Dr. Alicia Morgans:
Hi, and welcome to the ASCO Post Series on Targeted Approaches to Metastatic Hormone-Sensitive Prostate Cancer. My name is Dr. Alicia Morgans, and I'm a GU medical oncologist at Dana-Farber Cancer Institute in Boston.
Joining me today are two of my colleagues, and I will give them a minute to introduce themselves. Why don't we start with you, Dr. Ryan?
Dr. Chuck Ryan:
Hi, I am Chuck Ryan. I'm a GU medical oncologist, and I practice at Memorial Sloan Kettering Cancer Center in New York City.
Dr. Alicia Morgans:
Great. And Dr. VanderWeele?
Dr. David VanderWeele:
Hi, David VanderWeele, also a GU medical oncologist, and I'm at Northwestern University in Chicago.
Dr. Alicia Morgans:
Well, thank you both for being here with me today. Today we're going to be discussing the treatment and management of metastatic hormone-sensitive prostate cancer with three-patient case studies. Our final installment, we'll focus on recurrent low-volume metastatic hormone-sensitive prostate cancer, and we will dive right in.
So in this case, Mr. FH is a 62-year-old gentleman with a history of localized prostate cancer treated with radical prostatectomy 3 years ago. This was a Gleason 4 + 5 grade group 5 prostate adenocarcinoma with a PSA of 13.4 at the time of diagnosis. He did go through prostatectomy, and pathology demonstrated PT3 BN0 M0 disease with a positive right apical margin. And although his PSA was initially undetectable, it did start to increase about 6 months later. And PSA at the point of your sort of being brought into the fold was 0.7.
So he does have a family history that includes his father having a heart attack at 50. And the patient's comorbidities include the components of the metabolic syndrome, including borderline diabetes, or a pre-diabetes state. Blood pressure that ranges between 135 and 150 over 80 to 90, and a BMI of 28 with a waist circumference of 41 inches. So, he's got metabolic syndrome.
So, this patient undergoes bone scan and CT chest, abdomen, pelvis, that's equivocal with possible small pelvic lesion that appears sporadic on the CT scan, but then has a PSMA PET that shows several lymph node metastasis in the pelvis, retroperitoneal area and pelvis, and small pelvic lesion in an area of abnormality on the bone scan. So that's concordant.
All right. So you're thinking about this patient. He has some medical comorbidities, and metabolic syndrome is part of that list. He has what looks like low-volume, metastatic hormone sensitive disease, but this is recurrent after prior treatment. So, what are we thinking about doing next? Obviously, we have options like systemic therapy, radiation, we could do some additional testing. Dr. Ryan, what do you think we should do with this patient?
Dr. Chuck Ryan:
Well, there's a couple of key pieces of data here. One is that he has a PSMA PET scan that's positive, but I think we would agree he has relatively low-volume metastatic disease. You accurately point out that he has metabolic syndrome. So, as we're weighing treatment options, we have to think about the cost of the hormone therapy that we might put into this patient at this time in terms of worsening metabolic syndrome. And yet you have an opportunity in a patient like this where we might be able to do metastasis-directed therapy, which might be able to delay the need for androgen deprivation therapy, or it might allow you to shorten the duration of androgen deprivation therapy if you do use it. So, as I'm thinking about a case like this, I'm thinking about both focal disease and ablative therapy, but I'm also thinking about systemic disease and potential systemic therapy. And I think that's the key sort of mindset to get us into. This might be a case where we can do one, or the other, or both.
Dr. Alicia Morgans:
Yeah, I agree. This is definitely kind of a compilation of a lot of different studies, I think kind of thinking about all of them coming together to try to have the best possible outcome for this patient. But it is a little bit on the cusp of where data ends.
Dr. VanderWeele, what are you thinking about? Now, this patient had a prostatectomy, has a recurrence, hasn't necessarily had pelvic radiation yet, has these other areas of oligometastatic recurrence. What are you thinking about, especially since Dr. Ryan's saying maybe sort of this mix of different approaches?
