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Localized, high-risk prostate cancer with oligometastasis at diagnosis


Jason M. Hafron, MD: Case two is a localized high risk prostate cancer with oligometastatis, I can't even speak, at diagnosis. This case was submitted by David Morris from Nashville. Thank you, David, for this great case. I'll just start with the intro. This was a 64-year-old African American man was diagnosed with Gleason Score 4+3=7, adenocarcinoma of the prostate 13 years ago. The cancer involved two out of 12 cores. Pre-treatment PSA was 5.7. The patient was treated by primary brachytherapy in 2008 by his previous urologist. Adjuvant ADT was not administered at that time. The patient had great serum PSA nadir at less than, um, 0.2 with an incredible response.

And then unfortunately, in 2017 up to November of 2019, as PSA progressed, he had evidence of a biochemical recurrence with a PSA of 6.7. And then he was lost, for a period due to thee COVID pandemic, something that we're all challenged with today. We have a patient that was treated with primary radiation and now has developed a biochemical recurrence. You know, my question to the audience is how would you evaluate this patient radiographically with a VCR? Would you do a CT abdomen, pelvis with technetium bone scan? Whole body MRI? Would you use our newer agent, Ocimum fluciclovine F18 PET scan? Do you have access to a PSMA PET scan? Would you go with that? Or would you go with a traditional FDG PET scan? Chris, I'm going to give it back to you. How would you evaluate this patient with a VCR in your practice in New York?

Christopher Pieczonka, MD: So we do not have PSMA scan to be transparent. It would depend on the insurance. If insurance would let me, typically in my area, if they're Medicare, most of the Medicare's allowed me to go right to an Axumin scan. Um, if not, then I would have to potentially do a CAT scan and the bone scan and then potentially get the Axumin scan. I think though, in this particular case, obviously, until you prove otherwise, you want to make the diagnosis and find out if they're radiation failure for metastatic. I like that Dr. Morris was doing the evaluation here to kind of hone in on where the disease is. I can tell you that all too often, what I see in my referral practice is that this patient would be started on androgen deprivation therapy without trying to find where the underlying, recurrent disease might be.

Jason M. Hafron, MD: So based on your experience, you would ask the primary urologist to hold off until we get the imaging?

Christopher Pieczonka, MD: Yeah, good point. I think absolutely. So I think this patient would be imaged, if possible, ahead of time. Now, to be fully transparent, in our practice, these are still going to probably be at the level of the local urologist and they may not make it into the advanced clinic yet. We are not at the point that we're pulling patients of biochemical relapse into our advanced prostate cancer clinical but we're having conversations about that. But one of the concerns on this would be the patient's PSA is jumping through all my androgen deprivation therapy. Granted, this patient's PSA is pretty high. But what if it was half of what you originally presented? You could put that patient in ADT and then you might have no idea where the recurrence was.

Jason M. Hafron, MD: And that's an important point. And as we get through this case, that's going to be a difference. Dr. Gajra, you're a hematology oncologist. You're also a medical director at Cardinal Health. So you have a good perspective, national perspective, on you know, head imaging across the United States. You know, Chris touched on Aximun but there's so much good data coming out on PSMA. I just would like to hear your comments and where you think we're going with PET Imaging and biochemical recurrence, maybe even later this year. And, highlight what's coming to the United States for imaging.

Ajeet Gajra MD MBBS, FACP: The way I view it is, first of all, a couple of broad trends. We certainly see, uh, in our outreach and in our research here at Cardinal that urologists are, and urology practices are much more, the sort of cutting edge of imaging, than medical oncologists and, and perhaps rightly so. So, the second point I want to make is that Axumin certainly outdid a conventional imaging but it still has low sensitivity, and that's sort of Achilles heel.

At least based on our assessments, it almost seems across US geography that 50% of urologists and even more medical oncologists are not utilizing Axumin either because they don't have easy access to it or it's just sort of not caught up into their work up, if you will. The field is already moving now, as you said through PSMA. We've had remarkable data. So one is certainly being a medical oncologist ASCO's big meeting. The CONDOR study, which is a US-based study presented at ASCO, very well-designed, quite honestly, with FDA input.

