David Morris: Thank you.
Brian F. Chapin: Thank you for having us.
Neeraj Agarwal: As we know, a substantial number of patients with even advanced prostate cancer are treated by urologists out there. They are the backbone of treatment of even advanced prostate cancer. So I'd love to have your viewpoint on treatment of metastatic hormone-sensitive prostate cancer today.
We know ADT plus ARPI are the standard of care therapy. So we'll come to the triplet therapy in a moment and we will be talking about how do you assess response in your clinics and do you take treatment breaks anytime in your patients, especially who are doing well? So let's start with Brian first. I'll start with the role of definitive therapy for a moment in patients with metastatic hormone-sensitive prostate cancer. So I see this patient, a young patient, locally advanced lymph nodes are resectable, what should I do? Should I send to surgeon? Radiation? Both?
Brian F. Chapin: I think there's a bit of controversy about the roles particularly currently in the setting of PSMA-PET positive imaging in the absence of conventional imaging findings. So patients who are clinically node positive by conventional imaging, I think historically and traditionally have been treated by radiation oncologists and medical oncology with systemic therapy. With the findings of PET positive disease in the nodes now I think that there's been a little bit of a shift in mentality as how we're going to approach those, and are we going to approach those as if they are presumed localized in the absence of mets or if we're going to shift to the mentality that now they're actually clinically node positive.
In my practice, I tend to shift towards the clinically node positive group because I feel that those patients are likely going to have more disease than what's identified on the imaging at the time of pathology. And if they have multiple nodes, they often usually will go on to radiation therapy as well anyway. And so if that's the plan, I'd rather not have the added toxicity of having surgery followed by radiation and we'd rather start off with the systemic therapy and radiation approach.
Neeraj Agarwal: But how about those patients, prostate seems to be confined to prostate clinically, and there are a few lymph nodes which are lighting up on the PSMA-PET scan, but they're not really enlarged on the CT scans?
Brian F. Chapin: The specificity is pretty high. Chances are they're going to be pathologically positive. We generally see more pathologically positive than what we do see on the imaging. So if one or two nodes show up, usually that's equivalent to three or more nodes on final pathology. And that population I don't think benefit from an operative approach as the initial therapy.
Neeraj Agarwal: Moving to the metastatic hormone-sensitive prostate cancer, having addressed briefly the locally advanced prostate cancer. High volume, low volume, do you use PSMA-PET scan or conventional scan to determine volume status? David?
David Morris: From a urology perspective, I think PSMA-PET has unfortunately jumped and leapfrogged a lot of our conventional imaging data, and that was largely what we used to determine risk groups by volume status has been based on conventional imaging data. But in the modern era, patients with a biopsy that's high risk, almost a hundred percent of them are getting PSMA-PET as part of their staging workup and skipping the standard CT and bone scan. So we are kind of faced now with this whole host of patients who have metastatic disease with unknown conventional imaging status because we often have not obtained it.
And just Brian mentioned, some of those are still surgical candidates potentially or borderline if it's low volume, and we do a lot of multidisciplinary approach with radiation oncology in the community. And I think the simple answer from a community urology perspective is all those patients need intensified therapy and the era that we have now, ADT plus ARPI should be the standard in all of those patients and it's really what other things are you bolting onto that kind of platform of therapy, whether it's radiation, whether it's surgery to de-bulk and hopefully cure, but then maybe even need adjuvant radiation afterwards.
And then the high volume is we just get more intense because then we're talking about, as you mentioned, triplet and we're going to bolt potentially chemotherapy onto this idea of ADT plus ARPI.
Neeraj Agarwal: So newly diagnosed metastatic hormone-sensitive prostate cancer, prostate should be dealt with either with radiation or surgery. That's a separate question, but for the hormone sensitive, the metastatic part, ADT plus ARPI for most of the patients, if you will. Brian, how often these patients are followed or should be followed?
Brian F. Chapin: Yeah, so just to touch on for a moment, we do often get bone scan imaging actually just to have a better understanding of volume within our practice. Some of that might be academic purely, but we still don't really know how to interpret those PET scans sometimes when there's the inconsistencies with conventional imaging. And so what we really want to understand the volume status of the individual and then figure out how we're going to intensify that therapy.