Dr. David VanderWeele:
Yeah. He talked about the systemic therapy and the targeted therapy. I guess I also second that this is a big gray area, and I talk about this all the time with trainees who are in clinic with me. And so I guess I also think about it, what do I see on conventional imaging, and what does our data tell us from trials that have been completed and reported? And then what do I know from the PET imaging, and how am I going to incorporate that into my thinking about his cancer?
So, by conventional imaging, there's some suspicious things on the CT and bone scan, but largely negative. He has biochemical recurrence with a PSA of 0.7. Obviously, pretty high risk disease at the time of prostatectomy, although we are a few years out. So, I think it's at least a discussion about salvage. I would probably have a discussion with him about salvage radiation.
So, I think there was one area that was concerning the bone on PET imaging. I also would very much favor targeting that area with radiation. And then I think also had some concerning retroperitoneal lymph nodes. So that's a bit outside of the radiated region, or the area that we're thinking about for salvage radiation. So, I might have a closer look at that with the radiation oncologists and have a discussion about what's the likelihood of toxicity if we were to try to radiate those areas, or should we instead think about a more aggressive systemic therapy approach.
So, there's a lot of gray areas both in terms of, especially on the systemic therapy side of things, I think, in terms of how intensive to be, and how long the duration should be. Yes, he has metastatic disease on PET imaging, but I probably would think of this more as sort of a biochemical recurrence kind of scenario with salvage radiation, a defined period of systemic therapy, and radiation, and then stopping systemic therapy. Clearly, high risk for that not being the end of the road, but that's probably the mind frame that I would go into it with.
Dr. Chuck Ryan:
Can I make a quick point? He had a radical prostatectomy 3 years ago. And we don't know if he had a PSMA PET at the time before the radical prostatectomy. So we're assuming that he's got oligorecurrent disease, or metachronous disease, and he might not. He might've had asynchronous metastatic disease back then, was either not imaged, or had incomplete or old imaging that didn't demonstrate this. So, to your point, David, let's give this patient the benefit of the doubt that he may have relatively slow moving disease that is not particularly aggressive. And we want to make sure that we don't overtreat this situation, or that we nuance the treatment around the nuance of the extent of disease.
Dr. Alicia Morgans:
Yeah, I would completely agree with that comment, certainly. And with the approach to treatment, I commonly do just what David does, and I think it's a good way to kind of put that data into context. What are you sure of in terms of conventional imaging, what studies inform that in that decision-making, and what does the PET now add on top? And the reason that I think we all have to strategize in that way, for now at least, is because all of our data comes from conventional imaging, or the most part it comes from conventional imaging from studies that started years ago, and now we're trying to layer on the PET information on top. So I would agree with that. And I think there was some information presented at ASCO also, which suggested we don't want to just target what we can see on the PET. We do want to get complete pelvic salvage therapy as per traditional salvage pelvic radiation, because we will have a longer time to any cancer recurrence, which is of course our hope for this patient.
Now, when it comes to systemic therapy, we're certainly going to think about the type, the duration, and we could definitely kind of go down some pathways around what we want to do, but I think it's also important for us to remember the comorbidities. And we'll kind of get into that, and how our choices affect those risk factors for the patient. But let's start with the type of systemic therapy. Are you doing single ADT? Are you doing an ARPI? And approximately how long would you want to go for this particular patient? Dr. Ryan, I'm going to give you the first pass at this one.
Dr. Chuck Ryan:
Yeah. So, we move pretty quickly into another data-free zone here where, first of all, it's important to remember, all of the studies that we follow in hormone-sensitive disease, whether it's CHAARTED, or LATITUDE, or ARCHES, or any of these studies, they treated patients with continuous ARPI and androgen deprivation therapy. There was really not a position where patients were, on a routine basis, had their therapy stopped. So, that's where we get into a little bit of a data-free zone here.
