Alicia Morgans: Hi, I'm so excited to join you today from APCCC 2022 in Lugano, Switzerland, where I have the opportunity to speak with Dr. Evan Yu, who is a Professor of Medicine and a GU Medical Oncologist at the University of Washington and the Fred Hutchinson Cancer Center. Thank you so much for being here.

Evan Yu: Thanks for having me here. It's a real privilege to be here at this meeting and in this wonderful landscape here with the lake and mountains behind us here in Lugano. It's great to be out in this time of COVID or as we're recovering from COVID.

Alicia Morgans: Yes, and it's a wonderful thing to have our community getting back together again and I'm so pleased to have you here to talk about some of the things that have happened over the last few years that have really disrupted the landscape and, I think, helped a lot of patients. One of the big questions is the changing landscape of metastatic hormone-sensitive prostate cancer treatment, where we've been using combination therapies, maybe an ADT plus something else, for a number of years, but now potentially have the opportunity to use triplet therapy in that setting. And so the question is, what do you do, in the advent of all of that progress, in the first-line mCRPC setting? And, of course, we wanted to ask you what you think about that.

Evan Yu: Yeah, it's a great question and it's really a data unknown space. What you're alluding to a metastatic hormone-sensitive prostate cancers, I think we've known through all the wonderful trials that we've had, that adding all these novel hormonal therapy agents clearly adds survival benefit. And now we have data from PEACE-1, with abiraterone being added at ADT and docetaxel, and with ARASENS, to darolutamide being added to ADT and docetaxel that we know that that adds additional benefit for that select patient population, which tended to be de novo metastatic disease. Generally a more aggressive patient subset, so I don't think everybody will receive that triple triplet combination, but a good chunk of patients will.

It just goes to show that your question about first-line metastatic castration-resistant prostate cancer is not only an unanswered question now, but a big unmet need. Traditionally, we've had lots of agents for metastatic castration-resistant prostate cancer, but now that we're using them all earlier, this is something we're going to be facing every single day in the clinic when we see a patient and they're going to be like, "Well, what do I get next?" And the truth of the matter is, we don't have contemporary data in this setting now because this is all new data being generated earlier. So I think we have to be pragmatic in recognizing that this is a fruitful area for clinical trial design, asking important questions, testing new novel therapies, and asking the question, can we establish a new treatment paradigm in this day and age?

In the absence of that, I think we're left with saying, "Well, what did you receive before already?" If you came through the metastatic hormone-sensitive route or you came through M0 CRPC and you just received, let's say, enzalutamide, apalutamide, darolutamide, or abiraterone, didn't receive chemotherapy, and especially if you're starting to progress with a fast-rising PSA in that metastatic castration-resistant prostate cancer space, I think docetaxel is the next obvious thing.

That being said and done, what if you've received triplet therapy? Now, I think we can look to the VISION trial with lutetium-617-PSMA and recognize that the label's loose enough where that therapeutic could probably be inserted there already. And then you have to ask yourself, "What if you just received ADT and docetaxel and you didn't get abiraterone, enzalutamide, et cetera, et cetera?" Well, I think that's a fruitful place to use that.

The one challenge that we face is a lot of times for first-line mCRPC, our patients aren't progressing symptomatically or rapidly, they're just starting to see a slow rise in PSA. Those are patients that don't really want to change, maybe the abiraterone or enzalutamide that they're on, and that asks the question now, is there room for hormonal switch, back-to-back hormonal therapy? Which is something that we've kind of all discouraged because we recognize it doesn't work very well. But again, shared patient decision-making is important and a lot of our patients, that's what they want. They recognize that the response rates aren't high, but they're willing to try it for a few months and if it works, great, and if it doesn't work, then they'll move on to more aggressive therapy.

That's kind of how I lay it out. I will just add, occasionally you get somebody who has a lot of bone disease and they're progressing symptomatically. In that situation, I think it's still an opportunity to use radium-223. But again, I think there's going to be a lot of opportunity for newer therapies to move earlier and I think there's a good chance radioligand therapies move into that space.

Alicia Morgans: Well, thank you for walking us through that, because it's not easy, and as we can see, it's not a one-size-fits-all. What do you think about some of our older therapies, like sipuleucel-T, or newer ones, pembrolizumab, olaparib? Where are you working those in, if at all? And what about testing to identify patients?

Evan Yu: Yeah, excellent question. Sipuleucel-T is still something that I use, and I tend to reserve it for patients with pretty indolent progression. That might be the patient who has a very slow PSA rise. The challenge is if they've been treatment intensified. Let's say they're a patient that's on androgen deprivation therapy in abiraterone. My concern is, if their PSA's rising solely on that and you remove the abiraterone to give the sipuleucel-T, do things just take off on the patient? So it is a caution that I'd have and I'd do it for select patients. I think, for instance, if a patient received androgen deprivation therapy with docetaxel and hadn't received abiraterone first and had a slow rising PSA and lower volume of disease on imaging, that might be an ideal patient still for sipuleucel-T. So I still think there's room for it. It might be a smaller and smaller niche.

