Dr. Alicia Morgans: Hello and welcome to The ASCO Post Roundtable Series on Novel Hormonal Therapies for Prostate cancer. My name is Alicia Morgans and I'm a GU medical oncologist and an Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston. Joining me today are two of my friends and colleagues. We have Dr. David VanderWeele and Dr. Niraj Agarwal, and let's have them introduce themselves. Dr. VanderWeele?
Dr. David VanderWeele: Hi, David VanderWeele, also a GU medical oncologist at Northwestern University in Chicago.
Dr. Niraj Agarwal: Hi. This is Niraj Agarwal, Professor of Medicine and GU Medical Oncologist at the Huntsman Cancer Institute, University of Utah.
Dr. Morgans: So our first installment will focus on biochemical recurrence. Mr. RG is a 64-year-old man with a history of localized prostate cancer that was treated with a radical prostatectomy in June of 2017. He had a Gleason 4+4 or grade group 4 tumor that was notable for having positive extracapsular extension, and after prostatectomy was noted to have a positive right apical margin. Due to high-risk features, he did undergo adjuvant radiation therapy in October of 2017, and although his PSA was initially undetectable, it started to increase in October of 2019. His PSA reached 12.9 nanograms per milliliter in January of 2020.
Because of this, he underwent a bone scan that was negative for evidence of recurrent disease, and he had a testosterone level check, which was normal. What additional studies would be performed to assess his disease status in this situation? I'm going to throw it first to Dr. VanderWeele. What else would you do for this patient?
Dr. VanderWeele: Well, I’d complete staging with conventional staging first, would be my practice with a CT scan of chest, abdomen, pelvis. But if that also is negative and since the bone scan is negative, I suspect that might be, then I'd probably go on to molecular imaging with a PSMA PET scan. Get a better sense of where his disease is.
Dr. Morgans: Great. I think that sounds reasonable, and actually is what this patient experienced. So he underwent CT testing because of course his PSA was 12.9. So this is an elevated PSA. I think it's reasonable to use conventional imaging in this setting. That was negative, and he did undergo a PSMA PET also, and that was negative for evidence of metastatic disease. So now, you have a patient whose imaging is all negative, Niraj, and he has a normal level of testosterone, but a rising PSA. What else are you going to do to really assess and counsel this particular patient? What else are you going to calculate or think about?
Dr. Agarwal: So obviously, cardiovascular history is important. And then, of course, the discussion with the patient, what patient wants. Many of my patients are convinced to not do anything and delay treatment until there is onset of metastasis on the scans, but many patients do not want to delay. They feel very uncomfortable about delaying treatment, especially when PSA is rising. So would you like to tell us about the comorbidities in this patient?
Dr. Morgans: Sure. And I'll also tell you that his PSA doubling time, which you mentioned and calculated, is 6 months. So this patient has a family history that includes his father having an MI at 50. So that's certainly a cardiovascular risk factor. And then his comorbidities, to your point, include components of the metabolic syndrome. So he has borderline diabetes. He also has a blood pressure that ranges between about 135 to 150 over 80 to 90. So really consistent with at least early pre-hypertension, if not hypertension.
His BMI is 28 and he has a waist circumference of 41. So this gentleman, at a minimum, has what seems like metabolic syndrome. And as you mentioned, understanding these cardiovascular risk factors as we're considering treatment, as well as understanding the risks from the cancer itself, which is why of course we calculate that PSA doubling time, these are both going to be important.
So David, from your perspective, what are the options for treatment at this point, if he even needs treatment? What do you think about treatment in this biochemical recurrent setting, and what else are you thinking about, if anything, for additional workup in this setting?
Dr. VanderWeele: Yeah, those are good questions. And I think the proper first question is does he need treatment? And as Niraj said, I think that is kind of a shared decision-making question to be thinking about. I think it's reasonable to treat him, and I think it's reasonable to not treat him. I would discuss that some institutions historically would recommend against treatment until there was evidence of metastatic disease. As Niraj said, in particular, there's data from Hopkins that if the doubling time is 3 months or less, you're likely to have metastatic disease within a year, although it's significantly longer for any longer doubling times. Although also, as Niraj said, I think a lot of patients do have anxiety about a rising PSA and would be interested in starting some treatment.
