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Alicia Morgans: Hi, I'm delighted to have here with me today Dr. Evan Yu, Professor of Medicine at the University of Washington, Fred Hutchinson Cancer Research Center. Thanks so much for being here.

Evan Yu: Thanks for having me, Alicia.

Alicia Morgans: Of course. I wanted to talk to you today about the changing landscape in metastatic hormone sensitive prostate cancer, non-metastatic CRPC. There's been a lot in the air. Let's start with metastatic hormone sensitive disease. How have the new trials, the new drugs, the new approaches really come into play, I think, in your practice, and then what are you thinking about with sequencing downstream?

Evan Yu: Well, I think the principle that our agents that are efficacious and prolong survival in the metastatic castration resistant prostate cancer disease state, it's really coming alive in the earlier disease states. When we migrate these agents earlier, the survival benefit is really quite amplified. That really first started with the CHAARTED trial and the STAMPEDE trial where docetaxel was adding significant survival benefit maybe in the year and a half to two year median survival benefit range for those with new metastatic hormone sensitive prostate cancer. Then we saw the LATITUDE data and the STAMPEDE data with abiraterone in that setting with the hazard ratios looking very similar. There's quite significant benefit. I would say from my point of view, one wonders whether not knowing which one is best for which situation, whether the combination of all of it might be the way to go.

We saw just recently at GU ASCO that there was data using enzalutamide in that disease state and that improved radiographic progression free survival. Overall survival data is still not yet mature. At ASCO this year we'll see from the TITAN data the use of apalutamide in this setting. From these newer studies, as well as ENZAMET, we might start to learn some data in regards to the combination of all of it, and ARASENS as well. ENZAMET is with enzalutamide, ARASENS is with darolutamide, but some of these studies are really starting to do combination with androgen deprivation therapy, docetaxel chemotherapy and the novel hormonal agent. We may find that the way to go ultimately is to combine all of it to get maximal benefit.

Alicia Morgans: I totally agree. I think considering the heterogeneity of this disease or what we presume is heterogeneous disease, if we use different mechanisms of action, different approaches, we might do better, of course, but if we start incorporating chemo hormonal therapy and AR directed therapy in the metastatic hormone sensitive setting for example, what does that do downstream and how are you thinking about the next treatment that those patients need?

Evan Yu: Yeah, we're just starting to learn about that now because I think in the clinic we're just starting to see some patients emerge in that situation where they've had our therapies that traditionally have been used later, now received it in an earlier disease state, and what's emerging is something that's already resistant. The concern is that you have some super resistant cancer that you might not have great therapies for, but fortunately, in prostate cancer, we have all different therapeutic agents that have different mechanisms of action. That's kind of the principal I take to it. If the patient is getting early chemotherapy, early potent AR targeted therapy, when they progress to mCRPC, I'm really concerned that because they're pretty resistant already, I'm going to go to something with a different mechanism of action. For instance, if the progression is very kind of slow or indolent, that's an opportunity to introduce sipuleucel-T. If things are moving faster, if let's say the patient has more visceral lesions, then chemotherapy then. If a patient has bone metastasis, bone predominant progression, especially if they're having symptoms then radium-223 is the way to go there.

I'm looking for something with a different mechanism of action and I'm also looking to the future saying that this is really a great unmet need. Traditionally we have always started in the post docetaxel disease state for metastatic castration resistant prostate cancers, the newest agents should go right there at the very end, but I think one of the great unmet needs will be, as our patients receive all these therapies really early, first line mCRPC will really become a great unmet need there. I think we need to do more clinical trials with our novel agents there.

Alicia Morgans: Are there agents that you're particularly excited about in that setting or approaches? Are you thinking about genomics and profiling? What are you doing maybe in trials and in practice to address that?

Evan Yu: Yeah, so that's a good question. I think the first thing that I do is anybody who has metastatic prostate cancer, whether hormone sensitive or castration resistant, I am at least doing germline testing, because the data shows there's a 12% risk of a germline inherited DNA repair alteration. That not only has implications potentially for treatment, for instance, PARP inhibitors, platinum chemotherapy, et cetera, anything that induces double strand DNA break should work for those patients, but it also has implications for families. If this is germline inherited, these gene alterations not only predispose to prostate cancer, but they predispose to breast, ovarian cancer, other malignancies as well. Our hope down the road is that if you identify a patient with that, their siblings, their offspring if they're counseled and they undergo screening and we find that they have the same germline alteration, we're going to approach that patient differently in regards to their cancer screening. We might save a lot of lives down the road. That's one thing I definitely do and not only has therapeutic implications for the patient, but it has significant cascade testing, downstream family counseling implications there. That's one thing that I do.

The second thing is I'm looking at what's the real future of this field in regards to therapy? Well, I just mentioned PARP inhibitors and platinum because those that have homologous recombination deficiency, DNA repair alterations, the whole hypermutation, microsatellite instability field, that's emerging as well. We're finding that in maybe 5 to 10% of patients with metastatic castration resistant prostate cancer. Those patients, they have more targets for immunotherapies to work, immune-oncology agents like the PD-1, PDL-1 antibodies. That's another thing to keep an eye on, well, combinations of those, PARP inhibitors and PD-1, PDL-1 antibodies.

I would say the third thing that I would really pay close attention to are the theranostics, the radioligand therapies targeted towards something like PSMA, and you can attach beta emitters, alpha emitters, things like lutetium, actinium, thorium. These can be attached to either antibodies or small molecules that'll find their target, PSMA just being one, STEEP-1 being another target, and then bring the radiopharmaceutical to that area and it has very promising efficacy and is currently in multiple Phase 2 and Phase 3 trials, these classes of agents.

