much to our field. Before we jump into talking about hormone-sensitive disease and how we address the use of ADT, I wanted to ask what you do to assess fracture risk. Talk a little bit about any imaging studies or the laboratory tests you think about before we put patients on ADT.
McKay: Very good question. When it comes to bone health in patients with prostate cancer, as you stated in the introduction, there's two things to think about. There's the risk for osteopenia and bone loss just related to the ADT itself. Then there are risks that are related to having bone metastases. When we talk about the risks associated with bone loss for patients that are initiating ADT, I always think about the ages of patients when I'm starting them on ADT. How long are they going to be on therapy? What's their age? Have they ever had a fracture? Do they have a family history of fractures? These are all critically important factors to think about. In patients over the age of 50 years that may have increased risk, I certainly get a baseline dual x-ray absorptiometry (DEXA) scan just to assess where there are at the start of hormonal therapy. There are some patients who may already be at substantial risk from the get-go with profound osteopenia or even osteoporosis. It's important to assess their calcium levels. It's important to assess vitamin D levels because if vitamin D is low, people can be at increased risk for hypocalcemia when they're using the bone-strengthening agents. I always like to think about that and talk about the lifestyle that the patient lives. Are they sedentary? Are they active? What are the things that they're doing? I touch on all of those factors when deciding how high- or low-risk somebody may be for developing a fragility fracture.
Srinivas: We have several bone-modifying drugs that we use. Once you decide to put a patient on either zoledronic acid or denosumab, what do you do for monitoring? We talk about the risk for osteonecrosis of the jaw. Do all your patients go through a dental evaluation?
McKay: Very good question. When we have somebody who's high risk and have ultimately made the decision to go ahead and start them on therapy, I usually direct them against lifestyle management. I direct them against exercise management and am ensuring that they're doing weight bearing exercises. Sometimes, some people don't know what weight-bearing exercises are. For example, swimming. It is very good for people to swim. That's technically not a weight bearing exercise. Exercises where they're up, standing, bearing weight on their joints and doing that for a sustained period of time are weight-bearing exercises. We talk about calcium and vitamin D supplementation and talk about a patient's diet. If patients are getting enough calcium supplementation from their diet, they don't necessarily need to be on extra calcium. Sometimes, it's hard to get vitamin D supplementation in the diet, so some patients require being on vitamin D supplements. We also talk about other lifestyle variables like smoking cessation, alcohol use, those kinds of factors that can impact bone health. When we go ahead and decide to start patients on therapy, there can be differences in the side effect profiles of these agents, with zoledronic acid use, it's given as a 15-minute infusion generally. There can be an associated risk for an infusion reaction with administration. We warn against flu-like symptoms in the first 24-48 hours. With denosumab, that does not necessarily happen, but it's given as a subcutaneous injection. Sometimes, there can be a skin reaction to the subcutaneous injection.
I do advise patients to get a dental evaluation prior to starting therapies, and I tell them to let their dentist know that these are the drugs that my oncologist is thinking of putting me on to help protect my bones. I specifically tell them to ask about any planned dental extractions or dental surgery where their jaw is getting manipulated. Routine cleanings, cavities, those sorts of things are not necessarily going to put a patient at increased risk, but it's really if somebody is having an extraction or surgery that involves the jaw. The rates of osteonecrosis of the jaw are actually quite low, especially when the risk is quote low and we're utilizing these agents for prevention of bone loss, where they're utilized at lower doses with a spaced-out dosing. We do discuss that, and it's recommended upfront.
Srinivas: It's really interesting that these two drugs have different dosing, they have a different schedule, whether we use it for osteoporosis. Zoledronic acid is just given once a year. Denosumab is given every 6 months. Whereas when we think about our use, as we'll discuss in our next topic about castration-resistant prostate cancer (CRPC), the dosing is more every 3 months. It's good for our listeners to pay attention to this difference in scheduling. What doses of calcium and vitamin D do you recommend for your patients?
McKay: Very good question. In general, the dosing is about 1000 mg of calcium and about 1000 mg or IUs of vitamin D. For the vitamin D, dosing may be higher depending on a patient's baseline vitamin D levels. If patients are actually taking in adequate calcium supplementation from their diet through fortified cereals or cheese, milk, yogurt consumption, they don't necessarily need to take extra calcium; it can put them at risk for stones and other things. If they're getting it from their diet, they don't need extra. Sometimes, it's hard to get adequate vitamin D supplementation from the diet or environment, so I generally recommend 1000 IUs of vitamin D on a daily basis.
