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De novo Metastatic Renal Cell Carcinoma


DR. CONCEPCION: So in this last case, cover this was actually submitted by somebody in Travis's group, my good friend Dan Voglewede at Rio Grande Urology. So in 2012, we have 63-year-old white male was diagnosed with prostate cancer, 8/12 cores positive on biopsy.

He had a number of cores positive for Gleason group 3 (4+3) as well is Gleason group 1 (3+3). Staging workup was negative. He opted for a robotic or he actually opted for a radical prostatectomy at that point, had a pathologic T3aN1M0 and his single node was in the right obturator fossa. He refused adjuvant radiation therapy to the bed. He had a PSA at 3 months post op of 0.2 and from 2012 to 2014 was really followed just with serial PSAs.

He had a low rise from 0.2 to 1.2 over a period of 18 months. Started on intermittent leuprolide acetate for one year, then stopped. 2015, 2017 again, off androgen deprivation therapy. PSAs progressed from 1.7 to 4.6, again over a period of 18 months. Restarted leuprolide in 2018 and had a very nice response, which is significant to a PSA of 0.1. And then, there you see his data from 2019 to 2020.

And basically, he had a PSA of 0.9 in November 2019, essentially doubled in six months to 1.8. Three months later, had a PSA of 2.8 staging workup at this point is negative. So he is your typical, which again as urologists, we see nonmetastatic castration resistant prostate cancer. So questions and is only going to be to, I would order a next-generation imaging/biomolecular scan on this patient, yes, no, unsure, yes I would order but don't have access in my local market.

So obviously these are going to be, as we know, there's a lot of talk about next-generation imaging scanning. We know there's a couple out there, probably more coming on the horizon. And the question is, how does this impact, especially when you have somebody that at this point has only been staged with traditional bone scan and CT? And on the last question is, if at the time of diagnosis of nonmetastatic CRPC, the PSA doubling time was 18 months.

I would add an additional agent to ADT, yes or no? So again, when this patient first started off when he was first diagnosed nonmetastatic castrate resistant prostate cancer, we know right now his PSA doubling time appears to be somewhere on the order of six months. If it was 18 months, would you treat this patient the same way? And the question obviously is, does the doubling time make a difference?

So Jorge, does the doubling time make a difference on whether or not you treat nonmetastatic CRPC or not? And again, it would be helpful for you because I know you know this, is how those studies were designed and who was included, and was excluded for some of those trials.

DR. GARCIA: Let me start digging back into our question that we're going to answer. In a nutshell, any man with prostate cancer today in America will likely need genomic testing period. Next, to this question, if you look at N-0 CRPC, let's just first define what castration resistant really means. It means that you have a testosterone suppression. We define that statistically or by prostate cancer guidelines as less than 50, although some people believe that has to be less than 30 or 20, but the reality is less than 50.

And you must have either a rising of your PSA or clinical progression, meaning symptoms, or radiographic progression, meaning changes in your scans. Not need, again, do not need the three of them to make definition for castration resistance. You only need low testosterone one or the other three. Now in this case, this patient is castrated. You assume that his testosterone is suppressed. Let's assume that check to that, which is one of the first maneuvers that you really have to undertake.

Make sure that their testosterone is suppressed. And if, indeed, the PSA is rising, then for us, I don't think clinically it matters drastically, Raoul, but I really believe for clinical purposes, it didn't matter for us. So the answer to your question is - - is yes. A doubling time is a very strong predictor for prostate cancer specific mortality.

And that data came from the early datas from bone health agents from Dr. Matthew Snead [phonetic] at MDH where we clearly demonstrate that if you follow patients over time, in the n-0 space, as soon as your doubling time changes, your likelihood of finding disease in the scans is greater. In therefore, you're prostate cancer risk is greater for symptomatic progression, radiographic progression, and death from prostate cancer.

Three clinical trials that we now use to support role novel androgen receptor inhibitors in the n-0 space, all of them used PSA doubling time as part of the inclusion criteria and they have to be greater than 10 months. Now the big question is, if you have a PSA doubling time of 11 months, would you treat the patient or not? I think you have to really hone down to that particular patient phenotype that that you have in front of you.

But for the purposes of the trials, doubling time was an inclusion criteria for the three trials, SPARTAN, PROSPECT, and obviously - - ARAMIS data. What is intriguing is PSA doubling time is not part of the label all these agents, although some payers do take it I on those things and they put pressure on those prescriptions. Sometimes it has happened to me. But the reality of it is, doubling time is a very important tool for us when we're making treatment treatment decisions in the n-0 space.

DR. CONCEPCION: So if I can summarize that, doubling time is important. It was important to get patients on trial of less than 10 months but truly, from a clinical standpoint for you, because we have agents and because it is not required by insurance company, your preferences because we have agents that we know in a more high risk population vis-a-vis rapid shorter PSA doubling time, your preference even if there doubling time was 12, 18 months, your preference still be to treat and on a secondary agent, more than likely?