We have to realize that PSMA PET, for example, has been approved and, and used in countries like Australia for over three years now. So in that way, we are lagging behind because FDA laid down very stringent guidelines for what they wanted to see in a trial. So the CONDOR trial, which is a US-based study met all of those criteria. And, and I don't know if many of you know or if you're in practices at UCLA or UCSF where the FDA actually approved PSMA based path in December, albeit in a very limited geography. And, you know, certainly we expect later in the year that will become more widespread.

Where Axumin or fluciclovine is in terms of having both high sensitivity and high specificity and earlier on, there's the pro PSMA study, which was published in The Lancet. There was also a novel study, which actually it used both Axumin and gallium PSMA. And basically improved outcomes, improved the detection with gallium versus Axumin.

And then with PSMA versus Axumin, and the other point being that in the CONDOR study, a change in diagnosis, so 64% of evaluable participants had to change an intended management after the PSMA scan. And the vast majority, almost 80%, were because of detection of lymph nodes.

Jason M. Hafron, MD: Dr. Edwards, do you want to make any comments on your perspective?

Byard Edwards, MD: We're not doing this in our group, the PET imaging for just historical reasons. But everything he said was, was right on. I think that if you look at the statisti as soon as PSMA is rolled out, I assume it will kind of take over. It's clearly all the studies show that as superior. There's the one agent that's only approved at two centers of, UCLA and UCSF, but there are two other agents in trial. So I don't know the status of when those will be rolled out. But it, I assume as soon as it's available, it will be the go-to agent.

Jason M. Hafron, MD: Dr. Garja, I want to put you on the spot a little bit. You brought up the CONDOR trial, for the audience who hasn't seen that trial or review the publication, I think it was in Lancet, it's a pretty impressive trial. The performance of PSMA was, was through the roof. Um, and the design of the trial was novel, it was from Dr. Morris at Memorial. That's a different agent than what's currently approved at UCLA and UCSF. That's the PyL agent. What do you think, in New York or Michigan, when do you think we'll have access to these agents? And which agent do you think we'll be using?

Ajeet Gajra MD MBBS, FACP: So the way I look at it is, there's PSMA, that's a ligand, then there's a label, and then there's a prosthetic group. So, there can be various permutations and combinations of ultimately what is used to target PSMA. And we'll only talk in diagnostics, because there's also the theranostic piece. The therapeutic piece, which is coming down the pike, fast and furious, which is really exciting. The bottom line is I feel like they're probably going to be more similar than dissimilar, irrespective.

And there are, of course, some variations in terms of half-life and handling and such. In terms of diagnostic efficacy comparing, between trials across different countries and geographies, I mean, the results are very similar, that very high sensitivity, you know, upwards of 98%, which has been the problem with imaging and very high specificity. So improving on the sensitivity without losing the specificity. So I feel like they're going to be similar, even though the actual compounds maybe different.

Jason M. Hafron, MD: It's very exciting. All these trials…I strongly encourage you to start reviewing those and get comfortable with PSMA because they're not fully approved yet but the data is very impressive. Dr. Morris ordered the Axumin, which most of us have available.

I just pulled some representative images and you see in the presacral areas of activity. So now we have a guy with oligometastatic disease. He's Axumin positive in the pre-rectal or pelvic area, two spots. Chris, would you start ordering or considering genetic testing? Would you do germline? Would you do somatic? What would you do, uh, in, in your practice if you, once you made the diagnosis of metastatic disease?

Christopher Pieczonka, MD: It's interesting, because I'd argue that the poll question doesn't allow us to do what I think would be best. This patient has what looks to be some sort of oligometastatic disease, hypothetically. You could consider doing germline testing, as well as somatic liquid testing is probably what I would do. So I think in the COVID world, we're not putting needles and things to confirm tissue diagnosis at this point, by and large.

I think that's really changed. Maybe a year ago, we would have thought about that. But I think if there's a concern about there being a bit of extra prosthetic disease, particularly with this type of occurrence, we would get germline testing done, and we would do somatic testing, likely of the liquid.

Jason M. Hafron, MD: Yeah. And I think that's a good point, because we're kind of all over the place. But I think, generally, as urologists, as the two drugs were approved this year and there's more coming, we need to consider germline and somatic testing.

Ajeet Gajra MD MBBS, FACP: I was just going to play devil's advocate and ask if this patient is still that essentially hormone naive, that certainly castration naive. Is that justification to do somatic testing already? Should one wait? And this is just that, a question. Should one wait until a patient has CRPC before testing, especially for the somatic mutation part?