Srinivas: We've now had these agents for at least a couple of decades. But our practice in prostate cancer is so unique in that we have patients who are hormone-sensitive, and we treat them differently. All of these patients with metastatic hormone-sensitive disease ultimately end up developing castration-resistant disease. Talk a little bit about the clinical trials in hormone-sensitive disease, because most of the trials that we have that led to the development of these drugs were in castration-resistant disease. I see a lot of patients in clinical practice coming to us who get started on these bone-modifying drugs the minute they have metastatic disease.
McKay: Very good question. Let's step back and think about the indication for use. There are two indications for use of bone-protecting agents in patients with prostate cancer. There is the indication for use reducing fractures related to bone loss from hormonal therapies. In that context, the doses are lower. The schedule is way more spaced out like we talked about. There may be somebody with metastatic hormone-sensitive disease that may already have osteoporosis or may have a baseline DEXA scan showing that they've got profound osteopenia, and you're worried about them. In that scenario, it may make sense to put them on a bone-protecting agent, keeping in mind this is not for the indication of reduction of skeletal related events (SREs). The second indication is for SRE or symptomatic skeletal event (SSE) reduction. When these initial trials were developed, looking at zoledronic acid for metastatic CRPC, looking at denosumab for metastatic CRPC, this was even predating the era of using abiraterone and enzalutamide for these agents. This is right around the time that we were using docetaxel. We actually didn't have effective treatments to treat CRPC.
These trials were designed with a primary endpoint of reduction of SREs initially because the SSEs really wasn't defined until the ALSYMPCA trial. These drugs were identified to decrease the risk for bone metastasis associated SRE, which includes fracture to the bone related to metastases or compression, need for surgery, or need for radiation to the bone. The dosing indications in the metastatic CRPC setting on denosumab, it's given 120 mg every 4 weeks every month with zoledronic acid. The initial studies were conducted looking at monthly dosing and subsequent studies that were conducted through the cooperative groups actually looked at every-4-monthly dosing vs 3-month dosing and actually didn't demonstrate a difference with regards to SREs in the context of more prolonged dosing with zoledronic acid. That can be utilized given once every 3 months instead of once every month. Across the board, many of the studies of drugs in the CRPC setting, like enzalutamide, abiraterone, radium 223, have demonstrated that actually those effective agents do decrease the risk for SSEs, and they're effective therapies at treating the disease. What I will comment a little bit about is also the mechanism of action of these drugs. Denosumab is a receptor activator of nuclear factor kappa beta ligand (RANKL) inhibitor that prevents the progression or development of osteoclasts. It halts their development into being fully functional osteoclasts. Denosumab works a little bit different in that it's a bisphosphonate that binds to the hydroxyapatite crystals within the bone, and it actually gets taken up into the microenvironment and into the osteoclasts and works in that kind of fashion. We have to think about these agents and how we use them because when we abruptly halt the utilization of denosumab, especially when it's been given at a high dose on a short frequency like the 120 mg every 4 months, and we abruptly halt therapy for a 6-month period, people can be at risk for fragility fractures. What happens is all of those osteoclasts that have just been halted and that you've prevented the differentiation of all of a sudden now differentiate because you don't have the stop on the system, and people can be at risk for fragility fractures. In that context, if there's a patient where you're thinking about stopping their denosumab, you may actually give them a dose of zoledronic acid that stays bound to the bone for about 1 year, so that they're not at risk for those fragility fractures. In the metastatic hormone-sensitive setting, there has been a very large CALGB trial that was conducted looking at whether zoledronic acid prevents skeletal-related events in the metastatic hormone-sensitive setting. That trial was negative. One of the reasons why that trial was negative was probably because hormone therapy is very effective at controlling the disease. Utilization of zoledronic acid at a high dose and low frequency for SSE reduction or SRE reduction in the metastatic hormone-sensitive setting is not indicated at all. If you're going to use it for people with metastatic hormone-sensitive disease, it's largely for mitigating osteopenia, treatment-related osteoporosis, those sorts of variables.
