Evan Y. Yu, MD: We've talked a lot about the different agents that we can use for metastatic castration resistant prostate cancer. Something we didn't talk about Tanya, is, and it wasn't even brought up for this patient, is the idea of switching from one novel hormonal therapy agent to another and in this case declared himself as needing to go towards chemotherapy route. But will you take us through that data of switching from one novel hormonal therapy agent to another? And, since we're talking about the concept, the sequencing and the CARD trial was brought up and that was in the control arm versus cabazitaxel, maybe you can summarize all that for us.

Tanya B. Dorff, MD: Some themes have emerged in sequencing for mCRPC and one major theme is that we get a lot less mileage out of a second AR targeted agent for a patient who's progressed on the first one. Like enzalutamide after abiraterone, after enzalutamide. And despite that, it continues to be a control arm for many clinical trials. It was the control arm for CARD, so CARD was post AR targeted agent, post docetaxel and a randomization to cabazitaxel or the other ARTA showing clear superiority for cabazitaxel. PROfound, which was the study of olaparib in patients with homologous repair deficiency, a biomarker selected population. Again, the control arm being a second AR targeted agent and there was clear superiority for olaparib over that approach. And even back in older studies like PLATO, people ask the question of adding the second AR targeted drug and that didn't show any advantage, it seems like once you progress on an AR targeted agent, it's better, if possible, to switch to a different mechanism of action. And even combinations with more novel agents like radium 223 could be very appealing to add abiraterone with radium or enzalutamide with radium and so far, there's no study showing any benefit to that approach. In addition to the aspect of not using 2 ARTAs back to back, it's for now remains a sort of sequential, one therapy at a time kind of approach rather than combinations. Although, some of the exciting newer data with some of the targeted therapies being combined with ARTA may change that in the future. But for now, really, we're just going one at a time.

Evan Y. Yu, MD: I'm going to follow up with that because you did a great job of summarizing all the studies, we're going from one AR target agent to another. Certainly, it's the control arm in a lot of studies and didn't look phenomenal. But it still doesn't, the control wasn't placebo, it still had some activity in some patients and I'm going to press this group because today I was surprised to see the subgroup analyses presented from the VISION trial and one of those subgroups, it was just one line presented, but it seemed to imply, and again I don't think this was a preplanned analysis, but it seemed to imply that the patients who got lutetium in combination with a novel hormonal therapy agent did better than those who didn't get the novel hormonal therapy agent. What does this group think about that? Because I don't know what to think about it.

Pedro C. Barata, MD, MSc: The study was designed, we're talking about VISION Phase 3, 221, and the basically is lutetium in addition to the standard of care. The standard is relatively limited because you allow an NHT oral steroids or palliative radiation therapy. We were limited to things like radium or chemotherapy or investigational drugs. And at the time I also don't think we knew as much as we know today about the activity of lutetium by itself. And a lot, and it is true that a lot of patients were heavily treated because those meet the criteria, required 1 or 2 prior lines and one and at least one NHT if you will. And you're right. And we think about the second agent, either way I summarize it, I usually think about 3, 4 months RPFS if you will. It's a rough estimate. Don't quote me on that. But that's usually what we see when say the control arm is not underperforming. You expect about around those in terms of RPFS. It's not zero. But if you don't do anything to that patient, the question is when he is going to, the patient is going to progress by itself or declared progression. With all that said, If you've done abiraterone and abiraterone has worked for a long time and then you have never done a dexamethasone approach, some of those patients that I don't think we've seen the data clearly got abiraterone combined with lutetium with the dexamethasone and we have some data from Dr Attar, for example, showing that the steroid might matter, it's not trivial the steroid we use. And even though of course we got it approved, and by the way, we got prednisone approved initially as 10mg to compensate adrenal insufficiency then we come down to 5mg. But some folks will use dexamethasone. And I do think things like this might be nuanced, because it was not powered to answer the question, and then you have things like therapy comparing lutetium PSMA against cabazitaxel and you did it by itself. It's lutetium or cabazitaxel. You're not doing a combination approach. The way I put it all together is you don't quite know exactly what the second agent that's not lutetium is bringing to the table. We also know steroids is not placebo. And I do have to admit that in all our studies, in all our patients on study, we did it a standard of care and I have, I tended to do that in the expanded access to lutetium, I tend to do it as long as patient is not having side effects from the molecule and certainly has not seen one of the NHTs, I still, I'm still considering it.

Evan Y. Yu, MD: Would you use lutetium with something else?

Pedro C. Barata, MD, MSc: With something else, if knowing all the caveats or factors that I mentioned.

Evan Y. Yu, MD: Others? I'm curious.

Andrew J. Armstrong, MD, MSc: Yes, I agree with you. There's data that using an AR inhibitor can up regulate PSMA so it's possible the data is true in vision that there is an incremental survival benefit because you're upregulating the target of the vision therapeutic. It's also possible that, like Pedro said, patients who are, who have chosen to get that AR inhibitor have a different prognosis and that it wasn't due to the AR inhibitor. It's just the patient selection.

Evan Y. Yu, MD: Patient selection. Sure.

Andrew J. Armstrong, MD, MSc: When you have a trial where that aspect of the trial is uncontrolled, you don't know. So, it warrants prospective validation.

Evan Y. Yu, MD: It's of interest, but that analysis doesn't mean that we have to do it in that combination?

Tanya B. Dorff, MD: No, absolutely not.

Evan Y. Yu, MD: That's what I was thinking too but I wanted to hear what my colleagues have to say.

Mary-Ellen Taplin, MD: Andy, do you think there will be data with a PSMA PET scans to be able to show upregulation of PSMA?

Andrew J. Armstrong, MD, MSc: Yes, there's plan studies and funded grants around short-term PSMA, maybe 2, 3 weeks after the therapeutic agent to see if that's true. There's been some pilot data around that suggesting it may be true. Because it's transient. Because after you downregulate the tumor, you cytoreduce, it starts to go away again.

Evan Y. Yu, MD: But I will say there's also unpublished data that shows that that doesn't happen. There are groups that are working on it.

Andrew J. Armstrong, MD, MSc: Equipoise.

Evan Y. Yu, MD: We don't know yet about this transient upregulation in PSMA. Is it a real thing or not?

Pedro C. Barata, MD, MSc: And just to go beyond and she will also have the discussion around whether a multiple combination deficient has been affected.

Andrew J. Armstrong, MD, MSc: And the damage seems upregulated as well.

Transcript edited for clarity.