Activity Transcript

Alicia K. Morgans, MD, MPH: Hi, my name is Alicia Morgans, and I'm the medical director of the Survivorship Program at Dana Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts. I'm excited to welcome you to this program titled “Multidisciplinary Case Review: Approaches to Optimizing Androgen Deprivation Therapy in Advanced Prostate Cancer.”

I'm joined today by Dr Pranav Sharma, an associate professor of urology at Texas Tech University Health Sciences Center, UMC Southwest Cancer Center in Lubbock, Texas; and Diane Cope, director of nursing and an oncology nurse practitioner at Florida Cancer Specialists and Research Institute in Fort Myers, Florida. Welcome to both of you.

Just to sort of get us all engaged here at the beginning, I'd love to hear you, Pranav, tell us a little bit about your work with prostate cancer patients, how long you've been engaged, and how much of your practice is composed of patients with prostate cancer.

Pranav Sharma, MD: As a urologic oncologist, a large percentage of my practice is dedicated to prostate cancer. Obviously, the vast majority of that is localized disease, but I do work in a multidisciplinary setting with some of our metastatic patients, both castrate sensitive and castrate resistant.

Dr Morgans: Well, great. I really look forward to learning from your experience. Diane, I'd love to hear about your role with prostate cancer management. Do you see a large portion of patients in your practice with prostate cancer?

Diane G. Cope, PhD, APRN, BC, AOCNP: We do. Our patient population is basically focused on metastatic disease and the treatment thereof, and it's definitely an older population here in Florida.

Dr Morgans: Well, those are certainly areas that are near and dear to my heart because, as a medical oncologist, I've had the most experience dealing with those patients. Ninety percent of my practice right now is prostate cancer, and I see everything from early-stage disease all the way to the latest stage of advanced disease. I'm also thinking about things like palliative care and geriatric oncology on a daily basis.

Importantly, about 8% of newly diagnosed prostate cancer cases in the United States are actually metastatic, and this number is higher than, I think, any of us on this webinar wish it to be, especially since we do have options for screening patients. The incidence of local stage or localized prostate cancer really seems to have stabilized in recent years, but the incidence of de novo metastatic prostate cancer has increased.

Importantly, when we have patients who are being diagnosed with de novo metastatic prostate, that's incurable, and it really is what accounts for the majority of prostate cancer deaths. Although we're improving in our survival rates over time, including for these patients with the most advanced disease, that decline in mortality has seemed to slow, and that might be because there are so many more patients being diagnosed at an advanced stage.

Pranav, what are your thoughts about why metastatic prostate cancer, de novo metastatic prostate cancer, has been increasing in the last few years?

Dr Sharma: I think there are a couple of reasons for that. First, the US Preventive Services Task Force (USPSTF) made prostate-specific androgen (PSA) screening a Grade C recommendation, which means involving physician/provider counseling before actually getting a PSA. Also, there are some insurance limitations, which drive down PSA screening. These may be contributing to more metastatic disease because we're only seeing some patients when they become symptomatic, either with bone pain or lower urinary tract symptoms. The other thing we are seeing is newer modalities of imaging, such as nuclear imaging, which are detecting prostate cancer that previously was thought to be localized but now appears as metastatic because of the more sensitive nuclear imaging tests that are now available. Lastly, the population is aging, both here in the United States and around the world. As we know, prostate cancer incidence increases with age, which also means an increased incidence of metastatic prostate cancer.

Dr Morgans: Thank you for talking through that with us.

The backbone for systemic therapy has been androgen deprivation therapy (ADT) for many years. That's predominantly given as a gonadotropin-releasing hormone (GnRH) agonist and sometimes as GnRH antagonists, but most commonly it has been agonists in the past. We can also use surgical castration to try to implement ADT, but most patients prefer pharmacologic treatment. The goal is to achieve castrate levels of testosterone, which is going to be testosterone levels < 50 ng/dL. This approach is closely tied to the time when it was developed back in the 1940s by Dr Hudgins and Dr Hodges, who established that prostate cancer cells depend on androgens or testosterone to drive their growth and survival and certainly their metastatic spread.