If you're going to start treatment, it's going to be androgen-deprivation therapy. I don't think, currently, I don't think that there's a role for intensifying therapy, although that may change in the future, but it would be androgen-deprivation therapy. And then you could also talk about should you treat continuously or would there be a role for an intermittent therapy approach. And I would say in the biochemical recurrence setting, he’s negative imaging, and in this case, even a negative molecular imaging that it would be, I think it would be very reasonable to do intermittent therapy. I consider it to be non-inferior to continuous for the patients who are interested in that.
And again, not everybody is, so these are kind of shared decision-making. A lot of people just want to suppress the testosterone and keep that PSA level low. But I would counsel them that I think it's reasonable to make decisions either direction, sort of based on their personal perspective and approach.
Dr. Morgans: Great. Well, thank you. Thank you for talking that through, David. And Niraj, from your perspective, and you mentioned that many of your patients may, at this PSA level, have some anxiety around watching that continue to rise and may be interested in treatment. If you were going to start treatment after a shared decision-making conversation with this patient, would you use intermittent to androgen-deprivation therapy? Would you use continuous? How do you make that decision and what is your thought process really based on?
Dr. Agarwal: Obviously, intermittent ADT has been there for a long time based on PR7 trial presented by Juanita Crook. I think it has been quite a while, more than a decade. And in this BCR setting, really, we do not know if continuous therapy is superior to intermittent therapy. And if I'm going to pursue intermittent therapy, the goal is to allow patients to have their testosterone back, when there is an off-treatment period, if you will. And based on the data we saw from the HERO trial, that testosterone recovery was quite rapid with the oral GnRH antagonist relugolix, compared to leuprolide, for example.
And based on those data, I have started to use intermittent ADT with relugolix, is a common practice in my clinic. And I still follow a PSA level, PSA boundaries of 10 ng/mL, and 4 ng/mL. And ask patients who start ADT with relugolix when PSA is 10 and wait for PSA to go down to 4, and then stop, take the break. And I have been surprised by the rapidity of testosterone recovery in our patients. And during the off period when testosterone has recovered, patients actually feel good. They are able to carry on with their normal lives. And of course, this also helps with their cardiovascular morbidities, no doubt, in my view. So that would be my practice in this patient.
Dr. Morgans: Yeah. Well, and thank you for that. I think it is nice to know that there is this option that allows for potentially more rapid testosterone recovery. And I have to say, in my practice, I use a similar approach when using intermittent ADT because the goal of treatment cessation there is of course to allow that testosterone to come back to a normal level, or a higher level at a minimum, so that patients actually improve in terms of their quality of life measures. And certainly, we know that PSA is expected to rise. We have not eradicated the cancer. And so that holiday off of androgen-deprivation therapy will be some duration, but is not expected to be forever.
But this is all part of the counseling going into that conversation around intermittent ADT. So part of what we talk about and one of the reasons why a rapid testosterone recovery is sort of part of that plan, at least as I said in my clinic. Now, Dr. VanderWeele, I wonder from your perspective, this patient has metabolic syndrome, may have some overt comorbidities. It looks like he may have hypertension and perhaps maybe actually is developing or will develop things like diabetes on his treatment with androgen-deprivation therapy. How do you think about these comorbidities? Do they come into play as you're considering whether you should start androgen-deprivation therapy in a patient with biochemical recurrence? Does it affect timing or decision-making around that? And how do you include that in your calculus for this?
Dr. VanderWeele: Yeah, good questions, and for sure, it plays into the decision-making. Again, it's shared decision-making, but I do counsel the patient. Often people are most concerned about loss of libido, hot flashes and fatigue when thinking about starting androgen deprivation. But what would also definitely discuss potential effects on glucose control, on blood pressure control, with his family history would want to be controlling reversible cardiac risk factors to the best that we can. So my practice is to encourage them to follow up with their primary care doctor, reach out to the primary care doctor and say, "Hey, we may be starting androgen deprivation soon. Could you please help in trying to optimize management of these other things that could be exacerbated by that?"
