Around the Practice: November 18, 2020 - Episode 2

Non-Metastatic Castrate Resistant Prostate Cancer

Raoul S. Concepcion, MD

DR. CONCEPCION: So we got two more that I want to run through and these are going to be prostate cases. This first one is a metastatic castration sensitive prostate cancer that's de novo. And this was submitted by my good friend Jim Bailen at First Urology in Louisville. In December 2019, a 79-year-old white male presents to urology with acute urinary retention, PSA of 4.6 at his local primary care office he has a history of a cerebral vascular accident but is still pretty functional.

He undergoes basically a minimally invasive therapy to get him out of acute urinary retention, starts to void, but eight months later returns to the office worsening lower urinary tract symptoms, as well as now gross hematuria. He undergoes a cystoscopy in the office, which shows an obstructing prostate, questionable mass effect of a left hemitrigone at the left orifice, and a PSA of 8.1.

Undergoes a TURP to leave the worsening obstruction again, biopsy of the trigonal mass. Now he has Gleason grade group 5, Gleason 4+5 prostate cancer in all the tissue that is submitted. He has no visceral eats and on bone scan, he has multiple areas to the axial skeleton, fever, and pelvis which are all suggestive of of metastatic - -.

So for the polling questions that we're going to address to the audience and again, my discussions, I want you to kind of take these into consideration, for this patient I would initiate the following therapy: ADT monotherapy, complete androgen blockade defined as ADT plus first generation anti-androgen, ADT plus six cycles of docetaxel therapy, or ADT plus a novel hormonal therapy, which again I am using that terminology which is basically some of the newer androgen receptor targeting agent. So, those are your choices.

So again, this is an area that I think obviously many of you know has really just exploded over the past few years, as we discussed. All right, let's go to the next question. In addition to systemic therapy and having high grade disease, I would aggressively treat the primary tumor, yes or no? And again, I think this continues to change I take as urologists, I think we regret the day and radiation oncologists, I think we regret the day when we didn't take out the primary.

And the question is, is there any value to that, which will have a short discussion. And then the last question is, I would order the following genomic testing on this patient: germline only, somatic only, both somatic and germline, I don't know, or I would not order genomic testing? And again, as many of you know, genomic testing has really come into the forefront over the past five years as the evidence continues to mount on the hereditary component of prostate, not too dissimilar to what we're seeing in hereditary breast, ovarian, colon, obviously which Lynch syndrome and those types of things.

So, Travis, you're out of this discussion a little bit, so kind of sit tight. Ken, so we have a newly diagnosed de novo, metastatic, castration sensitive prostate cancer, with high grade Gleason. Give us your thoughts about what the data shows and obviously what agents. Are we doing a good job? Are we doing a bad job? What can we be doing better?

DR. KERNAN: This is a great discussion because Jorge and I actually sat in on, we did a tumor board like this a little while and go as well and there's some data out there that they basically took a lot of data between April '19 and March 2020. They collected data on 1400 patients in for de novo metastatic CSPC like this. And they found out what really going on in America because we know we should be guidelines based driven, NCCN guidelines, and will get into that in a minute.

But we found that 74% of all patients are treated with ADT alone or with just a first-generation anti-androgen. So we're basically in 2019, 2020, we're treating people with 1985 and 1989 technology. So that's the wrong answer. ADT alone plus or minus first-generation anti-androgen is is clearly the wrong therapy but I think it's important to get that message out that that's really what's going on right now in America for these urology patients. So I give you guys credit for doing this case.

And this is, I think, the importance of this tumor board is to get the message out that this is not what good looks like. So now that I've got that diatribe out of the way, I think that's critically important. So now, again, if you look at NCCN guidelines, basically these folks need either chemotherapy, an androgen synthesis inhibitor and androgen receptor inhibitor, or as you would say, just a novel hormone. And again, that's something to decide of what fits best for someone like that. But the wrong answer, obviously, is ADT alone.

