Activity Transcript

Karim Fizazi, MD, PhD: Hello, I'm Dr Karim Fizazi, a professor of medicine at Institute Gustave Roussy at University Paris-Saclay in Villejuif, France. Welcome to this activity, an interprofessional clinic, a team-based approach to intensified therapy in advanced prostate cancer. Joining me today are Emily Lemke, an assistant professor and doctor of nursing practice at the Medical College of Wisconsin Cancer Center in Milwaukee, Wisconsin, USA, and Katie Morgan, a hematology-oncology clinical pharmacy specialist at the University of North Carolina Medical Center in Chapel Hill, North Carolina, also in the USA. Welcome.

Emily Lemke, DNP: Thank you.

Katie P. Morgan, PharmD, BCOP, CPP: Thank you.

Dr Fizazi: Today we are going to discuss some of the key data for therapy used to manage metastatic castration-sensitive prostate cancer, and non-metastatic castration-resistant prostate cancer. Also, we'll discuss individualizing therapy selection based on patient specific factors, such as comorbidities and potential for drug-drug interactions. Finally, we’ll discuss the interprofessional team-based approach to optimally managing patients with both non-metastatic CRPC and metastatic castration-sensitive disease. We'll do this using some patient videos.

We have already 3 large, randomized phase 3 trials assessing next-generation hormonal agents, including darolutamide, enzalutamide, and apalutamide. These three trials are remarkably similar in their design, large phase 3 trials for each of them, > 1000 men who were randomized. All of them had elevated risk non-metastatic castration resistant prostate cancer with clear risk for relapse, and this was defined based on the PSA doubling time, which was < 10 months for each of these trials. Also, the primary endpoint was metastasis-free survival, and the key secondary endpoint was overall survival. Again, remarkably similar design across the board.

What about efficacy? Well, we saw good news, starting back 4 years ago in all these 3 trials. I'm saying that because the primary endpoint of the trial, which was, again, metastasis-free survival, was met in all 3 trials with ~60% to 70% reduction in the risk of metastasis or death, which is enormous. On top of that, even for those who are not completely convinced by criteria such as metastasis-free survival, approximately 2 years after the first read-out of these trials, we saw overall survival data also with good news. The survival is significantly improved in all 3 trials, with ~30% reduction in these trials, which is of course fantastic for all the patients.

Now, Emily and Katie, please, can you tell us more about the side effects of all these agents, apalutamide, darolutamide, enzalutamide, and maybe abiraterone? All these agents are not exactly made equal. The chemistry is different, but does it have some consequences to the patients? What do you think?

Dr Lemke: Well, as you said, Karim, we are so lucky to have a wealth of options in this space, that certainly choosing what fits patients' comorbidities, lifestyle, and performance status is useful when we're looking at these 4 agents. If you look just at the listed side effects, darolutamide has the least reported side effects, and that has been my experience in practice. I have been so pleased that men have tolerated this exceptionally well. When we think about abiraterone, certainly the addition of prednisone is a complicating factor, and we need to take that into account. Also, always having it in the back of your mind, if these patients are presenting with significant severe fatigue, you need to be thinking about adrenal insufficiency, which does not necessarily enter the picture with the other agents.

I seem to observe more hypertension and LFT abnormalities in our patients on abiraterone, which does match kind of what we have seen in the trials. Enzalutamide tends to cause a lot more brain fog in patients, has been my experience, and just overall fatigue. Then, apalutamide too, I think is well tolerated. We certainly can see that in the quality-of-life data that was reported from the TITAN trial. It seemed like changes in quality of life were no different between the placebo and the treatment arm, and I would say that echoes my practice as well. Rashes are the kind of one that peaks in the apalutamide group and an occasional thyroid stimulating hormone (TSH) abnormality. Katie, what do you think? Do you have similar experiences?

Dr Morgan: Yes, I think it's very similar to what you said, and some of this decrease in cognitive dysfunction and fatigue we see with enzalutamide and apalutamide are not that prominent with darolutamide, because although the mechanisms of action are very similar, there is an additional moiety on darolutamide that makes it harder to cross the blood-brain barrier, so we do see those reduced CNS effects of darolutamide, which makes it a little bit more favorable, especially in our elderly patients where enzalutamide and apalutamide can cause significant fatigue and cognitive changes that can affect their quality of life and their just ability to function daily activities, enjoying the things that they do, especially at that age.