And again, because I think you could either start or not start, you also have some time to try to optimize those things beforehand if the patient's open to that, if they're really anxious. It's things that are done in tandem, getting started and also trying to optimize. And I'm trying to get better at talking about lifestyle stuff in general. We mentioned the BMI, and so in just a change in diet and trying to improve exercise, if there's a poor diet to begin with and a more sedentary lifestyle, those things could go quite a ways towards sort of optimizing their overall health. And there's growing body of data that helps managing the side effects of androgen deprivation as well.
So yeah, try to make it a thoughtful approach to the whole health. And a lot of our patients aren't that engaged with their primary care doctor, and many of them very much are, but often, you need a lot of encouragement or reaching out to make sure that they are engaged with their primary care doctor and their primary care doctor's engaged with them as well, just to keep them in the loop too.
Dr. Morgans: I think those are great points, and really that multidisciplinary management strategy is so important when we're trying to take care of the whole patient, and ensure that we're managing and monitoring those potential comorbidities that can be a problem for patients with prostate cancer who are on androgen-deprivation therapy. And thank you so much for mentioning the diet and lifestyle because certainly, aerobic exercise can help to reduce things like fatigue and maintain muscle mass, reduce potentially abdominal adiposity, which can be a complication of ADT.
But any weight-bearing activity can also help maintain bone health, which is something that we want to do for patients on ADT as they do experience thinning of their bones or loss of bone mineral density. And when we really think about kind of addressing all of these issues and keeping the patient well, it does help that patient live better, I hope, and also will give us a way to try to ensure that that patient is here for years to come as he goes through intermittent therapy, and then hopefully feels well during that whole process. So any final parting thoughts, Dr. Agarwal, as we wind this down?
Dr. Agarwal: I always agree with what David says. So absolutely right on the point. Everything he said is so pertinent for our patients. In addition, I have realized that primary care doctors are one of the most hardworking people we see around. And many times, they may not have sufficient time to focus on preventive cardiovascular health issues of my patients. And like every other big cancer center like yours, Alicia and David, we also have exercise programs. So we are very proactive about referring patients to our exercise programs within the cancer center. And we do have a cardio-oncology clinic.
So if I have patients, in this patient, in this case, it was a 64-year-old man. But many of my patients are older and they have subclinical heart disease, which may become really obvious after they have started with androgen-deprivation therapy. So keeping in mind, we are quite proactive about making sure that patients are not developing any new cardiovascular symptoms, and I have a low threshold to send these patients to cardio-oncology clinic if they are developing cardiovascular symptoms like exertional shortness of breath and so on, if they develop these after starting ADT.
Dr. Morgans: Wonderful. Great advice and thank you for that. Any parting thoughts, Dr. VanderWeele?
Dr. VanderWeele: One more factor on the cancer side of things would be consideration of germline testing. I think the patient had grade goup 4 prostate cancer, and that would be indication for germline testing if it hasn't been done already at the time of diagnosis. And depending on the results of that, especially BRCA2 mutations, we tend to think of as both predictive and prognostic. And so that might push me a little bit more towards the aggressive side of treatment rather than a more relaxed approach to the patient. So that would probably be the other piece that I would add that we hadn't touched on yet.
Dr. Morgans: Fantastic. Well, I so appreciate both of you talking this through. Just to address some key clinical takeaways, timing of treatment in the setting of biochemical recurrence can be challenging. There is no standard of care here. So think about things like PSA doubling time, patient preferences and clinical factors, Gleason score, times in surgery, and of course, genetic testing, as Dr. VanderWeele mentioned, to make a shared decision with patients.
Addressing comorbidities including metabolic syndrome through attention and management of reversible cardiovascular risk factors can reduce cardiovascular risk for patients starting ADT. And ADT is associated with reduced insulin sensitivity, increased cholesterol, loss of lean muscle mass, and increased abdominal adiposity, and these need to be things that we're aware of and managing with our patients. Ongoing management of other non-cardiovascular effects can reduce patient burden during treatment of ADT too.
This brings us to the end of the case. Please see the other segments for further discussion about the latest data in prostate cancer, or visit ascopost.com.