Christopher Pieczonka, MD: I think I would do it. Because I think the patients would want to know that there is no FDA approved treatment for any type of precision guided therapy, it's something you would find on that particular biopsy. But in my experience, I'd like to try and have that done ahead of time to sort of pre-plan what those additional steps are. The other thing that I think is important for the viewing audience is that some of the commercial labs that are doing the somatic liquid testing are now being able to drill down well enough and to say that if the somatic testing has certain genetic features that they would be highly likely that those would have been hereditary in nature. As of right now, I still do traditional germline and traditional somatic testing.

Ajeet Gajra MD MBBS, FACP: The only point I'd make is if we're doing somatic testing, the general recommendation is that, especially there's a long interval and then there's progression to do it off of the new issue. So that's the only other point that I've made.

Jason M. Hafron, MD:Now, these are all great points. And, as our understanding of somatic and germline mutations evolve, I think we'll fine tune when's the appropriate time. I'm more like, Chris, I like to get it early. I like to get a good understanding of what I'm up against, so I can plan appropriately, but I think the key that we need to, as urologists do genetic testing involve genetic counselors. Because as we look at future trials, what's coming down the pipe, it's more and more precision-based therapy and we just need to be comfortable in this space and comfortable in knowing when to order these tests.

So the patient gets stereotactic ablative radiotherapy, SABR therapy. He got three doses, 3,000 Gray, um, in February of 2020. Dr. Gunter, so they didn't have a good radiation question, but you're an expert in radiation oncology at Oklahoma. Talk to us about SABR, and what's the indications and then, what can we expect? What does the data say for treating an oligometastatic lesion with SABR?

Tyler Gunter, MD: So, this patient with presumed metastatic prostate cancer, is a good candidate for SBRT. The rationale being that as far as we can tell, he has limited deposits of disease and may benefit from local therapy. One caveat to, to this situation in particular is that this patient appears to have received prostate only radiation in the form of brachytherapy. He didn't have elective nodal radiation, which, at the time, with a lower PSA and only Gleason seven disease was probably justified. But he is likely to have subclinical disease throughout his lymph node chains in the pelvis. And so what we're seeing on his PET is likely just the tip of the iceberg.

So you could make an argument for whole pelvic radiation therapy, to try and take care of any subclinical disease that you're seeing there. We don't have any prospective data comparing the two strategies, and so I think either one is justified. Certainly SABR is going to be less toxic than treating the whole pelvis. As far as the data that we have to justify our recommendation for SABR, we have a few recent phase two studies that suggest that SABR and the oligometastatic setting is beneficial to patients. Looking at kind of just overall oncology in general for oligometastatic cancer, we have a Canadian study SABR-COMET that looked at patients with all diagnoses, uh, that had five or fewer metastases in a controlled primary, and randomized them to either aggressive SABR versus a standard of care with palliation as necessary.

They didn't design it as a superiority study, but on their update, they did detect the survival benefits. Median survival was almost doubled. Five-year survival was more than doubled. And so there is presumably across many sites this oligometastatic setting where a local therapy can be beneficial. They didn't have enough patients to analyze subgroups to detect a benefit for prostate cancer in particular there. But we do have a couple other recent studies for STOMP and more recently, ORIOLE, that looked at this just in prostate cancer. They both included patients with three or fewer metastases, again, with a controlled primary STOMP. Uh, uh, had metastasis directed therapy, which included surgery or, SABR. And ORIOLE just looked at SABR.

STOMP saw a trend toward benefit with metastasis directed therapy. EEven on their recent update, it was still trending. They'll close with a PFS improvement, with a P value of 0.06. But ORIOLE looked at, 6-month PFS and saw significant improvements in both of those areas. So even though these data seem to be fairly convincing They're still phase 2 data. And even now, we still have some difficulty getting insurance reimbursement for SABR and oligometastatic prostate cancer.

Jason M. Hafron, MD: Now that's great information. Yeah, the ORIOLE trial was interesting and, clearly some signals there. But again, like you said, it's phase 2. We don't have phase 3 data, but hopefully, we can get those trials and get more information on SABR.

He has serum, PSA rechecked. He recurred, he progressed, he went up to 23 nine months later after SABR. Six weeks later, it went up to 44. Axumin was repeated and the SABR nodes look good. They had Axumin active. But now there was a new node in the sigmoid mesentery. Dr. Gunter should we re-SABR the guy or what would you do in this case? It's hard to tell, I know it's one image. Um, what do you think?