Alicia Morgans: Absolutely.

Evan Yu: Those are the things I look forward to.

Alicia Morgans: Great. Well, shifting gears just a little bit, but still talking about this disrupted landscape, the non-metastatic CRPC setting has also really undergone a lot of advance recently. We didn't use anything in that space before. We didn't have any drugs that we knew actually were efficacious, at least in terms of this new endpoint that we have, metastasis free survival. What do the changes in the non-metastatic or M0 CRPC space, what do those changes do to your practice in the downstream sort of thinking about again sequencing and what do you do after someone progresses?

Evan Yu: Well I think it's quite similar to the metastatic hormone sensitive disease state in the fact that if we take our efficacious agents for mCRPC and we move it earlier, then what emerges is likely to be a more resistant beast. What you're alluding to are three randomized controlled trials for the M0 castration resistant prostate cancer setting, so patients on androgen deprivation therapy, castrate testosterone levels, rising PSA. The study required eligibility where PSA doubling times were less than 10 months. If you look at the studies, I think over 70% of the patients had PSA doubling times less than 6 months. This was not an indolent patient population. These patients are prone to and will imminently, eventually develop metastases found on standard imaging studies.

What they found in three different randomized controlled trials are that agent's like apalutamide, enzalutamide, darolutamide, these are all pure AR antagonists, that these improve metastasis free survival. Metastasis free survival, in the ICECAP study, showed that it has pretty good surrogacy when compared to overall survival. It's an approvable endpoint in prostate cancer now, and hence we've seen the approval of apalutamide and enzalutamide, and we'll wait to see what the agency says about darolutamide with that data. Again, I think the principle's the same. Now that we have these agents here, now that we're using them there, what emerges on the back end when somebody develops mCRPC is much more resistant. The same kind of buckets that I used earlier where more indolent progression, I'm going to give sipuleucel-T, if it's more visceral disease, we are at rapid progression is going to be chemotherapy, and then for bone metastases, bone progression with symptoms, that's going to be radium-223.

Alicia Morgans: What do you think about those patients getting radium? Are these patients who necessarily need to be symptomatic because that's something that I talk to patients about a lot? How do I choose between chemotherapy and radium and what is the thought process that you use there, other than visceral disease?

Evan Yu: Yeah. I think when you look at this trial, how radium was designed in the Phase 3 trials, ALSYMPCA trial, they mandated that you had bone metastatic castration resistant prostate cancer and that you had some symptoms. Now the thing to keep in mind is many of the patients did not have a lot of symptoms. It was very mild symptomatology, maybe a site of bone metastasis that correlated with a site on a bone scan. They said, "It hurts here," or just Tylenol, ibuprofen. I think over 40% of the patients were not even receiving narcotic pain medications. Everyone equates symptoms with, oh, really bad bone pain, but that's not the case. You don't need a lot of symptoms, which gets to the point that you probably don't even need symptoms. If you have bone metastases, this probably should work. That being said and done, the label says with symptoms, but I think symptoms is subjective and we can find patients with minimal symptoms from their disease pretty easily if we ask the right questions.

Alicia Morgans: Okay, great. When you think about this changing landscape and all that seems to be going on, what is your overarching message or what would you say to clinicians who are watching this and trying to understand how do I sort through all of these options in my practice?

Evan Yu: Yeah, I think one thing that I have heard people ask me about, not just patients but other clinicians, are that, oh yeah, we're using all these drugs earlier, but you even agree that we're creating some kind of super aggressive beast downstream. There's some caution about that, moving these agents earlier. I urge people not to have caution. The data is the data. There's huge benefits there, huge survival benefit, huge metastasis free survival benefit. It's not subtle benefit, it's big survival benefit. The principle holds true that moving these agents earlier leads to dramatic survival benefit. Yes, you might create a more aggressive beast later, but at the end of the day, the benefit you get and all that extra time you get by using it earlier still outweighs what sort of aggressiveness you might see later. I'm confident in our field with all these new therapeutics that are coming that we'll be able to address what sort of aggressive beast arises later.

I mean, we're learning so much more about the biology of prostate cancer, the DNA repair deficiency issues, the microsatellite instability, hypermutation issues. There's amphicrine phenotypes that express both androgen receptor and neuroendocrine phenotypes, like synaptophysin, chromogranin A. There's double negatives that don't express any of them that might be driven by fibroblast growth factor receptors. We're learning a lot more about the biology. We're eventually going to be able to molecularly stratify better and have agents that can attack those different mechanisms. Again, the benefit's real. Don't be cautious in using those agents when there's clear benefit there earlier. We'll address it later when we get there because we have so much exciting biology that we're learning and so many exciting new therapeutics that are being developed.

Alicia Morgans: Absolutely. To really think about, and you said this several times, making sure that you choose a different mechanism of action. After you move these things forward, you have to use a different strategy to attack. We've seen this in the PLATO trial and we've seen this in other settings, that you have to vary that mechanism. Then though we may be driving the biology in a different direction, we are actually evolving in a way, at least in terms of available therapeutics, that we are going to be able to attack different targets later on. I entirely appreciate your expertise and your message of hope and encouragement to everyone. Thank you so much for your time, Evan.

Evan Yu: Yeah. Thanks for having me, Alicia. It's always great to be here.