Then importantly, when we're thinking about these medications, although they have a lot of drug interactions, enzalutamide and apalutamide are both strong 3A4 inducers, and the majority of medications that patients take are metabolized by that cytochrome P450 enzyme, and so that tends to lead to a lot of medication management at the beginning of their treatment to ensure that common medications, including statins, anticoagulants, direct oral anticoagulants (DOACs), specifically, blood pressure medicines, antidepressants, things like that, are identified. The concentrations of those medications could be potentially decreased by the induction of the metabolizing enzymes. Apalutamide additionally is an inducer of PGP, so it adds an additional restraint on a lot of the medications because PGP inducer plus 3A4 inducer can cause a lot of problems with some common medications.

Dr Fizazi: We are completely changing the way we are treating these men with non-metastatic castration-resistant disease, which is great. These drugs are mostly approved around the globe, but there is also another setting where we have also dramatically changed the way we are treating all the patients in the last 5 to 7 years -- this is metastatic hormone-sensitive disease. Administration of docetaxel and next-generation hormonal agents improves overall survival when used in combination with androgen deprivation therapy upfront.

The key question we were asking was to whether we should combine these agents, docetaxel and an AR axis inhibitor upfront, to try to intensify treatment for better outcomes for patients. We have the PEACE-1 and ARASENS phase 3 trials that have released their efficacy data in the last 6 months or so, and they both point to the same direction. In PEACE-1, what we saw was those men receiving the triplet systemic therapy, ADT, docetaxel, and abiraterone, will enjoy a ~25% reduction in the risk of death on top of other clinical benefits, including radiographic progression-free survival, which is reduced by half, which is a big change.

Just a week ago, we saw at American Society of Clinical Oncology Genitourinary Symposium (ASCO® GU) and now in the New England Journal of Medicine, similar data with the ARASENS phase 3 trial, which has also a similar design. ADT and docetaxel were given to all patients with mostly de novo metastatic castration-sensitive disease, so there was a subgroup of men with a relapse, and half of them were randomized to receive darolutamide on top to chemohormonal treatment. Here again, the news is good. The primary endpoint of survival is significantly improved with an ~32% reduction in the risk of death. This came together with improvement in key secondary endpoints, such as time to first skeletal-related events, time to castration-resistance, and time to next treatment, etc. Very good news from these 2 randomized trials, but again, Katie and Emily, I would like you to tell me what you think, not only about the efficacy that we saw in these 2 trials, but also, what is the price to pay from a patient's perspective in terms of side effect?

Dr Morgan: Yes. I think the data is super exciting because we know that potentially this upfront therapy with triplet therapy is more beneficial than our sequential therapy as we would use it today. Then from a side effect standpoint, I think that we didn't see any new safety signals with these, which is good as well because in the ENZAMET trial, there was some safety signals with enzalutamide and docetaxel, so there might have been a concern with increased peripheral neuropathy, especially in the ARASENS study, but it was not seen. In both of the trials here, PEACE-1 and ARASENS, we see mainly that the toxicity is, as we would expect, more burdensome during the chemotherapy portion, but no new safety signals arising; there's nothing new to expect from those combination therapies.

Dr Fizazi: Fantastic. Emily, any additional comments?

Dr Lemke: I was excited to see that ARASENS also included the recurrent population as well, so that we know we can apply the same triplet therapy in that population. I think, from a realistic, day-to-day standpoint, what has been the biggest barrier is, these patients have just been diagnosed with de novo metastatic disease for the most part and telling them they need to go on 3 different agents, sometimes that acceptance piece can take a little bit longer. We can talk about data to the patients all day long, but it's been nice that we haven't seen any new safety signals so that even though this is new for us, we can help coach these patients through what kind of side effects to expect and how this is going to change their life as they absorb this shocking news and accept the reality of a lot of therapy in their future.

Dr Fizazi: Absolutely, but you're very right. Let's come to the actual patients. The first patient is Robert. Emily, would you mind introducing this patient to us?

