Case 3: Clinical Relevance of the AR-V7 Biomarker in mCRPC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Alicia Morgans, MD:Thinking about another biomarker that everyone was so excited about a few years ago, which is still very elegant work, and I commend the team for doing this—the AR-V7 [androgen receptor splice variant 7] story. Where does that stand today for you, Neal? Are you thinking about testing? There is a test that’s available. What are you doing?

Neal Shore, MD, FACS:I use AR-V7 outside of trial work. But from a practical standpoint, if I have a patient who is progressing on an AR inhibitor, typically abiraterone or enzalutamide, and they say, “You know, I don’t want to go on to chemotherapy,” or, “I don’t want to do something,” for whatever with the radium-223 or sipuleucel-T. And if they’re really kind of pushing that because they like the idea of an oral therapy, I will use it there for sort of an equipoised way to say, “You know, you have the AR-V7 splice variant, and it’s really not going to be of any benefit to you.” But generally, I’m not a huge proponent of it based upon the SWITCH data that we’ve already discussed, and based upon the fact that there are other really good therapies with different mechanisms of action. We also did the ARMOR trial, where we were looking at galeterone and were trying to find all these patients who had AR-V7. As we all know, it’s a very small percentage of patients, and they progressed so quickly. They have that primary resistance to an AR drug. You kind of see them. They’re phenotypically so aggressive. They progress so dramatically quick. So I haven’t really found it to be, other than outside of some trial work that we’re doing, clinically relevant in my practice.

Alicia Morgans, MD:And what about you?

Kenneth Kernen, MD:You know, similar. We kind of all thought we were going to use it a lot. But again, I think once the patient starts failing 1 AR inhibitor, we pretty much know they’re not going to do well on the other. So we really haven’t used it very much at all. Plus, it’s not an inexpensive test. What are you going to do if it’s a small number? So we really haven’t used it much at all anymore.

Alicia Morgans, MD:Jorge?

Jorge Garcia, MD:So, 2 points. Number 1, I think for the SWITCH, I think a splice variant is irrelevant. I the CARD data to me rips the point. I don’t use it by the way, and I don’t use it for the same reasons as you gave, Neal. I think the bigger question is, if I see a patient who comes with a splice variant 7, who is positive, and he’s just developing castration-resistant disease, and the patient asks me the question of, “Well, I’m on ADT [androgen deprivation therapy] alone…oral therapy, or docetaxel as frontline therapy?’ If I were to see that splice variant with the CARD data, maybe I want to lean toward chemotherapy. The likelihood of you benefitting from an oral agent is going to be low. But the splice variant is also volume dependent, which means that if you treat disease, it doesn’t mean that you cannot ever get an AR inhibitor.

And although we talk at length as to the importance of sequencing, layering, I would argue that if I’m the patient, I want to get exposed to all of the treatments that are life-prolonging in nature. And I would defer to my doctors to layer them, or use the ideal sequence for my case, but I want to be exposed to all of them. And the question is, how do you do that? So if I see a splice variant up front, I may pick chemotherapy over an oral agent. But it doesn’t mean that you cannot come back and get an oral agent later.

Neal Shore, MD, FACS:I think you make a great point. We’re all totally committed to this theme of, “Look, this is a terminal disease,” unless the patient dies of a cardiovascular event, or something else that’s non-prostate cancer related. And so, at the end of the day, when the patient succumbs, you want to make sure that they were given all of the approved therapies; and then, ideally, a fairly important trial, unmet need, unmet combination. And we do that. I’m sure we all do this. And when these patients who have been in our clinics for years succumb, you want to basically go back retrospectively and say, “Did I sequence optimally for this? Did I give them the best chance?”

Transcript edited for clarity.