Importantly, there are roles for ADT in almost every state or stage of prostate cancer, which I think is unique among cancers -- to have so many applications across the disease spectrum. It's estimated that 40% to 50% of patients who have prostate cancer may undergo treatment with ADT at some point during their disease treatment. Today, though, we're really focused I think on metastatic castration-sensitive prostate cancer (mCSPC), being disease that is responsive to ADT or has never been exposed to ADT. Most patients will have some response to ADT when first exposed.

Let's move on to a case presentation and really dig into some of the nuances of ADT in men with prostate cancer. Let's start with an older patient who is coming in. A 76-year-old man went to his primary care doctor with back pain and stiffness that started a few months earlier. The primary care doctor suggested physical therapy, but the pain did not get better. The patient had a history of hypertension, hyperlipidemia, and osteoarthritis. He was otherwise pretty healthy with a good performance status. He was able to get activities of daily living done pretty easily and was up and moving about and active for most of his day.

His primary care doctor ordered a back X-ray, which showed areas concerning for bone metastases in L2 and L3 and the right posterior seventh rib. His PSA level was 46 ng/mL. He was sent to a urologist who performed a prostate biopsy. He was found to have Gleason 4+4 prostate adenocarcinoma, and of course we know this as grade group 4 disease. Computed tomography scanning of the chest, abdomen, and pelvis and a bone scan showed the same areas of metastatic spread. He underwent germline genetic testing, which is recommended for patients with metastatic disease. Regardless of family history, all of these patients should get germline genetic testing.

When we look at the National Comprehensive Cancer Network (NCCN) guidelines for systemic therapy, as we've already said, ADT is the backbone, but so importantly, things need to be added to it. Intensification is the standard of care. The backbone alone -- ADT -- is not recommended for the vast majority of our patients because it's not sufficient. Our options here include chemohormonal therapy with ADT and 6 cycles of docetaxel or ADT and an antigen receptor directed therapy or our newest combination, which is chemohormonal therapy with ADT plus 6 cycles of docetaxel followed by or given concurrently with either abiraterone or darolutamide. The androgen receptor-directed therapy is continued until progression.

Pranav, I'd love to hear your thoughts on ADT options. Can you talk us through what are the different approaches to achieving castration with ADT?

Dr Sharma: An underutilized yet what I believe to be a very effective option is bilateral orchiectomy. Now, there is a lot of stigma with having the testicles removed, but it achieves castration levels very quickly, it's very cost effective, and, unlike a lot of the pharmacological treatments, there's no recurring cost because it's a 1-time treatment. A major disadvantage is that it is irreversible. It is something I discuss with every patient, but as you mentioned, most patients don't choose that option.

Then the pharmacological therapies are either grouped into luteinizing hormone-releasing hormone (LHRH) agonists or LHRH antagonists, both of which target the GnRH receptors in the anterior pituitary gland. The main agonists are leuprolide, goserelin, and triptorelin vs the antagonists, which are the newer medications degarelix and the oral version of that, which is relugolix. Degarelix is an injection therapy that's given monthly, and relugolix is oral.

With LHRH agonists, there's usually an initial surge in LH and testosterone levels within 2 to 3 days. After the first injection, that typically lasts for approximately 1 week. With LHRH antagonists, you don't experience as much of that flare phenomenon, and you can achieve castrate levels within 3 to 4 days. This eliminates the need to take them with an antiandrogen for that first week like you have to do with the agonists.

Both surgical and medical castration should achieve equally effective testosterone levels to achieve an androgen-deprived state.

Dr Morgans: That's fantastic. Thank you so much for going through that. Diane, can you talk about the side effects of ADT? I'm certain that you have seen a number of men who are treated with this.

Ms Cope: That's sometimes the hardest thing to go through with patients because they've heard a lot. Somebody's told them that this is going to cause that, and so it's really breaking down those barriers and working with them.

Some of the common side effects of ADT are hot flashes. Almost 80% of men get hot flashes. It's usually more intense right after the injection but will decrease as further time passes since the injection.

Also, sexual dysfunction from that drop in testosterone and estrogen can definitely cause problems such as erectile dysfunction and decreased libido. That's something that definitely needs an open discussion when trying to start individuals on ADT.

There is some weight gain with ADT, also due to the decrease in testosterone and estrogen, with metabolic syndrome causing issues with insulin resistance. These individuals therefore may be at increased risk for diabetes. There are also changes in the lipid profile, with a decrease in low-density lipoprotein and high-density lipoprotein. Patients can also experience kind of a general achiness -- myalgias, arthralgias -- right after the injection.

