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Dr. Alicia Morgans: Hi, and welcome to The ASCO Post Roundtable Series on Novel Hormonal Therapies for Prostate Cancer. My name is Alicia Morgans, and I am a GU medical oncologist and Associate Professor of Medicine at Dana-Farber Cancer Institute. Joining me today are two of my colleagues, Dr. Neeraj Agarwal, and Dr. David VanderWeele. Let's hear from both of them. Dr. Agarwal?
Dr. Neeraj Agarwal: Hi. I'm Neeraj Agarwal, very pleased to be here. I'm a Professor of Medicine and Director of Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah.
Dr. Morgans: Wonderful. And Dr. VanderWeele?
Dr. David VanderWeele: Hi. David Vanderweele, Associate Professor of Hematology Oncology and a GU medical oncologist at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.
Dr. Morgans: Fantastic. Today we'll be discussing recent updates in prostate cancer and integrating these new developments into three patient case studies. Our second installment will focus on de novo metastatic hormone-sensitive prostate cancer.
Mr. TK is a 74-year-old man who presented to his primary care physician for evaluation of worsening back pain after not coming to clinic for the last few years due to concerns about COVID. He had a past medical history of hypertension and some osteoarthritis in the lower back, and he was a current smoker. Medications included omeprazole and ibuprofen. He's married and has three adult children and five grandchildren, all of whom live nearby and can provide support. He's a retired construction manager.
Because of the back pain, he underwent a workup that included x-rays that demonstrated an area in T12 concerning for metastatic cancer. His primary care doctor completed additional lab assessments, which included a PSA of 23. And I wonder, Dr. Agarwal, what other testing would be important for this patient?
Dr. Agarwal: I'll definitely do the complete workup for prostate cancer, which includes CT scan, bone scans, and if they're negative with a high PSA level, definitely functional imaging like PSMA PET scan. Patients with metastatic prostate cancer, if I do find metastatic disease, germline testing and somatic testing are the standard of care in my clinic and in all our clinics. So I think those will be the first steps for this patient in my clinic.
Dr. Morgans: Absolutely, I think I would do the same things. And in this case, the patient underwent the same assessments, at least the imaging assessments. This demonstrated multifocal bone metastases, metastatic disease in the liver as well. And I think, you mentioned germline and somatic testing, Dr. VanderWeele, would you do these in a patient with metastatic disease? Is that part of your standard practice and approach?
Dr. VanderWeele: It is part of my standard practice and approach. Generally, I presume somatic testing for patients when they're no longer considered to be curable or undergoing curative therapy. So maybe not for people undergoing salvage radiation, but if they have metastatic disease, generally that's my threshold for doing somatic testing.
Germline testing of course, is indicated per guidelines for patients with localized disease as long as it's high-risk disease. Often that has been done already depending on where the referral is coming from. But I do tend to get somatic testing earlier on. I recognize that the biomarker-directed therapies like PARP inhibitors, like immunotherapy, they don't really come into play until the CRPC setting. But I still think that the alterations that are identified do sometimes make me think about the cancer a little bit differently.
In addition, there's the issue of the age of the tissue. So if you're doing the sequencing from archival prostate tissue, just given the natural history, sometimes by the time you order the test, it's a little older and the DNA may be a little bit less likely to be of high quality and useful. So I tend to get it earlier on, basically when they're metastatic or even if not technically metastatic when they're past the curable setting.
Dr. Morgans: I could not agree more, and I do think that there are clinical trials that are also looking at other ways of intensifying for patients in this setting. There are at least one or two that are trying to be more aware, I think, of some high-risk prognostic features that you can find in somatic testing that might indicate a more aggressive disease phenotype and one that we might consider intensifying. So this, I think, will be increasingly important and as you said, nice to have that information up front to counsel the patient and also to think about where you might be headed in the future.
So I don't know, Dr. Agarwal, any other comments on germline somatic testing, how this goes in your clinic? Because I think this is something that we really as a field need to continue to progress to do at a better rate.
Dr. Agarwal: Yes, as you said, Alicia and David, selecting these patients and referring these patients for clinical trials, which are happening in metastatic hormone-sensitive prostate cancer setting. So CAPItello trial for example, looking for PTEN-deficient tumor. Patients with PTEN-deficient tumor, TALAPRO-3, AMPLITUDE trial looking for homologous recombination repair-mutated patients. And beyond that, beyond the trial selection, if I see presence of more aggressive players in my patient's cancer such as p53, PTEN, or RB loss, if I see two of them, I follow them more closely than I would if I don't see any of those mutations.