DR. GARCIA: Yes, but to some extent remember that doubling time alone is not enough. Obviously, if you look at a history of this patient, he's been seven years getting to the n-0 space. So biologically, although it is PSA doubling time is moving, you also look at his Gleason.You look at the pathology and so when you sort allow you to gauge the need to embark on treatment rapidly.

I think for us the pragmatic is, we induce n-0 CRPC states because we start androgen deprivation therapy in the rising PSA syndrome after surgery, radiation, or the combination of both when patients progress biochemically. And it would be very hard, at least in my opinion, when I tell a patient going to actually I'm going to actually put you on ADT, whether I do it intermittently or not because your PSA is rising, you don't have disease.

You have biochemical recurrence. And then when you become castration resistant, you're still n-0, then I'm going to slow down and tell you don't worry, let your PSA get to be higher or your doubling time to be faster, you develop these in the scans. So that's a very hard discussion because you already make that decision to start the patient on therapy, even in the absence of disease.

So that is where patients sort of pushback and said well Jorge, you elected to treat me earlier. Why now you're going to wait? But the rule of thumb I think doubling time becomes very important for us and to me remains one of the pivotal points that I pay attention to when I make that decision.

DR. CONCEPCION: Travis, what are your thoughts on next generation imaging in this particular patient?

DR. MANDEL: I actually emailed Dan what I saw you emailed me. When I saw this case, I emailed him and I was like why haven't I seen this patient because I was just like for me, if you have one node, this guy should've gotten radiation but anyways, I would get a PET scan for sure, a PET Axumin just to see if there's any disease in the bed or in the nodes. And if there is, then I'm going to convince them to get treatment.

Axumin is the greatest for detecting bone metastases. And so it was all negative, it honestly might be worthwhile for him to get a PET PSMA. I sent a couple patients to get those scans just so we can locate the disease because it is something I can target, I can treat it. I think that's a better solution because he has potentially a chance of being cured as opposed to just continuing the systemic therapy. And then the disease will eventually find a way so that's probably how I would approach this and probably how I'm going to approach it here in the next couple of weeks.

DR. CONCEPCION: Ken, let's just say that next generation imaging because as we know Axumin and choline are the only ones currently approved by the FDA. PSA, PSMA we think maybe next year. But let's just say you get an Axumin scan and you got this history. And you've got some nodal disease in the pelvis, maybe a couple of shotty nodes 1.5 to 2 cm. How aggressive would you be relative to going in and trying to get those out?

DR. KERNAN: So a couple of things I would think about. You and I have talked in the past about the role of immunotherapy and we are believers in - -. One of the things to think about is once metastatic, always metastatic. So he had nodal disease at the beginning, obviously just one node. Now he's got more nodal disease, if the Axumin scan is true. But he's N-1 but m-0 potentially depending on where those nodes are.

I don't know that I would be that aggressive or going in for to do a live node dissection but I definitely think you could split the uprights and consider giving him sig-t [phonetic]. You would qualify castrate resistant metastatic nodal disease. And then you could consider him again nonmetastatic because he's M-0 and then go to one of the overall oncolytic. And we've done that a few times because I really believe this guy at this point is what, 71 years old.

It sounds like he's still a really healthy guy. And so I really believe that immunotherapy is we're trying to utilize that patients whenever we can. So might be one of those guys I might try to split the uprights.

DR. CONCEPCION: Jorge is raising his hand.

DR. GARCIA: So here's my comment. I don't think that's unreasonable, Ken. I want just simply remind you also that in addition of doubling time for the three n-0 CRPC trials we actually did allow lymph nodes up to 2 cm. Now to get to your point, most of us clinically will see a traditional CT or a CT let's say. If I see a patient with a 1.9 cm pelvic lymph node, I would call that patients in my mind is M-1, right? It's just that the trial allows that because of how we restructure resist defining disease, if you will.

I think to Travis's point that the bigger question if you were to actually do a fancy PET Axumin or - - PET or a PET PSMA is that you may change the natural history of the patient and and now you may label them as having metastatic but they still will have probably oligometastatic disease. And I think the bigger question is if you were to identify a target, would you use radiation alone? Would you do surgery alone? Or would you need to use systemic therapy plus SRS, if you will? So those are the questions in the field right now and I don't really know that we have the right answer but I really think that functional imaging as we see it more often coming into this space will likely shift our patients to have an objective disease. And it will pose the question as to the role of targeted therapy, specifically to those specifically to those regions. It is not systemic. It's going to be either surgical and nature or radiotherapeutic in nature.

DR. CONCEPCION: No, I think that's a great point, all the points you guys may. I think in this particular case, it opens up a lot of different options. Could you get them off ADT by surgically attacking them, giving them radiation, and again Jorge, to your point, which again I think is going to have another discussion next year, next generation imaging is going to change things, especially once we get theranostics and radio like in therapy. Anyway, we are out of time I truly appreciate everybody that logged on.

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