There are also cardiovascular complications, with an increase in atherosclerosis that can predispose patients to an increased risk of cardiovascular accidents or CVAs (strokes). There are also issues such as an increased risk of myocardial infarction and sudden cardiac death.

An additional side effect that's quite important in our older population with prostate cancer is bone loss. Patients can have a decrease in bone density of 13% the first year, and bone density loss continues each year. This puts these individuals at increased risk of fractures. That is quite important when you're looking at this population and the implications as far as falls and fracture risk.

Dr Morgans: Absolutely. Those are such important things to keep in mind. Thank you so much for going through those, Diane. One thing you mentioned related to side effects were cardiovascular complications, and I want to emphasize those. They are the leading cause of non-cancer death in men with prostate cancer.

There's some overlap in the risk factors for prostate cancer and cardiovascular disease, including increasing age, metabolic syndrome, obesity, and other things. These can be worsened, of course, by ADT.

Also important, two-thirds of men with newly diagnosed prostate cancer who are considering ADT have high baseline cardiovascular risk, either because they've had a cardiovascular event in the past or because they have risk factors that put them in a place where they have a higher chance of cardiovascular disease.

Pre-existing heart disease is associated with an increased risk of these major adverse cardiovascular events, also called MACEs, with ADT. One study found a 4-fold increase in MACE in patients with prostate cancer and high baseline cardiovascular risk after they were exposed to ADT for a prolonged period.

The difference in cardiovascular risk between the LHRH antagonist relugolix and the LHRH agonist leuprolide was assessed in HERO as one of the key adverse events. HERO was a study that randomly assigned patients who had a need for at least 1 year of androgen deprivation therapy to receive relugolix or leuprolide. Importantly, 92.5% of patients in HERO had cardiovascular risk factors at baseline; 13.9% of patients actually had a history of MACE.

The relugolix arm had a 54% reduced risk of MACE compared with the leuprolide arm in that follow-up. The reduction in MACE with relugolix was even more pronounced in the 14% of patients with prior MACE. The rates were 3.6% with relugolix vs 17.8% with leuprolide. Thus, it seemed like patients with the highest risk had the greatest reduction in risk with this alternate treatment strategy.

The PRONOUNCE study was specifically designed to assess cardiovascular toxicity and risk in patients. They wanted to compare 2 different approaches: a GnRH agonist, which was leuprolide, vs the GnRH antagonist degarelix. Ultimately, 545 patients enrolled in this study, which was about half the number of patients they expected to need to enroll to answer the question of whether there was any difference in cardiovascular risk between these 2 approaches to ADT. This, of course, means that the study was dramatically underpowered. Also, importantly, the study included cardiovascular management by cardiologists for all enrolled patients, which I think in many cases decreased their risk of cardiovascular events.

Ultimately, the study did not find a difference between these 2 treatments, partly because there was a very low event rate, likely related to those cardiologists; and likely partly because they only enrolled about half the people they planned to enroll. At this point in time, I don't think this study answers the question of whether there's a difference between these 2 approaches, at least for these 2 drugs degarelix and leuprolide, and it remains an open question.

Pranav, I'd love to hear your thoughts on the implications of this and the HERO study.

Dr Sharma: Well, I favor LHRH antagonists for patients with significant cardiovascular risk because, despite the limitations of the study you mentioned, I think there is a strong indication that LHRH antagonists such as degarelix and relugolix are less likely to cause a major cardiovascular event in patients with significant cardiovascular comorbidities.

Dr Morgans: I tend to agree with you. Certainly, the HERO trial seemed to clearly show a difference, especially in patients who have a cardiovascular history, with relugolix having lower cardiovascular risk. So, so important.

You know, in thinking about the patient we talked about who has metastatic castration-sensitive disease, combination therapies are going to be the backbone of treatment. Multiple therapies have a proven survival benefit when combined with ADT. Enzalutamide, apalutamide, abiraterone, and darolutamide seem to have a synergistic response with ADT. They are all associated with improved survival vs ADT alone -- the caveat being that the darolutamide study we have access to at this time also included docetaxel chemotherapy. So, these are all options. Radiation to the primary is also an option, and chemohormonal therapy remains an option.