So even scan frequency in my clinic, and of course we are talking about our personal experiences, so especially during the pandemic when we were hoping to not see patients quite often in our clinic, if I saw those mutations, I used to do scans quite often. Because what are the chances of developing AR in different prostate cancer in those patients versus say somebody has SPOP mutation and who is on ADT plus apalutamide.
So I think in all, we will take time to generate level I evidence, in this context of follow-up for many years, but while we do that, it is good to have that information on somatic testing for trial selection and how we follow our patients and of course therapy selection.
Dr. Morgans: Absolutely. Well, thank you both for that great discussion. I think as we move forward with this patient, he started on androgen-deprivation therapy or ADT as his initial treatment for metastatic hormone-sensitive prostate cancer. Of course, this is de novo metastatic disease because he has not had any evidence of prostate cancer in the past.
As he's starting on this treatment, this hormonal therapy, how do you counsel the patient? Are there ways to reduce his risk of complications related to this initial therapy? What do you think Dr. VanderWeele?
Dr. VanderWeele: Yeah, so multiple complications here. Certainly on the metabolic syndrome side of things, want to be monitoring blood glucose, cardiac risk factors, blood pressure included, and then also unfitness. I tell patients it's harder to stay in shape, to stay fit, and so counsel with good diet recommendations and continued exercise, try to do both cardio and weightbearing resistance exercise if you can, that just overall helps you to stay fit.
Dr. Morgans: Wonderful. And Dr. Agarwal, we've talked about some of these things in the past and I wonder from your perspective, how do you best engage in co-management of cardiovascular complications in particular in these patients? Are there patients that you preferentially send to cardio-oncology, recognizing that not everybody has access to cardiology support or cardio-oncology support? Are there some patients where it is perhaps more important or patients that might follow more comfortably with their primary care doctors?
Dr. Agarwal: Yes. So a first step is of course, tell the patients that they are at a higher risk of developing cardiovascular complications on long durations of androgen-deprivation therapy, which is the case in these patients with metastatic prostate cancer. The next step is to send them to exercise programs, whether it is locally in our cancer center or locally through their primary care physicians. And if my patients report any problems with doing those exercises, if they develop any symptoms which are suggestive of cardiovascular problems, I think that's a red flag for me.
For example, if a patient reports to me that they are feeling shortness of breath on relatively lower level of exercise, I have a much lower threshold to send these patients to the cardio-oncology clinic in our hospital or to their primary care doctor, specifically asking for some kind of further evaluation for cardiovascular issues or problems.
Sometimes I say, "Would you mind ordering a stress test if you think that may be reasonable from your perspective?"
So without getting into their domain, without making the decision for primary care doctor, I do suggest them to think about that possibility.
Dr. Morgans: Absolutely. I think that we would all be perhaps surprised and perhaps not, if we're reading the latest literature, but a majority of these patients will have at least a cardiovascular risk factor or a lifestyle-related risk factor, if not overt cardiovascular disease. And so it is important for us to recognize this, counsel our patients, and the American Heart Association's most recent publication on this, on ADT and hormonal therapies and really managing these patients, is that if patients have at least two cardiovascular comorbidities, so things like diabetes, hypertension, hypercholesterolemia, we should be considering getting them engaged with cardiologists or cardio-oncologists too, just to have that extra support and to ensure that those reversible risk factors of cardiovascular events are addressed and monitored. So really, really important. Does this come into play if patients have multiple cardiovascular comorbidities as you're choosing treatment, your ADT backbone treatment for these patients with metastatic disease or otherwise, Dr. VanderWeele?
Dr. VanderWeele: Yeah, it does. I guess for me, even more so an AR pathway inhibitor, and we haven't really talked about treatment intensification yet. I do think that abiraterone has a little bit higher risk of cardiac toxicities than the AR antagonists do. In general, I think at least comparing abiraterone and enzalutamide, there tends to be a little bit less fatigue, and because it's available as a generic that tends to be a go-to for me is abiraterone, but it certainly runs a risk of increasing blood pressure and other cardiac issues. Certainly have detected some arrhythmias on exam, as well. And so depending on preexisting hypertension especially, or other cardiac risk factors that can push me one way or another, especially for therapy intensification.