Tyler Gunter, MD: The the previous scenario, our targets were quite a bit further away from organs at risk like bowel, colon. However, in this case, it sounds like it's quite a bit closer to the sigmoid colon. I don't think that necessarily counter indicates SABR in this scenario. We may not be able to get as high a dose as 30 Gray in three fractions like he, this patient received before. Um, but we might, uh, be able to do a more protracted five fractions to something like 30 to 35 Gray, um, which is a regimen that's employed routinely for oligometastatic cancer.

We should be able to keep the, the risk of complication on the sigmoid relatively low. So I, I think that, that, that's could potentially be worth trying. More concerning, though, is this patient has a PSA of 44 at this point. Um, a- and I would wager, it's pretty unlikely that hi- this is his only site of disease. Um, so we, we could try it, but he's likely to progress elsewhere.

Jason M. Hafron, MD: Dr. Morris, the, the radiologist didn't want to repeat SABR, it was too close to the bowel, they weren't comfortable. The clinical question is what next line of therapy would you recommend? The local radioloogists weren't comfortable with more radiation. I'm going to open it back up to Chris and then I'll ask Dr. Gajra, what would you do next? What would you do with this patient in your clinic?

Christopher Pieczonka, MD: I love the fact that we did stereotactic radiation upfront. Because if you swing and you hit it out of the park, you might give the patient, at the very least, a long disease-free interval, or perhaps delay the need for androgen deprivation therapy. I think kind of what that reoccurs with, and that patient has a nasty PSA doubling time when it re-occurs the second time, I think that patient needs to have something else. Um, quite honestly, this patient in our particular practice would be screened for clinical protocol. We have a variety of different clinical protocols and some of them are starting to become quite precision guided.

I can think of really two, we have clinical protocols and the big pharmaceutical players are playing in this market. J&J, Pfizer, they're looking at patients who have homologous repair deficiencies. And those patients potentially could be put on androgen deprivation therapy with some sort of AR-targeted plus or minus a PARP inhibitor or placebo. AstraZeneca is now playing in this market with patients who have PTEN abnormalities. PTEN abnormalities happen in roughly 20% of these types of patients with metastatic disease. And they have a targeted drug called Capivasertib, which is not FDA approved and they're using that with Abiraterone.

If I didn't have access to clinical protocol, this patient would get combination Androgen Deprivation Therapy with some sort of AR-targeted therapy. They would absolutely not get monotherapy with androgen deprivation therapy. And at least, in my practice, I have a pretty frank conversation with the patients who are found to be metastatic and tell them to resist the temptation to intermittent therapy, which sort of begs the question of would you do intermittent therapy with ADT monotherapy alone? Would you do intermittent therapy with Androgen Receptor Targeted Therapy, uh, with ADT?

I just went through this actually, with one of my patients today. I have a very similar case. He got radiation, he ended up recurring. ESA is undetectable. Now he's asking me you know, he's on apalutamide with leuprolide acetate injection. That, "Do I need to stay on this lifelong?" Got a petty honest conversation about it. I said, "Yes." That was that ... So that's, that's how I'd approached this patient.

Jason M. Hafron, MD: Dr. Gajra, what would you, how would you, if this patient was in your clinic, what, what would you recommend?

Ajeet Gajra MD MBBS, FACP: My urologic oncologists are in agreement and I think this is one of those times. Chris and I go back a long way. So I think I agree. I mean, I think we have data on Enzalutamide. In terms of ADP plus Enza. We have very similar data with apalutamide from the TITAN trial. Both of them suggest significant improvement in progression free survival. And importantly, because this is low volume disease. So, so I think I like these two files better because they categorically, in a pre-emptive manner, plan for low volume patients, and about a third on, of the, of patients on each of those trials were these patients.

And those patients got the same amount of benefit, got hazard ratios. The low volume patients got even more benefit than high volume patients with the addition of apalutamide and enzalutamide, respectively. Which AR agent you choose depends on individual comfort. There are folks who use Enza for so long, they learn a new agent. And then there are folks who feel like, "Hey, if it's new, it might be better." Um, so, so either or. So I completely agree with Chris.

And I mean, in my practice, I think this would be the time, perhaps, when I might do the somatic testing, even if it's liquid, but overall, I agree, Chris, exactly with your approach. And, and that's what I would do at this point. And intermittent, I've never been a fan of intermittent, any of these were really weak. And once in a while, there's a young patient who will really force your hand. And then really, I feel like that data is only there to like, support me, because when they explode and have terrible disease and, and, and decide to come after me.