Dr Lemke: Yes, absolutely. Robert is a 75-year-old man with non-metastatic castrate-resistant prostate cancer diagnosed 10 years ago, and he is currently asymptomatic and on an anticoagulation with apixaban.

Patient Vignette 1: I’m starting to feel like a real regular at this clinic now! So now I need to start taking some new drugs, does that mean that my cancer is getting worse? What side effects can I expect from these new ones and how are they going to impact my daily life? I’ve started going out a lot more recently and have even started doing some exercise classes at the local center. I’d love to be able to keep doing those as they make me feel good about myself.

Oh, and I’ve been reading on the internet that healthy eating and exercise can help people with cancer, is there anything else I can do to stop it from getting worse?

Dr Fizazi: We've heard Robert, and he is a typical man with non-metastatic castration-resistant prostate cancer. Initially with local prostate cancer that relapsed with PSA increased. He received salvage ADT and then after some time, the PSA rose, and we were not able to detect any lesions on the bone scan and the CT scan. He is just about to start one of our novel agents, enzalutamide, darolutamide, or apalutamide, and I think he's asking good questions -- he's doing quite well. It's just about his PSA, his disease now. We know it's not a good disease because PSA doubling time is not a good one, but he's asymptomatic. He lives a normal life, and he would like to keep this normal life, if possible. I think this is important. He is also asking some questions about whether he should do some healthy eating, whether he should exercise. What should we give to Robert as advice? What do you think?

Dr Lemke: What I try to tell patients is, as healthy as you can be, the better. As active as you can be, the better. The American Cancer Society does recommend 150 minutes of exercise per week, and so that's kind of the starting block that I give patients to work towards and splitting that up to 5, 30-minute walks a day.

I think as healthcare providers and in the nursing specialty specifically, that a lot of these patients worry about what to expect and that fear of unknown. If we can help walk them through what's the most likely side effects, how frequently they're going to need to be seen, and reassure them that we're going to help them manage these side effects and get to a place where it's not going to interfere with their quality of life in a major way, I think that reassurance goes farther than anything, but I know drug interactions can be very important in driving our therapy decisions here. Katie, what is your experience?

Dr Morgan: Yes, I think that that's a good question, and especially with these medications, because enzalutamide and apalutamide do have those significant effects on the 3A4 metabolism. Specifically, with this patient, he is on apixaban, which is a complicated order when you're trying to start one of these medications, because it is metabolized by 3A4 and PGP. Apalutamide could not even be an option in this patient if he needs to maintain on his apixaban, but there's a lot of questions to be asked. What is the indication for his apixaban? Can we recalculate his CHADS score? He's 75-years-old, if his CHADS score is only 1, does he really need this? Looking, if it was clot, how long has it been? The enzalutamide will drop that apixaban concentration about by 50%, so can we get away with calling it 2.5 mg twice daily, and feel comfortable with that on the apixaban dose? or do we need to avoid it altogether because he is high risk for stroke?

You have to kind of think through these things and make sure that the medication management is solidified upfront before we make the decisions on the medications. I think I talk about exercise every time I talk to patients. You do a little bit of motivational interviewing sometimes to get them to be exercising, because fatigue is the biggest concern with these 3 medications, and especially adding ADT in the mix, which they've already been on for a long time at this point.

Dr Fizazi: Okay. We still have a couple of patients to discuss. We now have Rick, also, who is a man with metastatic castration-sensitive disease. Katie, would you mind introducing us?

Dr Morgan: Sure. Rick is a 62-year-old man with metastatic castrate-sensitive, symptomatic high-volume prostate cancer. His medical history includes type 2 diabetes and coronary artery disease, and he's currently on a statin, atorvastatin, and metformin for his diabetes.

Patient Vignette 2: Wow doctor, I don’t know what to say. I wasn’t expecting cancer, I thought I was just getting old with all these aches and pains! Who would have thought that back pain could be prostate cancer. And it has already spread. It really doesn’t seem real.

I suppose the big question is what happens now? Is there something that can help me get better or is too late? If there’s chemo or radio or some other drug that might help, then I’m ready to try it. Although I have heard that cancer meds have nasty side effects, am I going to get really sick? If I have options, then I’d prefer something that has less side effects. I already have heart disease and diabetes, is this going to limit my options?