For the ADT backbone, there is some data suggesting that LHRH antagonists, especially relugolix, may be better for patients with significant cardiac risk factors. I think there are confirmatory studies underway as well to really suss that out. I guess my interpretation of the data is that the effects seem to be pretty big, but it is from a relatively small group of patients. So it is a consideration, although that one maybe is not quite as strong a consideration for me as for therapy intensification.
Dr. Morgans: Well, thank you for that. And to speak to therapy intensification, Dr. Agarwal, what do you think about when you're making those decisions? This patient has de novo high volume metastatic hormone-sensitive prostate cancer. Obviously there's a spectrum of disease risk, disease burden, for patients with metastatic hormone-sensitive disease. How do you think this through, and are you generally intensifying therapy or are you continuing ADT alone for some patients? What are your thoughts?
Dr. Agarwal: Great question, Alicia. So first of all, our patients are living much longer. The median overall survival was in the range of 3 years, just 10 years ago. And with the recent publications, we are seeing almost doubling of that median overall survival. And I have no doubt that in next 5 to 7 years we are looking at a median overall survival, which may, and I'm keeping my fingers crossed, always, we may be talking about a decade. The whole issue of cardiovascular disease status becomes so much more important as our patients are living longer.
Coming back to the choice of therapy intensification, based on the data, what we have currently, 7% patients with newly diagnosed, hormone-sensitive metastatic prostate cancer present with liver metastasis. So when I see liver metastasis, I used to pick ADT plus docetaxel as the therapy of choice.
And now based on the data from RSL trial, based on the data from PEACE-1 trial, we know that ADT plus docetaxel can no longer be considered standard of care. And adding a novel hormonal therapy, either darolutamide or abiraterone, based on those two trials, is the current standard of care now.
Having said that, we are talking about a 74-year-old man. In this context, and I see patients who are even older who present with liver metastasis. So I don't want to just assume that all my patients are the candidate for triplet therapies or all my patients are candidate for ADT plus docetaxel plus something, especially important given the low use of even doublet therapy in the real world domain. We have seen multiple publications showing that use of doublet therapy, ADT plus a novel hormonal therapy or AR pathway inhibitor, was around 30% to 40% until 2020. ADT plus docetaxel use was 7% in 2020 in the real world.
Putting all of that in mind, keep it together, in my decision-making, I think I like to go with ADT plus docetaxel plus a novel hormonal therapy in any patients who are candidate for docetaxel chemotherapy and who wants to go with docetaxel chemotherapy.
There are 25%, 30% of patients who present with aggressive features. So in addition to liver metastasis, I also keep in mind those aggressive players in somatic mutation domain, p53, PTEN, RB loss. If I see two of them, I go with docetaxel chemotherapy. Altogether, I think in my practice there are 20% patients or 25% patients who are candidates for triplet therapy. With other patients, other 75% patients, I still go with ADT plus one of the novel hormonal therapies.
Dr. Morgans: Great. Well, thank you so much for talking that through. Final words from you, Dr. VanderWeele, as we wrap up and then we'll get a final word from Dr. Agarwal before we close.
Dr. VanderWeele: Mostly just agreeing with what Neeraj said and yeah, I really don't use... I think the triplet data, what it tells us is that adding a novel hormonal therapy in addition to docetaxel really adds quite a bit of benefit. Of course, that question remains of who really needs the docetaxel, but I agree with him with my thought process of when to be thinking about triplet therapies. I think he'd said it very well.
Dr. Morgans: Great. Thank you. Anything you want to add, Dr. Agarwal?
Dr. Agarwal: As patients are living much longer, focusing on their quality of life and cardiovascular status is more important than ever.
Dr. Morgans: Well, I certainly could not agree more and thank you both.
Let's go through some key clinical takeaways. So treatment of metastatic hormone-sensitive prostate cancer with ADT alone is no longer the standard of care. Intensified treatment with couplets, which would be an ADT plus an androgen receptor signaling inhibitor approach, is associated with improved survival versus ADT alone. Intensified treatment with a triplet, ADT docetaxel and abiraterone or darolutamide is also associated with improved survival in this case, versus ADT and docetaxel. ADT and docetaxel, to be clear, is no longer recommended as a standalone treatment. If you are using that approach, add on either darolutamide or abiraterone for a triplet approach. Attention to reversible cardiovascular risk factors, including things like hypertension, hypercholesterolemia, smoking cessation, these are all things that we can do to reduce the cardiac risk of patients treated with ADT, and as we have heard, these patients are living longer and longer and attention to their cardiovascular risk and health is critically important.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.