Case-Based Discussions Illuminate the Complexities of Oligometastatic Prostate Cancer Treatment - Phuoc Tran

June 21, 2021

Alicia Morgans and Phuoc Tran explore the intricacies of treating oligometastatic prostate cancer, focusing on high-risk patients identified through advanced PSMA-based imaging. Originating from ASCO 2021 case-based discussions, they emphasize the need to reconcile modern imaging data with historical treatment evidence. Dr. Tran notes that these high-risk patients may benefit from hormone therapy alongside radiation, while both clinicians mention the potential efficacy of systemic therapies like androgen receptor signaling inhibitors, though definitive data is still pending. The conversation explores limited evidence on metastasis-directed therapy (MDT), cautioning against sole reliance on advanced imaging for treatment decisions. They also delve into varying patient scenarios with rising PSA levels, discussing therapeutic approaches like salvage radiation. The dialogue concludes without a definite stance on MDT but underlines the urgent need for more comprehensive data to guide treatment decisions.


Phuoc T. Tran, MD, PhD, Associate Professor of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today, a good friend and colleague, Dr. Phuoc Tran, who is a Professor of Radiation Oncology at Johns Hopkins University in Baltimore. Thank you so much for being here with me today, Phuoc.

Phuoc Tran: My pleasure.

Alicia Morgans: Wonderful. So I wanted to speak with you a little bit about some case-based discussions that you had at ASCO 2021, to really help everyone think through how we can best treat patients who develop oligometastatic disease in various settings. So thank you for taking the time today. Let's start first by thinking about a patient who has high-risk localized disease at baseline, at diagnosis,  conventional imaging, which we will define for the purposes of this conversation as a bone scan and either a CT scan or an MRI, they were negative for evidence of metastatic disease, but of course, the patient is high-risk by Gleason score and by PSA. A PSMA PET, PyL PSMA, is actually positive for one area of lymph node metastasis in the retroperitoneum as well as, let's say, an L1 area of metastatic disease, or areas that are concerning for metastatic disease because we are not able to easily biopsy these successfully.

So in this setting, which of course is an untreated setting, what are your thoughts about treatment for the oligometastatic disease? How do you approach it? How do you think through it?

Phuoc Tran: This was actually a very similar case to one that was presented during our educational session of what's known as de novo or synchronous oligometastatic, or low-volume castration-sensitive prostate cancer. Oligometastatic or low-volume is based on, as you were saying, new functional imaging or DCFPyL PSMA-based imaging.  The participants in this educational session were me, and I was very fortunate to be a part of a great cast, including our moderator, Dr. Howard Sandler, Dr. Nick James, of obviously STAMPEDE fame, and Dr. Robert Given, who was one of our urologist participants.

So Dr. James brought up an excellent point, which is that just because we have this new fancy imaging, we shouldn't throw away all this, basically a treasure trove of prior data that we have in this space. So as you mentioned, this patient is essentially on conventional imaging, just a high-risk, for all intents and purposes, localized prostate cancer patient, perhaps locally advanced. We have level 1 evidence via NCI and also UK studies, Ward et al., and Widmark et al., showing that in patients who have high-risk or locally advanced prostate cancer, radiation does add on a significant benefit onto hormone therapy.

We have alternative trials asking and answering the same question, what is the benefit of hormones on to radiation? Bull et al., RTOG, or now NRG, studies showing that, again, adding on hormones onto radiation in a high-risk, potentially, in this case, a patient who has metastatic disease, but not seen on conventional imaging, those patients can do quite well. They are benefited tremendously by the addition of both therapies and just because we now see on PSMA imaging that this patient may have metastatic disease, we should not consider them non-curable because many of the patients on those trials, previous phase III trials that I mentioned, were cured.