Dr Fizazi: We've just heard about Rick. This is typical also of my patients with high-volume de novo disease. It's a big shock for patients -- they come to us, they have a cancer diagnosis, they have diagnosis of metastasis, and they have some symptoms bothering their normal life. It truly comes from nowhere; they didn't know anything about this just a few weeks or 1 month before it happened. This is typical. The good news for Rick is that it's very likely to improve in the near future, not only thanks to androgen deprivation therapy, which we will probably prescribe today when we see him upfront, but also because we now have demonstration that we should intensify androgen deprivation therapy, and probably for Rick, who is a 62-year-old man with a high-volume disease, would clearly advise him to go for both chemotherapy with docetaxel and androgen receptor axis inhibitor.

Having said that, I need to take in consideration his previous history, including type 2 diabetes and coronary artery disease. I will refer Rick to his cardiologist to make sure we know what the current situation is, maybe also his diabetologist. His past history would probably be a very good reason for me to use darolutamide instead of abiraterone/prednisone, of course, assuming this is off label. I'm saying that obviously because long-term prednisone is not that easy to use in a patient with type 2 diabetes. Katie, do you have any comment regarding the clinical management of Rick?

Dr Morgan: Yes, I agree with you. Abiraterone does come with some additional cardiac risk on top of our ADT, because it has that risk of mineralocorticoid excess syndrome. The patients do have to take prednisone as well, but you can see increases in hypertension, decreased potassium. Depending on what his cardiac status right now, it might be too high risk to put him on something that could put him at risk for a cardiac event. In addition, he has the diabetes. Hopefully, it's well controlled, and we don't have to send him also to endocrinology to get that under control prior to starting, because we not only have the concern with the prednisone, which we can avoid by using darolutamide, but also there's a big dexamethasone load with docetaxel, so either way we would use that. Diabetes would need to be well controlled prior to starting.

Dr Lemke: I think shock, fear of the unknown, is one of the biggest things that we kind of navigate. I try to spend a lot of time with these patients talking in as plain of language as I can about what to expect.

Similar with our previous patient, outside of kind of this fear of unknown, its side effects, and I think we've got good medications to help with nausea, vomiting, diarrhea, and constipation. It's the fatigue and the decreased appetite that seem to be the 2 that are very tough to deal with. Now we've got a patient who has symptomatic high-volume disease, and so exercise becomes a little bit harder, I think, and we sometimes don't know the risks. After they kind of get 1 cycle under their belt and they're kind of in it, I usually recommend they meet with either an exercise physiologist or a physical therapist to get a routine for themselves, knowing, especially if they have bone metastases, to help tailor to them so that they feel they have that guided support of an expert.

Dr Fizazi: Very good. Thank you very much. I think we have a 3rd case, which is even perhaps more challenging. This is Grant, an 85-year-old man, and he also has metastatic castration-sensitive, symptomatic, high-volume prostate cancer, which was diagnosed just 2 months ago. He just started recently on abiraterone. ADT was started when he was diagnosed with his cancer, but abiraterone is more recent. He has frailty due to his age and comorbidities, and he's currently on an antidepressant, fluoxetine, and a beta blocker, metoprolol. Let's hear about Grant.

Patient Vignette 3: Thanks for seeing me today doctor. Well, I’m finally starting to accept that I’ve got prostate cancer -- it really took a while to sink in. At least I’m not in pain anymore, that was a big thing for me. One question for you -- how long do I have to take this morphine for? Not that I’m complaining, but I don’t want to take pain killers forever.

To be honest with you doctor, I’m not feeling so well, but I suppose that is what you get when you have cancer. I’m tired all the time, nauseous at times and getting pains and hot flashes all over my body. Is it from the drugs or is my cancer getting worse?

Dr Fizazi: Again, Grant started his systemic treatment just 2 months ago, and because of his age, we could not use docetaxel chemotherapy, so by default, he received ADT and more recently abiraterone/prednisone. He remained symptomatic; hopefully, this will go away, but we can hopefully see some improvement very soon in Grant. Emily, how do you deal with these patients who are in pain with also potentially some side effects from morphine?