As we think about cardiovascular risk, one thing I would say regarding these androgen receptor-targeted agents is that they all seem to have some potential cardiovascular risk in and of themselves, particularly abiraterone and enzalutamide, particularly again among patients who have multiple comorbidities. It's important to think about that as we are trying to treat patients.

Pranav, what are some of the disease-related and patient-related factors that help you make decisions around treatment when you're choosing an ADT?

Dr Sharma: One of the disease-related factors we obviously have to take into account is the patient's prognosis in terms of life expectancy, which can sometimes be difficult to determine. That includes their performance status. We also take their disease burden into account -- whether they have low-volume or high-volume metastatic disease; and we take into account whether they have de novo metastatic disease vs recurrent disease after attempted primary curative treatment.

The other thing I consider is whether patients are actively symptomatic from their metastatic disease. I tend to favor LHRH antagonists in these patients because LHRH agonists can significantly impact their symptoms and increase their bony pain during the initial weeks of treatment.

We also take into account patient-related factors in terms of their preference of taking something oral vs injectable or if they would prefer to take something daily vs something that may be given monthly or quarterly.

Then we take into account their comorbidities, including cardiovascular risk; concomitant medications that they're taking for blood pressure or diabetes; their access to care, including insurance limitations; and the side effects of treatment.

We usually also take into account their age, and we like to get the opinion of our medical oncologist colleagues in kind of an interprofessional team to determine their fitness for some of these treatments. Another thing we consider is their cognitive ability because ADT can affect cognitive ability, especially in patients in early stages of dementia. We also take into account their bone density, maybe even getting a baseline DEXA scan, and we get our cardiology colleagues involved for a cardiac assessment.

Dr Morgans: Fantastic. Multidisciplinary care is so important. We're going to get to some of the aspects of that I think in a few minutes when we have Diane talk to us about how she educates and supports patients as they're starting these treatments.

This patient, in particular, is 76 years old, so a bit older. He has low-volume metastatic castrate-sensitive prostate cancer and has several cardiovascular risk factors. In talking to him, he strongly preferred an oral therapy so he could have delivery over his dosing and ensure that he could be adherent with his therapy even during the winter months when there might be snow or other weather that could prevent him from coming in as planned to get his injections. He really felt strongly that that's how he wanted to proceed. That helped make the decision easy -- that, and the fact that he had these cardiovascular risk factors. We ended up using relugolix for this particular patient. It is the only oral option, and it has a favorable cardiovascular risk profile.

Diane, as you're educating the patient and working with the nursing team and the other supportive care members on the team, what do you do in terms of education? What are you talking to patients about?

Ms Cope: Usually we're giving them the initial kind of side effects profile. Our patients meet with a nurse on a one-on-one basis. During Covid, we met with patients virtually to try to continue that important education. It is usually an hour-long session with the patient, bringing in their family, going through each of the medications in detail, including how to take it and where they can access it. We also get a perspective of the patient and their lifestyle: What is their home situation? Have they had any previous falls? That is so important.

We also explain to them the studies that we may be doing, such as periodic bone density scans and periodic cardiovascular assessments. We also include pharmacists as far as drug-drug interactions with their other medications and helping to reinforce to the patient that they need to keep on their antihypertensives and insulin or other medications for diabetes.

Dr Morgans: Fantastic. And I wonder, can you comment at all on the interprofessional team and how everybody works together?

Ms Cope: Once we identify any issues at home, we can bring in a social worker. A dietician and a nutritionist are really important because of the possible weight gain that patients may experience. Exercise has really been shown to be beneficial for all types of cancers, so we want to get them to some type of physical therapist to get a program started. It doesn't have to be rigorous. Any type of weight bearing exercise will benefit both the weight gain and their bones.

Dr Morgans: Diane, I'm really curious from your perspective, how do you optimally monitor and manage patients in terms of their cardiovascular risk when they're on ADT?

Ms Cope: Definitely monitoring their blood pressure and telling them things they need to report immediately, like shortness of breath and any type of chest pain. We also really work with the cardiologists on that multidisciplinary team to get those periodic cardiovascular examinations and to make sure from echocardiograms or electrocardiograms that nothing has changed that would prompt us to think treatment could be worsening any preexisting cardiovascular disease.

Dr Morgans: Great. Thank you for that.