Neeraj Agarwal: I'll second that. So we also do CT scan, bone scan for everyone for one more reason. It is so difficult to get PSMA-PET scan reimburse for imaging for multiple times during the treatment course of metastatic hormone-sensitive prostate cancer. So we do CT and bone scan for every patient regardless of how they were diagnosed to have metastatic disease so that we have a baseline for subsequent CT and bone scans. So I was asking you, beyond treating the prostate, it seems to backed by evidence, solid evidence, how do you follow them over time? As PSA only scans, both PSMA-PET scans came up, what is your practice?
Brian F. Chapin: So we've also had problems with the PSMA reimbursement, particularly in the setting of a responding patient by PSA alone. The denial rates go up dramatically if you're trying to get PET scans and unfortunately sometimes they're done and then denied on the backend. So we don't use sequential PET scanning outside of a clinical trial, we do do follow up CT and bone scan imaging, and generally on about a three-month basis, those patients are being evaluated and seen both by labs. And imaging just depends on the response, sometimes it's three months, sometimes it's six months. Obviously a lot of clinical nuance to that.
Neeraj Agarwal: Any different style or?
David Morris: I think it's very similar. We start therapy and then typically it's a PSA tracking, it's two three-month intervals until you're comfortable with how they tolerate the medication. Imaging, I usually obtain a nadir image at some point when the PSA has had its "best response," And then can compare that. And we do often have CT and bone scan obtained after PSMA-PET, but by that point they've already technically been labeled and often have started medication before we even have some sort of volume metrics based on conventional.
But we will repeat conventional anytime the PSA is rising and then roughly every year, even if the PSA is not rising, just for the small isolated less than five to 10% chance that you could have imaging progression but no real PSA change.
Neeraj Agarwal: Yeah, I agree with you. This question comes up so often, how often to repeat imaging in these patients? And I'll be honest with you, in my practice also, I don't repeat CT and bone scans every three months, especially when the PSA is responding beautifully. I do want to catch them when they have nadir PSA because at that point of time when we do the CT and bone scan, any rise in the PSA will pick up any growth in the imaging. So I think the point you made of doing imaging during nadir PSA is so important. Now once you get a PSA nadir of 0.2 or less, what is your opinion about the survival of these patients who achieve these very low PSA on ADT plus ARPI?
David Morris: So a bunch of interest from the registrational trials on PSA cutoffs and almost every single one of them, the lower your PSA got, the better difference, the better benefit, the hazard ratio was a different spread. And so we look for undetectable PSAs by the ultrasensitive or PSAs less than 0.2. And I use that for patient counseling just really to tell them, congratulations, you're on the best arm of that trial, you're going to have the longest duration before PFS potentially and you're going to have an OS benefit.
And then unfortunately in this conference we were kind of debating that group of patients to say, when is it appropriate to consider ceasing therapy? Is it ever appropriate to cease therapy? And I was tasked to say, no, we should stay on therapy because that's how every trial was run. But I think patients are very interested in saying, I've been at a PSA of zero for two years now, do I have to keep taking this medication? And we need some data I think to try to be able to answer that.
Neeraj Agarwal: And frankly, this is a question which keeps coming up with every therapy with lutetium, for example. If the PSMA uptake is zero after two doses of lutetium, should you continue lutetium? Is it going to help? Same for immune therapy. We never give immune therapy for indefinite duration. We take a break after one or two years depending upon the type of response.
I think this is a very potent systemic therapy question. I'm so glad we are talking about this, but if you have to take a break, let me rephrase the question, if you are going to take a break, where do you feel comfortable? Six month time point, 18 to 24 months after starting ADT plus ARPI, or would you like to observe the patient on ADT plus ARPI for a little longer?
David Morris: I feel pretty comfortable in the 18 to 24 month, especially for the lower volume disease. Higher volume, a little more concern, but there's a concern obviously if you keep them on for much longer, they don't really recover much of their testosterone therapy anyway. So if your intent is in kind of intermittent approach, I think the shorter makes sense from a science standpoint, but you do need enough to get that deeper response.