DR. CONCEPCION: This patient has a history of cerebrovascular accident. He's got high grade disease. He's got relatively asymptomatic disease. So, what I was studying for boards, we had residents that site well, we could do this, we could do this. And my chairman say well, well we could do a lot of things. So Ken, what would you do? Based upon his past medical history, his presentation what things you consider in terms of additional agents that enter into your computer as you try to add that additional agent, which you have clearly stated should be the standard of care?

DR. KERNAN: I think first of all, you have to you have to get them on some sort of hormonal therapy. We tend to use degarelix first and it really lowers the testosterone almost immediately. That's to us our first starting point. And then you have to decide novel hormonal agent versus chemotherapy. And he's had a stroke, so that kind of eliminates enzalutamide so that you can think about Erleada for him versus chemotherapy.

He's got high volume disease. In the TITAN trial, it had high volume and low volume patients. Both did very well. He's somebody I would probably lean more towards Erleada as opposed to just standard chemotherapy. I think he would tolerate it pretty well. And that's probably our sequence of events for him at the beginning.

DR. CONCEPCION: Jorge, so Ken has brought up a concept that high-volume versus low volume and obviously sort of moving a little bit towards an androgen receptor targeting agent. So for the audience who may not be as well versed in the literature, and I'm sure they are, but kind of describe for us, give us an overview of the definition of high versus low volume metastatic disease, what's the significance of it and how that might play a role in what agent you might prescribe upfront for this particular patient.

DR. GARCIA: So just going back to what Ken said - - I think that a year or two ago I probably would've been a bit more putting more pressure on the volume question. But I think the data right now would suggest, as Ken mentioned, that regardless of volume, what you do need is treatment intensification. So historically, just to get the audience instead of from 2013 to 2020 we basically chemotherapy up front with docetaxel base approaches as the American data, the ECOG data, and STAMPEDE data, which is the - - system.

Two to three years later, we demonstrate also then the addition of the adrenal biosynthesis inhibitor abiraterone acetate at front also leads to survival improvement. There is the French LATITUDE data and also the STAMPEDE data. And then obviously over the last two years we recognize then the addition of apalutamide as an androgen receptor inhibitor and let TITAN data also led to benefit, regardless of volume, high or low.

And the ENZAMET data, which is looking at enzalutamide in the same patient population also leading to a survival improvement, which means, simplistically speaking, that you have as a provider four choices for that patient. One is to add chemotherapy up front. Two is to add abi abiraterone to that patient upfront. Three is to add apalutamide or four is to add enzalutamide. None of those trials have been compared head to head so it is very hard for us to know which is the best regimen.

But suffice it to say that I think most of us in the field is, in my personal opinion, I have shifted away from chemotherapy to abi, just for simplicity's sake and from abi to the ARIs just by virtue of the lack of prednisone and the lack of fasting. So my agent of choice right now for the most part are likely to be apalutamide or enzalutamide. I agree with Ken that CVA may push me away from enza a little bit just because of the issues with increasing the risk for seizure activity, which I still don't buy fully.

But I think it's fair to say that I think the issue with volume is that this gentleman has high-volume disease for two reasons. Number one, he has Group 5 disease and number two, he has more than three bone metastases. That is the definition that we use in the LATITUDE data, which is the French data from Dr. Karim Fizazi. Now in the American data, more than likely he would have been high-volume as well.

And although in the American data did not include Gleason score, it was only the presence or absence of visceral disease in the presence of more than three bone metastases, four, excuse me, at least to outside the spine. That may have made the criteria for this patient. I think there is STAMPEDE data over the last two years challenged that notion that volume really matters and that volume actually is relevant when you make these selections because the heterogeneity data of the follow-up from that stampede analysis would suggest, in fact, that regardless of volume, men with metastatic castration naïve or castration sensitive disease will derive a benefit regardless of the agent selected.