Now, you ask, another great question is, when do you do testing for next-generation sequencing? You can make the argument to do it for anybody with metastatic disease. I tend to do it when somebody has metastatic castration-resistant prostate cancer, recognizing that I might not reach right away for a PARP inhibitor if, let's say, they have a homologous recombination deficiency, BRCA1 or BRCA2 alteration, I might not reach right away for pembrolizumab if they have microsatellite instability, mismatch repair deficiency, or hypermutation, but that might be my next line agent for mCRPC, second-line agent. Now, that's debatable. Some people might want to reach for it right away. But if you stick strictly by kind of the labels, regulatory labels out there, they probably wouldn't be your first-line therapy. But the first line, because it does take some time for testing, that's probably where you ought to test these patients if you haven't sequenced them already. So I will definitely do that sequencing, looking for opportunities to use PARP inhibitors to use immune-oncology agents.

Since we're talking about pembrolizumab, I think many people have heard that the KEYLYNK-010 trial has read out, and we haven't seen the data yet, we'll see it soon, but that's a combination of pembrolizumab plus olaparib versus switch to another novel hormonal therapy agent that did not read out positive in its initial press release. We'll certainly see data at an upcoming meeting there. But I don't think that means that pembrolizumab combinations are out just yet. There's still a great combination trial of docetaxel plus/minus, and that would be very, very interesting and would reach a broad patient audience if that were a positive trial. So, we still have to wait and see, but I think there's opportunity for some of these other agents still.

Alicia Morgans: Wonderful. Again, thank you for that great answer. The final thing I want to pick your brain about is the combination, PARP abiraterone, and we saw two studies recently really combining abiraterone with the olaparib or abiraterone with niraparib, and saw a PFS benefit in both of these situations. In one, in an all-comers population, in the other, in a DNA repair defect selected population. This was first-line mCRPC. What do you think about incorporating that? How frequently will that occur? And in whom would you say that data is ready for prime time, if anyone?

Evan Yu: Yeah, great question, and you leave the toughest one for the end. It's real provocative data, so I think you're referring to the MAGNITUDE data with niraparib, where that was a biomarker-selected patient population and two cohorts. Clearly, the biomarker-negative patient population that didn't have homologous recombination deficiency, that was negative. So we'll take that out of the way. But for the biomarker-positive population, there was an rPFS benefit with abiraterone plus niraparib. I think it'll be interesting to see. Is radiographic progression-free survival enough in that situation? There is no label for niraparib in this setting, but certainly we know that there's a label for rucaparib, there's a label for olaparib, it's all within a similar class. Will rPFS be enough?

I do have some questions, however, in the fact that, what I don't know is, is combination of abiraterone-niraparib better than sequencing of abiraterone followed by niraparib, and this study can't answer that. It would be nice to be able to answer that because obviously when you combine two agents, I think the toxicity profile was quite well tolerated, but it is more when you give them together than when you just give them separately and sequentially. I think that's an unmet question or an unanswered question, and I do ask that. So, I guess, without seeing overall survival, without knowing whether sequencing versus combination there, is a definitively in favor of combination, I think I want to see more data.

The other study you allude to is the PROPEL study with combination abiraterone and olaparib, and that's really interesting, is that it was completely biomarker unselected. They obtained the biomarkers and did the next-gen sequencing after the fact and then reported it out the data. But for the entire unselected population, there was an rPFS benefit. I think we have to ask ourselves, what is it? What's the biology there? We don't know. There's some preclinical data that shows that, yeah, sure, when you use an agent like abiraterone, maybe it makes the environment more potentiated to response to a PARP inhibitor, and vice versa. When you give PARP inhibition, maybe it makes abiraterone work better.

These are all early preclinical studies and I would say that maybe this is some evidence that that is panning out. Maybe it's also that we know that PARP inhibitors aren't completely clean and there's some off-target effect and that when they were developing niraparib, they had to lower the dose a little bit in that study, whereas olaparib, they went full steam ahead at the higher dose. Maybe there's some off-target effects there and some cell cycle effects. I'm just theorizing right now, but I think that's what we can do here at UroToday.

Alicia Morgans: Yeah, of course, of course.

Evan Yu: So, just throwing out some random thoughts. I think that'll be really interesting to see. I definitely want to see overall survival data, but I'm keeping my eye closely on that, and it is an opportunity to change standard of care in the future, especially if we see overall survival data. So very provocative questions. More to come later.

Alicia Morgans: Wonderful. Well, thank you so much for indulging me today, because these were some provocative questions and I really appreciate your time and your candor. Thank you so much, Dr. Yu.

Evan Yu: Well, thanks for having me here. It's great to be here again at UroToday.