With regards to this particular case, if I'm using a focal therapy, metastasis-directed therapy, if he's going to get radiation, I might shorten my duration of hormone therapy. In some cases I'll use ADT monotherapy for 6 months time with a brief course of metastasis-directed therapy. And there are some studies in which that has been done. They are continuing to mature, but they demonstrate that there may be some benefit to that, some sort of synergy to those two approaches. So again, a lot of those things being taken into consideration. Younger person, I think this is, and has the metabolic issues to worry about. So, it kind of depends on the situation, because sometimes with younger people you want to be a little more aggressive seeing if you can get more ablation, a better time off therapy with more aggressive therapies. I have even given chemotherapy to young healthy individuals who have relatively low-volume disease, but rapidly recurrent, and with high genomic markers. So again, a lot of nuance there.
Alicia Morgans:
Absolutely. And David, what are you thinking about in terms of choice of systemic therapy duration? What do you think?
Dr. David VanderWeele:
Well, first I'll pick up on something that Chuck just mentioned about the genomic markers. So if it hasn't been done already, I would get genetic testing, somatic and germline. And again, that kind of helps me think about the disease, and sort of the level of risk associated with the disease.
So, the Medicare study was presented recently, which was in, well, there are multiple different arms, but in the B2 and B2 expansion arm was in the oligorecurrent setting, and then patients received either 6 months or 10 months of doublet therapy. And at 24 months most patients still had an undetectable PSA, which was PSA less than 0.1, if I'm remembering the data correctly. And so that might be an approach that I follow. I think you could make an argument for ADT alone, so monotherapy, or doublet therapy. And for either 6 months to 2 years, I think I could make an argument to myself for any of those. And I'm not sure that there's a clear winner. But I think this patient probably would've been eligible for Medicare. And so I probably would follow something along those lines.
I think they have potentially lethal disease, but also potentially curable still, I think. So, I would probably encourage thinking about a doublet therapy for some defined period of time, and I don't know the right duration, but probably, I don't know, in my mind, a year-ish, maybe 6 months. And also, radiate the things that we... So, pelvic standard sort of salvage pelvic radiation, radiating the bone in the pelvis, and then discussion, I think, about the RP nodes, about what added toxicity would come from trying to radiate those. Yeah, that's probably where I'd come down. But the genetic testing may also push me one way or another in terms of how aggressive to be depending on what came back on that.
Dr. Alicia Morgans:
Great.
Dr. Chuck Ryan:
Can I interject another point? Which is, it's really remarkable to me how rapidly our field went from having a study years ago that demonstrated that intermittent hormonal therapy was probably inferior to continuous hormone therapy, to having all of these phase III trials where hormone therapy was continuous, to now us discussing how continuous hormone therapy, lifelong hormone therapy in a case like this would be inappropriate. We've really evolved our thinking over the past decade, which is I think great, because of your work, Dr. Morgan, and others, we know about the toxicity of long-term androgen deprivation therapy. So we're really weighing those options against this in a very serious way, which is really great.
Dr. David VanderWeele:
Yeah. And I think if you're looking just at the PET imaging, saying this patient has metastatic disease, and therefore should be on continuous hormone therapy and is non-curable. But if you're going by the conventional imaging, they would've been eligible for many of our salvage studies that have read out. And nobody, well, at least not in the last couple decades, is planning for continuous hormone therapy. So, how do you put all these things together? Use your clinical judgment.
Dr. Chuck Ryan:
And just one other quick point is, if we did standard imaging and it was negative, and we're left thinking this is a patient with serologic relapse, then we haven't talked yet about enzalutamide monotherapy in particular, or combination therapy. Again, a brief period of time to use those therapies. But those are evidence-backed approaches.
Dr. Alicia Morgans:
Absolutely. So, enzalutamide alone or enzalutamide with leuprolide in the study, but a GnRH analog, was associated with a longer time to metastasis, or longer metastasis-free survival, and a strong trend towards overall survival. Though of course, we need updated data to see that. And that was generally in a population that probably mostly had salvage radiation to the pelvis already. But still, a systemic treatment option and something to inform us.
So, wonderful discussion. Just a quick comment from each of you as we are wrapping up. We talked about how we are moving in a direction of decreasing duration of systemic therapy. We're actually doing this in multiple studies outside of the scope of this conversation, even in hormone-sensitive metastatic disease. So, I think our field wants to get rid of this pharmacologic castration approach, we want to try to limit that when possible. One of those reasons is comorbidities. And just wonder if either of you have advice or guidance on how you monitor a patient who's going through this. David, what are your thoughts? Any suggestions here?