So again, not to throw away old, but very useful data, I would continue to treat that patient as though he were high-risk or locally advanced. Now, we have, thanks to Dr. James and his colleagues in the STAMPEDE with their RMA trial, data that with conventional imaging, if you see a patient who has low-volume or oligometastatic de novo or synchronous castration-sensitive prostate cancer, that treatment to the primary prostate, which was the randomization to their arm A of STAMPEDE, improved overall survival by 8% at three years. So I see this patient as, essentially, very much fitting into the older data with M0, but we know based on the molecular imaging that he has at least PSMA positive disease, and just remarking that the specificity of PSMA, particularly DCFPyL, is very high. So it's likely that those sites of disease do represent metastatic prostate cancer, but you are right, those areas are traditionally very difficult to biopsy.

Alicia Morgans: So in that setting, agreed, and I appreciate your comment that absolutely, treatment of the primary tumor is indicated in this setting. What are your thoughts about SBRT to the L1 lesion, for example, and what would you do with systemic therapy?

Phuoc Tran: Of course. So taking a step back and thinking about the presentations, which is what we covered during the educational session of oligometastatic prostate cancer, we started out with the case very much like the one we just spoke about, which is de novo or synchronous castration-sensitive prostate cancer. Then another very common, the most common, presentation really of oligometastatic prostate cancer is known as metachronous or oligorecurrent. So you have a patient who is castration-sensitive prostate cancer, they have been previously treated for their formerly localized, or at least potentially curable, disease with radical prostatectomy or radiation alone plus or minus hormone therapy, and then they undergo biochemical recurrence and then recur on conventional imaging or in this case, soon to be functional imaging, new functional PET imaging, and that would be classified as a metachronous or oligorecurrent patient. So that's the second, presentation and it's the most common, really.

And then the third case that we talked about is oligometastatic or oligoprogressive castration-resistant prostate cancer. So you have a patient who has a number of lesions, more than the three or five you would consider oligometastatic,  and then they are placed on ADT or in this case, typically intensified ADT with one of the new androgen receptor signaling inhibitors. We usually have very good responses either tremendous partial responses, but certainly stability of the majority of the disease, and then after a while, you have small clones of cells become resistant and you start to see what's known as oligoprogression.

So those are the three kinds of major presentations. Going back to that first case of oligometastatic de novo or synchronous, and how we handle the two issues you mentioned, which is systemic therapy and metastasis-directed therapy. The systemic therapy, so again, we don't know quite yet how to handle these patients who are conventional M0, but in this case, an M1a/M1b patient on functional imaging. There are studies coming out that are treating basically high-risk M0 conventional patients with some of these new AR signaling inhibitors and I think those trials will show us some positive data.

Incidentally, STAMPEDE, one of the arms with abiraterone contained a lot of locally advanced patients, so non-conventional metastatic patients, and although the data trended towards better freedom from failure and overall survival, there weren't enough events for it to be definitive. But I think that data are coming. At this time, I would say for this patient who is, on conventional imaging, M0, I think it would be perfectly reasonable because that is where the bulk of the data is, to have just normal androgen suppression therapy. But, based on STAMPEDE, you could argue that adding abiraterone/prednisone would not be unreasonable. In the United States, and myself, in particular, I have on occasion had patients who were eligible for that at least per their insurance and so we've allowed them to do that. And like I said, there are a number of trials that are going to be coming out. ENZARAD is one, we have a few in the NRG that are looking at these advanced androgen receptor inhibitors in this setting.

Alicia Morgans: And what about metastasis-directed therapy?

Phuoc Tran: Sure, and then metastasis-directed therapy. So an excellent point that actually Dr. James made at the very beginning of the educational session is that we are in a space where there is a paucity of prospective evidence. We have, of course, some prospective trials looking at metastasis-directed therapy, but they are essentially all in that second grouping of patients, the oligorecurrent and metachronous. We have really very few to no prospective data either in de novo or oligoprogressive CRPC. So we really don't know what to do based on prospective evidence. We have some early phase trials, so really early kind of registry trial data from a few institutions.  We have some retrospective data that suggests that MDT in the de novo or synchronous setting may be beneficial. There are a number of trials that are accruing or under development right now that are trying to answer that question. So I would say, there really isn't a lot of evidence to support that at this point. I mean, obviously, it makes sense, but we have to be careful about, obviously, appropriating evidence from different spaces into this setting.