Let's talk about how this patient did. His testosterone level decreased to 7 ng/dL. Remember, we want it under 50 ng/dL, so this was great. Under 20 ng/dL is even better, and we achieved that. His liver function tests remained within normal limits. This is important to monitor when you're starting patients on relugolix or most of our treatments. His PSA level was originally in the 40s and had decreased to 2 ng/mL by the 1-month check, which is a really fast response.

His primary care doctor really engaged in interdisciplinary management with us, monitoring his cholesterol and his hemoglobin A1c over the first 6 months of treatment. His hemoglobin A1c remained in the normal range, and his cholesterol levels remained stable. He was on a statin, which helped keep that in line.

He did gain 6 pounds during the first 6 months because of decreased physical activity resulting from an increase in arthritis pain in his hips and lower back. To Diane's point, he was referred to a physical therapist who could develop a systematic plan for stretches and exercises so he could start moving again and get back into gear with a lifestyle that will hopefully help him maintain the weight if not allow him to lose some of it.

Pranav, this was an oral therapy, relugolix, that he was taking and, luckily, I think he was pretty adherent with that. His testosterone level suggested that he was. Do you have any thoughts about adherence?

Dr Sharma: First of all, I think adherence is critical because we want to maintain those testosterone levels at a castrate level. Usually adherence with oral therapy, at least based on prior studies, shows decreased compliance compared with nonoral injectable treatments because the injections are typically given in a clinical setting and are scheduled ahead of time. To the patient, they almost seem like a separate medical visit, but with oral therapy, you’re relying on the patient to take the medication every day.

Even with injection therapy, compliance isn't perfect. We see that approximately 80% of patients do not exactly stay on their treatment regimen and can miss a dose, resulting in testosterone levels above our desired castrate level of 20 ng/dL.

One of the other things I have noticed with degarelix is injection site reactions, which may limit the patient's compliance to treatment. They may then favor either an oral alternative or switching back to an LHRH agonist, which has less risk of injection site reactions.

Dr Sharma: Another thing that could help improve compliance is making sure you go over all the potential side effects ahead of time with patients, so they don't experience something they weren't expecting, specifically with erectile dysfunction. I feel that if men start to experience sexual side effects they were not expecting, they're more likely to discontinue treatment without notifying the prescribing physician. So, I think counseling these patients about all the potential side effects ahead of time is also important to improve compliance.

Ms Cope: Also reinforce with the patient that there are things that can be given or directed towards those side effects. So many of them feel kind of hopeless that they're going to get hot flashes or have sexual dysfunction. Giving them that hope that there are things we can use to intervene can give them a better outlook and improve compliance.

Dr Morgans: Those are great points. We can work with specialty pharmacies to help with that monitoring and ensuring that patients are getting refills of their drugs. They'll also remind patients that if they're not getting a refill, they need to talk to their doctors. And of course, it requires creating a safe space where we encourage our patients to be honest with us. If they're unable or unwilling to take their treatments, it's important for us to be aware of that. We might be able to make tweaks or changes to the regimen that they're receiving to both treat their cancer and address their concerns.

To conclude, ADT is part of standard therapy for men with advanced or metastatic castration-sensitive prostate cancer. Guidelines for metastatic castration sensitive prostate cancer recommend giving an LHRH agonist or antagonist to patients in the form of a treatment intensification approach. That would be ADT plus docetaxel, ADT plus docetaxel plus an AR-targeted agent, or ADT plus an AR-targeted agent. For low-volume patients, we can also add radiation to the primary. This all needs to happen. ADT alone is no longer the standard of care for most of our patients.

Choice of ADT and of agents included in treatment intensification is individualized, and you heard both of our experts talk about how they think about the patient, the drug profiles, and the side effects to help match the patient with the right treatment.

ADT increases the risk of cardiovascular events, and patients require careful cardiac assessment, conversations, and ongoing management and monitoring during treatment to ensure they're in best of health. Remember, cardiovascular disease is the number one competing risk for mortality for our patients with prostate cancer other than prostate cancer itself. An interprofessional team is indispensable in treatment planning, mitigating and managing those adverse events, promoting adherence, and promoting health in general for our prostate cancer survivors.

I want to thank you, Pranav and Diane for this wonderful discussion. I feel like I've learned so much about ADT and how we work together with multidisciplinary care to support patients during their management with this treatment. And I want to thank all of you in the audience as well for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.