Dr. David VanderWeele:
Yeah, good question. I probably should be doing more. Before starting on systemic therapy, we have discussions that patients with diabetes or borderline diabetes, it may be more difficult to have control of that, talk about cardiac toxicity with these agents. We're certainly paying attention to blood pressure in clinic, and managing that. Although I think you could make a very strong argument about referring a lot of these patients to a cardiologist to help manage and sort of optimize their cardiac risk more than I do in my practice. How much availability do the cardiologists have? This is a large number of patients.
And so I think there's probably some room for us learning a little bit more about cardiology management, especially for those that are lower risk, but also being quicker to involve our cardiology colleagues for patients that are on the higher risk end of things.
So, I think it starts with an upfront discussion that, while fatigue, hot flashes, low libido, are the things that you're going to be feeling, there's added risk going on and other effects to your other underlying health that we need to be paying to. And so that upfront discussion, and then continuing to address those things along the way, either with a team, with your own team in the oncology clinic, or involving others from other fields.
Dr. Alicia Morgans:
Great. Thank you, David. And then Chuck, I know you're very interested in encouraging patients to exercise and have good nutrition. Any comments there as we wrap up?
Dr. Chuck Ryan:
Well, yeah. And before I get into that granular recommendation, I would say that patients feel that they've lost control when they are cancer recurs. And one of the most important things that we can do with our patients is give them agency. Give them areas where they have control over how things go, to some degree. And we also don't want to make them feel like all of their outcomes are under their control or their responsibility. But having said that, I have had innumerable conversations with patients about exercise, and diet, and things that they can do. Things where they have agency that can improve their outcome.
I talk to patients about the Prostate 8, it's an easy thing to remember, you can look this up, it's in Google that you can find me talking about it on videos and whatnot. It's eight lifestyle factors that are demonstrated to be associated with an improvement in survival for people after a diagnosis of prostate cancer. And they are exercise three times per week, don't smoke, avoid processed meats, avoid multiple vitamin supplements, like lots of supplements, not a good outcome associated with that. The things you should do, stewed and cooked tomatoes is a great diet; fatty fish like salmon, and sardines, even and anchovies are all high in omega 3 that may slow down the proliferation of prostate cancer; cruciferous vegetables three times per week, that's kale, broccoli, collard greens, those kinds of things are really good for you. And cooking with olive oil and those types of oils are associated with a better outcome. There is a ninth, which is avoid whole milk.
All of these are published, and these are all things that patients can simply change their lifestyles, not a big revolutionary change in their lifestyle. Some of these are little increments that they can do. If I can only do one recommendation, I tell people to exercise three times per week. I tell people to buy resistance bands, or go to a gym, or get some dumbbells, or even just go for a walk 30 minutes a week if they're total non-exercisers prior to starting.
Dr. Alicia Morgans:
Wonderful. Well, thank you so much for listing all those out. I think those are really practical and relatively low-burden things for patients to do. And I love the reminder that patients do appreciate having some control, especially in the midst of losing it, in the setting of a recurrence.
So, let's wrap up with some key clinical takeaways. Germline and somatic testing remain important parts of the workup of patients with metastatic hormone sensitive prostate cancer, and you've heard that reiterated today, in this case. Imaging with PSMA PET scans can reveal oligometastatic recurrent metastatic hormone-sensitive prostate cancer. Systemic treatment with ADT and ARPI remains really standard in this low-volume setting. The duration, I think is something that we're still trying to figure out. And some patients may also benefit from metastasis-directed therapy as this is currently under investigation.
And recommendations regarding addressing reversible cardiovascular risk factors, either through a cardio-oncology team that's helping with that, recommending your own dietary changes, exercise implementation, are really important survivorship considerations to reduce the risks of competing mortality.
So, this brings us to the end of this case. Please see the other segments for further discussion about the latest research in metastatic hormone-sensitive prostate cancer, or visit ascopost.com.