Neeraj Agarwal: Thank you. So Brian, if your patient is desiring a break, really wants to take a break and you are going to take a break, it's not a matter of whether you are taking break for everyone or no one. Say if a given patient, you are going to take a break, what is the time point in your view, in your experience, that you can start the break?
Brian F. Chapin: Sure. I mean it's a fairly nuanced conversation. I think it matters if they're synchronous mets or metachronous mets. So if they're a de novo patient, low volume, are they de novo high volume? Had they had prior therapy and now they have new metastatic disease? What was the starting PSA? I mean there's a lot of factors that go into that conversation and decision. I mean I think we know, and we've already mentioned, that PSA is one of the strongest prognostic indicators of how a patient's going to do. So if you're hitting that target of less than 0.2, you're likely to have the patient who's going to be responding well and doing well in the long term.
The challenge is that that doesn't always correlate directly with volume and it doesn't always correlate directly with the starting point of when they were diagnosed. So if they hit a 0.2, and that occurs usually generally in the first six months is when we see the majority of those nadirs, although we can see additional nadiring beyond the six-month time point, I actually am okay with stopping it a little bit earlier. And part of that is because of the issues that come up with patients that are on it for two or three years, a percentage of those patients are never going to recover their T anyway. So we have a variable practice within our institution, I can tell you for sure, but many providers will actually do nine to 12 months and then make a decision about stopping.
David Morris: I think it's great you bring up the nine months. So we use nine months a lot with EMBARK sort of high-risk BCR patients. And so that metachronous lower volume, they're often PSMA-PET avid, but not a whole lot on conventional imaging. And so that lower volume of disease burden, there's a trial that used nine months and people stayed off for almost two years. And so that's the point, I use that as the low end of the potential stop point. And then it's shocking sometimes the number of patients who want to continue therapy because it's working. But that's the earliest, I think I would probably just because of the EMBARK data.
Neeraj Agarwal: Based on the evidence, I'm not going to push taking a intermittent therapy or a treatment break in any situation when patient is not asking for it. I think this is all starting with the patient's desire because of the side effects. Regarding the testosterone recovery, I have similar treatment paradigm as far as treatment break is concerned, nine to 12 months or six to 12 months because testosterone doesn't recover after that. So even we are taking the break, we are just taking the break from the injection, not from castration.
Coming back to Relugolix, which I personally find very helpful from the perspective of intermittent therapy or treatment break. So if I suspect patient is going to have a lot of side effects, for younger men who may want treatment break down the line, I tend to start them with Relugolix, one of the ARPIs because that's a overall pill. Degarelix can be used, but monthly injection is not that desired by the patients. What is your experience with Relugolix with ARPIs?
David Morris: We have a lot of experience with Relugolix primarily in the localized therapy setting with radiotherapy, defined periods of time, want to get T recovery because those are curative intent. We think they're cured. But I do use it in the metastatic situation like you've discussed, where you're almost bringing it up as this may give us an opportunity to have an intermittent period or a holiday and actually have you recover during the holiday as opposed to the long duration depo injections.
Brian F. Chapin: If you're going to do that, would you consider continuing it longer than you would if you were doing injectable therapy because of the lag time of recovery?
David Morris: So that's actually been brought up and discussed that there was, the transport analysis looked at kind of optimal duration of ADT dosing and the dose that you give is not necessarily the dose that they received. And so I do bring it up to them that if two or three years of depo injections was the benefit to get high-risk radiotherapy patients their survival benefit, do we really get that if I only use 18 months of an oral, that then washes out sooner? And the answer is, I don't know. But those patients are often so interested in their quality of life that they're willing to trade minuscule unmeasured benefit for the fact that they will feel better for the next 18 months.
Brian F. Chapin: Yeah, I will say I use it quite a bit in patients in the high-risk localized setting when they're fearful of going on to radiation and having to be on hormones for 18 to 24 months. And I talk to them about the ability to try it and see how it goes and if they're really unhappy with their side effect profile, they can come off it more quickly and then we can make adjustments based on that.
Neeraj Agarwal: So many other aspects where relugolix is applicable.
Well, it has been a pleasure getting your insights on how to treat metastatic hormone-sensitive prostate cancer, and thank you for sharing that and thank you for being here.
Brian F. Chapin: Thank you.
David Morris: Thank you, Neeraj.