I think you say, "Wow, that's what they want. And this was the data I based it on." But definitely not a fan of intermittent androgen deprivation. And those studies have major flaws. And I mean, you know, these days, one is, I mean, and we talk about M0CRPC. But M0CRPC is a joke, because it's only limited by the sensitivity of your imaging. So, you know, so that is a whole entity that's going to disappear.

Jason M. Hafron, MD: I think those are great points. And I think when you look at our polling of our audience, 67% of the audience would use combination therapy. Not everyone has access to clinical trials, but always important to consider. I think the mistake that urologists make is just treating with monotherapy. I think that's a bad habit we got to get rid of. And if you look at the NCCN or even the AUA Guidelines, combination therapy, ADT plus androgen receptor are critical. And, you know, both Chris and, as you didn't mention chemotherapy, there's really no role for chemotherapy with this low volume. Do you agree with that, Dr. Gajra?

Ajeet Gajra MD MBBS, FACP: We saw low volume benefit and subsequently, there have been other studies. You know, STAMPEDE as this whole other issue. And, and there is a metaanalysis out there that shows that low volume also gets benefit from those attacks. So let me, just by being a medical oncologist, I wouldn't offer that really for low volume disease. I trust the US data better, because STAMPEDE was all a mishmash of all kinds of patients, just categories, stages. So I agree, I wouldn't offer chemo and I wouldn't offer…either, but I would offer Enza or Apa.

Christopher Pieczonka, MD: I concur with Dr. Gajra on this. There is a joint consensus, AUA, ASTRO statement indicating that a patient should be given ADT plus some sort of additional androgen receptor targeted therapy for these type of patients. As our own National Society for the Urologist on the call are not recommending ADT as monotherapy.

Jason M. Hafron, MD: Yeah. And I think another thing that urologists frequently missed, used inappropriately is bicalutamide. Most recently, the AUA made a very strong statement about complete androgen blockade with bicalutamide where first generation AR is no longer indicated. The only indications for biclutamide are for prevention of flare. So, I think as urologists, we really got to stop using biclutamide. ADT plus biclutamide is no longer recommended and based on the trials that we have, ARCHES, TITAN, ENZAMET. Clearly, we see a survival benefit and all these trials pretty strong hazard ratios using ADT plus an androgen receptor at this point. Chris, any other comments you would make about this case?

Christopher Pieczonka, MD: I think this really covers the gamut. These are the type of people we're seeing all the time in our practice. I think we kind of hit the highlights of this. I think it's important for the audience to realize that the five-year survival for these patients is not great, no matter how you look at it. And I think throwing everything plus the kitchen sink at them needs to be kind of the mentality because we all got brought up using ADT on everybody and now it's important to use ADT in the right settings, not in every setting.

Jason M. Hafron, MD: I think that's a great point. And I think we, as you know, we need programs like this to educate our colleagues on the importance of combination therapy.

We're getting back to the genetic testing. A, a couple great points in, in the chat box: "A negative somatic results would not indicate that germline would be negative. Gene coverage and varying classification is different for somatic and germline." I think that's a very important point. That's because a negative somatic does not indicate a negative germline. And if we're going to offer comprehensive cancer care and patients with these life threatening cancers, we need to do both somatic and germline.

There's a comment here about PTEN mutations. Chris, you brought it up. The CAPItello Trial is very exciting for this space. PTEN mutations are very common, you mentioned 20%, 25%. So, that's, again, another option to consider. We’ll, obviously have to wait for that data as it moves forward. Any closing comments?

Tyler Gunter, MD: Apart from this great discussion in this setting, radiation kind of takes a backseat until the patient almost invariably develops symptomatic mets, in which case, we're certainly there. There's definitely some work being put in in that respect. We're looking at dose escalation in SABR in symptom palliation, not just in the oligometastatic setting. Some groups have shown benefit in terms of symptom control in that case. It seems like we're, we're just moving toward more sophisticated techniques, higher doses.

Jason M. Hafron, MD: No, I think that's important, too, is as these patients develop symptoms, don't forget about palliative XRT. It offers some minimal disease control, but the symptomatic relief, is so critical in these patients with such terrible disease. That's a great point, Dr. Gunter.

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