Alicia Morgans: All right. So no hard yes, or hard no on metastasis-directed therapy in this setting. I can guarantee that there are a number of approaches that are made, some people continuing to monitor them, and others, I'm certain of it, radiating those areas, but there is no evidence to really push us in one direction or the other until we have some more data.

So let's move on to sort of the next case scenario. You mentioned this scenario that's oligoprogressive, where we have a patient who has had, say a prostatectomy in the past, a bit of a rising PSA, and this patient has a PyL PSMA PET scan that is performed that demonstrates say, let's go back to L1 lesion, so an L1 lesion demonstrating something is present there. Now, this patient has not had pelvic radiation and does have a rising PSA, let's say it's approximately 0.5, what is your thought about salvage therapy in this setting? Would you radiate the pelvis? What do you think about systemic therapy and what about metastasis-directed therapy in this patient?

Phuoc Tran: Yeah, so that was that second grouping, that oligorecurrent or metachronous castration-sensitive prostate cancer patient space, which is by far the largest number of patients because, as you know very well, most of the patients present with localized or seemingly localized disease. We treat them as though they're curable, but unfortunately many of them recur and then pass through this biochemically recurrent state. And there are a number of data sets, including some that are prospective, a TROG trial that I'm thinking of, in particular, the data set from Hopkins natural history data set as well, suggesting that when patients become biochemically recurrent and then ultimately pass over into a metastatic setting based on conventional imaging, they often have five or fewer metastases, classifying them as low-volume or oligometastatic disease, and it's about two-thirds of those patients. So the vast majority of those patients actually will end up having, when they are diagnosed, ultimately, with metastatic disease, will have oligometastatic disease.

The prospective data in that setting is really three trials. So two that are prostate cancer-specific to this ... three now, actually. So two randomized, one single-arm, and then another, histology agnostic, so four trials. The two that were randomized are the STOMP trial from Piet Ost, the Belgian trial, and then our Baltimore ORIOLE trial were the two randomized trials that took a patient like this, or very similar to this, and randomized them to essentially short observation or metastasis-directed therapy. There was a trial out of PMH, which was a single-arm trial using DCFPyL PSMA PET/CT to diagnose these patients and then treated them single-arm fashion with SABR MDT, as well as a few had lymph node dissections. The fourth trial, which is the histology agnostic trial, the very famous SABR-COMET trial, which included a ton of different histologies, lung cancer, breast cancer, and about a quarter or a third of prostate cancer, they were all oligorecurrent, such as this patient here.

All the trials, all the randomized trials, were essentially positive trials either for, in the case of STOMP and ORIOLE, for essentially a progression-free survival type of endpoint. Obviously, the PMH trial was a single-arm trial. They showed a very favorable PFS advantage. The SABR-COMET trial, histology agnostic, so hard to say, but positive for overall survival advantage both at the first reporting and then more advanced five-year data. So I would say there is perhaps not level 1 evidence for MDT in this space, but there is certainly plenty of prospective or randomized phase II evidence.

Going back to the question of what to do about a patient who has not failed radical prostatectomy, rising PSA, found to have an L1 bone met, not had salvage postoperative pelvic radiation, I would, in general, go back to the pathologic factors and so if they had, for instance, pathologic T2 or fully contained disease with negative margins, I would tend to not favor salvage radiation in that context or post-operative radiation in that context but I don't think it would be unreasonable. My general tendency and this has yet to be proven with prospective data, is to fully consolidate patients. So if we are going to try to go for something that is potentially curative, I would like to consolidate the pelvis as well as go after that L1 met, but it's an area of, again, where there is really not a lot of data. But based on, again, trials in the past, this patient was PSMA positive only, and so what would we have done in the past? We know there's pretty good data that there is an advantage, a survival advantage, to giving post-operative radiation in patients like this.

So I don't think we should throw away that data altogether and that was another point that was made in this educational session, is that because, as you know very well, DCFPyL was FDA approved a number of days ago, and we're going to see a ton more of cases like this. So we need to do a better job. Our point was, we need to do a better job of trying to incorporate these advanced imaging techniques into our current trials to allow some kind of ability to learn from past trials, without ignoring the enhanced sensitivity and specificity of these new imaging agents.