Srinivas: That's a great point to bring up. I remember earlier our endocrinologists were totally shocked by the frequency in which we were giving these bone-modifying drugs. The trials supporting the use of every 3 months vs just doing it monthly, I think is a great add-on to our body of literature. While we are on this topic, one thing that even I struggle with in clinical practice is our patients are living much, much longer with — I can count up to six or seven — life-prolonging drugs that we have in CRPC. When we started these trials, that wasn't really true. What's the optimum duration of treatment? In multiple myeloma, did they stop after 2 years. In your practice, do you give people a break or do you just continue these drugs indefinitely?
McKay: It's a very good question. We don't actually know what the right answer is. The way that I like to think about it in my clinical practice is actually the best thing that I can do for somebody to decrease their risk for a skeletal-related event is put them on highly effective therapy to control their disease. If they're on therapy and their disease is controlled, their prostate-specific antigen is down, it's responding, and their imaging looks good, there isn't an urgency to be treating them around the clock with the bisphosphonates or even denosumab because their disease is controlled. I use those periods to potentially think about more protracted dosing or even giving people a holiday per se. I don't think we know what the right answer is, especially when we're using it for the indication of SSE reduction or SRE reduction as opposed to improvement of osteopenia, where you can actually track somebody's bone health with a DEXA scan, you can see how they're doing. If things tremendously improve, they made lifestyle changes, you can potentially peel back and skip a dose, and there are more parameters to monitor in that context.
Srinivas: Rana, I was just going to talk a little bit about the impact that these drugs have made for men with prostate cancer. That's well highlighted in the PEACE III trial, where they looked at the addition of either of enzalutamide with radium and those patients who were not on these bone-modifying drugs prior to really instituting it, their risk for fractures and SREs were extremely high. Once bone-modifying drugs were instituted, that dropped to dramatically low levels.
McKay: It's a very good point. There is actually the ERA study with abiraterone and radium 223 that actually looked at the combination. When radium first came out, there was a big question of whether we can just keep their hormonal therapy ongoing while they're getting the radium. In clinical practice, people were continuing these agents concurrently with the radium. What the ERA trials showed us was that in fact, there's an increased risk for fragility fractures in those patients without appropriate bone protection and also receiving radium with abiraterone with prednisone. When the PEACEIII trial was initially designed prior to the results of the ERA study, and then, actually, they instituted a protocol-wide amendment mandating the use of the osteoclast-targeted agents, the rates of fragility fractures actually declined.
Srinivas: Totally. When we start patients on hormonal therapy, what do you instruct them? It just seems like there's so much information to give patients so that they are aware of the side effects. What's your typical discussion when you start patients on ADT?
McKay: We always talk about the purpose of the therapy, the duration and extent of what they're going to be on. A lot of the time, being in clinic is talking about survivorship and talking about how to mitigate the symptoms associated with ADT and maximize quality of life when somebody is on ADT. I like to combine that with talking about bone health. We talk a lot about the metabolic changes that are associated with ADT, the changes that, there's an increased propensity to gain weight, increased propensity to have your cholesterol go up or blood sugar go up. We do touch on the cardiovascular changes that may be linked to some of the metabolic effects like hypertension. Sometimes, there can be arrhythmias. Knowing if somebody has underlying cardiovascular disease is important. Do they need to start on a protective aspirin or protective beta blocker? Sometimes, some patients need to see a cardiologist prior to starting ADT. We also talk about the physical and sexual changes because those are real for patients. They experience the decreased libido, change in hair growth pattern, change in smell, and change in testicular size. These are all the things that sometimes, we don't address, and then patients start to experience them. Of course, there are the mood changes that can happen or sleep issues. We do talk about all of those things. The key is addressing them and giving patients tools to help them improve their quality of life while they're on therapy.
Srinivas: Thank you so much. Rana. I learned so much about bone health and the importance of addressing the assessments that patients need when they start ADT. We have some incredible data supporting the use of bone-modifying drugs. I really think your points about informing our patients about this so that they are aware is totally important. Thank you for tuning in. Please take a moment to download the Medscape App to listen and subscribe to this podcast series on prostate cancer. This is Sandy Srinivas for Medscape InDiscussion.
Addition of Radium-223 to Abiraterone Acetate and Prednisone or Prednisolone in Patients With Castration-Resistant Prostate Cancer and Bone Metastases (ERA 223): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial
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Cite this: Androgen Deprivation Therapy and Prostate Cancer: Bone Health, Survivorship, and Side Effects - Medscape - Jul 19, 2023.