But I do want to actually reminded the group that if you look at the median survival, which is getting and drilling into Ken's very important point as to single agent monotherapy with LHRH agonist and antagonist based therapy, the median survival for someone with high-volume metastatic disease today contemporary data over the last three years is around 30 months, 33 to 34 months.

If you double that, and intensify the patient regardless of the agent used, you can double that survival improvement to almost 60+ months, meaning that you are reducing the relative risk of mortality by almost 40%, something that is clearly unheard in the history of prostate cancer. So undoubtedly, treatment is a big issue and it's needed.

I think volume matters to some extent but I think that data from all of us wrong in the sense of defining treatment by volume. And I think most of us in America would probably use one of the novel androgen receptor inhibitors for this patient and probably just by virtue of the CVA, probably apalutamide would be the agent of choice, at least in my opinion.

DR. CONCEPCION: Okay, Travis, let's just say this gentleman, instead of being 79, let's just say he was 60 and still presents with this. What are your thoughts on treating the primary with radiation?

DR. MANDEL: So in these cases, we've kind of had a lot of back and forth in my practice about this. But I use the STAMPEDE data again to kind of guide me in this. And there was a paper that was published back in 2018. The first author is Parker [phonetic] and they looked at definitive treatment essentially of the primary with radiation versus just standard systemic therapy with the other patients. This was a randomized trial. They had hundreds of patients.

And initially, there didn't seem to be an overall survival signal with treatment of this. But then, they stratified the patients to low-volume and high-volume disease. And they found that patients that have low-volume disease actually benefited from treatment of their prostate. I think their definition was three or less but the term oligo metastatic is is starting to be thrown around a lot in radiation oncology, especially in prostate cancer.

And so I use five, like five lesions. If they have five lesions are less, then I'll treat the primary and treat those lesions. And I use the STAMPEDE data and there's two other trials. One is called STUMP. That was a couple of years ago as well, data ADT survival benefit, I think it was, where patients that they did not need to be on ADT as long. And then the other one is the SABR-COMET trial and this is looking at multiple cancer types, lung, prostate, breast.

And they treated these lesions, these oligo metastatic lesions and were able to detect an overall survival benefit that was statistically significant within the design of the trial. So those are the three trials I used, STAMPEDE, STOMP, and SABR-COMET to kind of rationalize treating patients with low-volume disease. This patient does not have low-volume disease. He sounds like he's riddled with metastasis.

And so in these patients, I would just reserve external beam radiation for palliative purposes. And then he might be a candidate for possibly zofeo [phonetic] in the future once he becomes castrate resistant.

DR. CONCEPCION: I think the problem with a lot of the trial is that the endpoint by treating the primary with metastatic disease, is that the endpoint they always look at is, does it affect survival. And I think Ken, you and I have been in practice long enough is that yeah, that is one endpoint. But what we see is the problem in that interim period is the people that suffer from incredibly locally aggressive disease, whether it's bilateral or ureteral obstruction, whether it's gross hematuria and clot retention because they've blown through their hormones.

And I think people kind of yes, we care about living longer. But at the same time, we also have to maintain quality of life in some of these patients. So Ken, I'm going to let you.So let's just say this guy, he's already got gross hematuria. He 79. What are your thoughts about treating the primary with a robotic prostatectomy?

DR. KERNAN: So 79 definitely would not put this guy—he's already had a CVA, so he's not my optimal robotic prostatectomy candidate. But as you mentioned, we do see a lot of people suffering with really bad local disease in which hematuria,, obstruction of the ureters, etc. again, to kick it over to Travis, this is where I think radiation therapy really shines. Comorbidities going through radiation is very low.

I don't know that it says the size of the prostate. Another option would be local cryotherapy. It also works on unobstructing. It depends on how aggressive the TURP and the defect was. But I do believe that combination therapy of hormones, obviously the chemotherapy in treating the local therapy is really critical because these guys, like Jorge mentioned, these guys are probably going to live a long time. And you do not want these guys suffer because it's miserable.