Alicia Morgans: Absolutely, we need a crosswalk, essentially. A way to sort of bridge from the old to the new, and I appreciate that because it will not be uncommon that we don't see something in the pelvis, but our data says that we should radiate the pelvis. We're already seeing that in our clinics. I'm sure you are. And I, like you, tend to favor consolidating, relying on that old data and then saying, you know what, I'm also going to go after what I can see, because I think the morbidity is low, and as you said, there is some evidence that, that may be helpful to these patients.

So thank you for talking that through and being so detailed and really helping us understand and sort of think through that data. So final setting, before we let you off the hook, is to think about a patient who now has had a recurrence after a primary prostatectomy. This patient has had radiation to the pelvis, has also been on androgen deprivation therapy for biochemical recurrence after that, with a PSA that reached, say, a six, and had a PSA doubling time of about six months at the time when his, let's say medical oncologist, we'll put them on the hook, started androgen deprivation therapy, PSA fell, now rising again on androgen deprivation therapy, PSA doubling time, less than 10 months. We repeat bone scan and CT scan, and we do not have evidence of metastatic disease, we did not at the time of initiation of ADT either. And this patient undergoes a DCFPyL PSMA PET and has one lesion, again, we'll put it back in L1, because this patient has not had one there before.

So now we have a standard bone scan and CTs that are negative, we have a PSA doubling time that is less than or equal to 10 months, and we have a patient with a rising PSA, and one L1 lesion on this functional imaging, this PET imaging. What are your thoughts?

Phuoc Tran: Yes, again, many have suspected that the non-metastatic CRPC space is actually a virtual one. That there obviously is a systemic disease and whether it be micrometastatic or in this case, subclinical, only to be detected on something like a DCFPyL, I think many people thought that that was going to be the case. And again, not wanting to throw out all this wealth of data, we do have these phase III randomized trials now, showing the benefit of these more advanced androgen receptor signaling inhibitors in this non-metastatic CRPC space. So I do, I think it's very reasonable to start one of those therapies.

Again, we really only have prospective data on MDT in that oligorecurrent castration-sensitive space. There is a number, and it was during our educational session, we pointed out a number of retrospective studies, but that is obviously the very lower level of evidence. There are a number of phase II randomized and even one phase II/III trial that is looking at the potential benefit of MDT in patients who are oligoprogressive CRPC, but those await full accrual and reporting. We have certainly done it ourselves at Hopkins, sometimes on certain clinical trials. I think it can be reasonable in some settings, but I wouldn't, again, disregard the level 1 evidence because this patient is essentially non-metastatic CRPC, but have some discussion, a balanced discussion, about the potential benefits with all the caveats I mentioned of MDT in a patient like this.

Alicia Morgans: Thank you for pointing that out. I think that we saw, I believe it was the Fendler paper that demonstrated, that about 98% of patients who technically meet the criteria for non-metastatic CRPC will have some evidence of measurable metastatic deposit on one of these functional PSMA PET scans. So it's not actually unusual, in fact, it is usual to see metastatic deposits by these functional PSMA imaging techniques in patients who meet the criteria for non-metastatic CRPC. And I do think it's important, as you mentioned, to ensure that our patients have access to those therapies, or at least hear about them, those therapies that we know prolonged, not only metastasis-free survival and improve quality of life, but also demonstrate an improvement in overall survival.

So thank you for pointing that out, and again, the data are still outstanding. We have to learn still whether or not metastasis-directed therapy in this population will further bend the curve and help patients live even longer and have further disease control. Something that we are still assessing and I look forward to talking to you about in the future, as we learn some of the answers to these questions we've raised today. So thank you so much for taking the time to walk through these patient cases. Of course, thank you for your presentation at ASCO 2021, and for your ever-evident expertise in this area. Of course, as you push the envelope and continue your clinical trials, we always appreciate talking to you, Dr. Tran.

Phuoc Tran: My pleasure. Thank you very much.

Alicia Morgans: Thank you.