Dr Lemke: This is going to be a patient that we're going to be keeping a very close eye on, and probably seeing him at more frequent intervals than we would, say, a 62-year-old on abiraterone. Anytime patients are on any opioid pain medications, especially an 85-year-old, the first thing I want to ask them is, are they getting pain relief? How frequently are they taking their medications? Who's at home helping them with these? It becomes somewhat of a scary situation when you think of somebody in this state being alone, and so understanding their support system I think is key to tailoring their education to them. I think that these patients do better on long-acting opioids, so if we can get them on something long-acting as opposed to a short-acting and then slowly taper that as their disease hopefully responds and their symptoms improve, I think is ideal.

Especially knowing what their bowel management is when they're on opioids, because these men can get super backed up quickly, and that becomes almost more problematic than their prostate cancer. Making sure they know how to take their blood pressure at home, so that again speaks to the support system and who's there to help them. If they don't have somebody, maybe figuring out resources in the community that can help with that, because obviously we're going to need to be monitoring both his labs and his blood pressure on a regular basis. We know that patient survival improves when palliative care is involved from an early standpoint, and so that is something I try to be very proactive about with that referral.

Also, if I didn't mention it, physical therapy. These are great patients to be referring to our physical therapy colleagues, because the muscle and bone mass loss and the risk of falls while you're on opioids is just going to skyrocket in this patient.

Dr Fizazi: Thank you. Katie, any comments?

Dr Morgan: Yes, so with abiraterone, one is the mineralocorticoid excess syndrome, so as Emily mentioned, we want to monitor his blood pressure, have some way to monitor his blood pressure regularly so that they can let us know in between visits if they're having increases in blood pressure. Also swelling, any fluid retention, and then we'll be monitoring labs, and the laboratory monitoring mainly for the LFT elevations. LFT elevations are rare, but they do happen. We see them happen all the time. That can result in requiring a dose reduction. He will be getting frequent lab monitoring every 2 weeks for the first 3 months. We can look at the potassium at that time as well, making sure that the potassium's not dropping.

Then, a couple of concerns with, as far as drug interactions. Abiraterone, although it doesn't have as many, is an inhibitor of CYP2D6, which can inhibit metabolism of beta blockers, specifically metoprolol and carvedilol. As a result, an assessment needs to be made of the patient's baseline heart rate. If their baseline heart rates in the 60s, you could drop them into the 50s and 40s and that'll be bad for an 85-year-old. A dose adjustment of the beta blocker may need to be made at the beginning of treatment, and that is a good assessment to make prior to starting anyone on abiraterone who's on a beta blocker. Then, antidepressants are important to consider. CYP2D6 also does metabolize a lot of antidepressants. Luckily, fluoxetine is not one of them, and so we would need to monitor his depressive symptoms though, because ADT can lead to depression, and again, palliative care would be a great option for this patient. If there's a cancer support program at your institution, this would be a great patient to refer to for several different reasons.

Dr Fizazi: Thank you very much. I think we're almost at the end of this presentation and discussion. Emily, any final thoughts, any final remarks?

Dr Lemke: I'm excited to see what the triplet therapy in real life looks like. Certainly, we're at a major change in prostate cancer management, and when we reconvene at GU ASCO® a year from now, I'll be interested to see what kind of the updates are. Another final thought too, is, it takes a village. Every team member is so integral to the success of these patients, and when we're lucky enough to have dedicated healthcare members that can proactively call these patients and check on them, they do better.

Dr Fizazi: Excellent. Thank you very much. Katie, any thoughts?

Dr Morgan: Yes, I agree with Emily. I think all of us have our roles within the team and we come with our specialized skill set that are different from each other, to promote the best care possible for patients. I think that that's a wonderful way to approach these patients, especially with the complexities and nuances that we discussed today. I am also very excited to get more patients on triplet therapy. As we intensify treatment for these patients, multidisciplinary care is increasingly important because of the complex nature of IV medications, oral medications, and monitoring different side effects, all kind of coalescing together. I think it's very important to establish a multidisciplinary approach to care.

Dr Fizazi: All right, Katie, Emily, it was really a pleasure. Thank you very much for this great conversation and thank you for participating in this activity. Please continue to answer the questions that follow and complete the evaluation. Thank you very much.

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