Alicia Morgans: Hi, I'm so excited to have here with me today Dr. Neal Shore of the Carolina Urologic Research Center, where he practices in Myrtle Beach, South Carolina. Thank you so much for being here.

Neal Shore: Great to be with you.

Alicia Morgans: Wonderful. So I wanted to talk with you about non-metastatic, castration-resistant prostate cancer. We've recently heard updated data that some of the agents that are currently approved for non-metastatic CRPC actually prolonged survival, w9hich is something that we've been waiting for for some time. We had a metastasis-free survival endpoint on which these agents were approved. But now we see that they're actually helping people live longer as well. I'd love to get your take on that.

Neal Shore: Yeah, so I think this is a really remarkable and tremendous breakthrough in many ways for the people who conducted the research, for the patients who've participated in the studies, and most importantly for patients to benefit, and also for clinicians to expand our armamentarium for patient shared decision making. So let's recall that as of January 1, 2018, we had no Level 1 evidence for any treatment for index case one AUA CRPC guidelines. The nmCRPC patient or the M0 CRPC patient. And we say M0 based on conventional imaging, CT scan technetium bone scan, the basis of all of the Phase III trials that led to approval and all the globally approved mCRPC agents. Fact, right?

Alicia Morgans: Absolutely.

Neal Shore: So then fast forward from 2018 to now we have Level 1 evidence that three different drugs, apalutamide, enzalutamide, darolutamide, met the primary endpoint of metastasis-free survival. Or kind of a co-primary endpoint of progression, imaging progression, and/or death. And to your point, up until literally a week or two ago, we didn't have any OS, overall survival data. And so some of our colleagues were like, "Well, I don't know about this MFS endpoint. I don't know, even with the rigor of a PSA doubling time of 10 months or less, it's not enough for me. I want OS data." Well, now we're going to get OS data. And two of the trials, the PROSPER trial, which is the enzalutamide trial, and the ARAMIS trial, the darolutamide trial, have now had a public release statement saying that they successfully met OS. And that's all we really know at this point that's been released. And I suspect we'll probably see it at an upcoming major conference this year, that data presented. So I think it's great.

And so in some ways, it puts to bed the argument that... Not completely, but some will say, "Well conventional imaging, what if I get next-generation imaging and I demonstrate that a patient is positive, say, on a PSMA gallium?" Well, in my mind now with OS data that's positive, in addition to the MFS data that's positive. These are really good drugs and drugs that should have an opportunity to have the conversation with patients and say, "You can benefit from this delaying metastases, delaying the need for antineoplastic therapies, delaying the need for chemotherapy, and survival benefit as well."

There have been quality of life measures and the data's been published very nicely by our colleagues showing that there's minimal, really a very small impact in terms of taking the active treatment, whether it's apalutamide, enzalutamide, or darolutamide versus the placebo control arms. So I think this is really a sea change in terms of conversation and the importance of getting these therapies in earlier, rather than later. Because we have many other therapies that can still benefit patients.

So the nmCRPC approved therapies, we have three of them now. And I just think it's really wonderful that we have the ability to be really proactive prior to 2018 when we were just sort of like, "Well, we'll just kind of keep an eye on your PSA and keep imaging you and at some point, we'll convert you to mCRPC." Patients would say, "Well wait a minute, my PSA is going up and you don't have a Level 1 evidence to give me information." And now we do. Now we have survival benefit.

So I think it's really great because we can add on afterward when patients will invariably progress. In the US we have immunotherapy in the form of Sipuleucel-T. Pretty much globally we have the ability to have both docetaxel and cabazitaxel, as well as radium-223, and of course clinical trials. And then going forward into the future is the whole notion and excitement around biomarkers and genomic profiling. And I'm sure in 2020 we'll see the approval of probably at least two PARP inhibitors for the patients who would benefit as well.

And there are so many other druggable targets that we're working on. So our goal as you've said earlier is we want to make sure we get as many of the effective therapies in a timely way. That helps patients not only prolong their survival, but preserve the quality of life, and prevent complications of therapy. And sort of a fourth thing that I've become more interested in, and I know you have to, is trying to understand people's preference values and trying to understand their risk-benefit analysis that the patient may take into it. Vis-a-vis their sense of AE assessment.

We, I think as clinicians, have sort of been sometimes not as tuned in to what is truly important to patients because we've learned a lot more, haven't we? We've both done a lot of work on the importance of cardio-oncology assessment, but now we're starting to do a lot of work, and you're really one of the world's experts now on this, is neuro-oncologic effects and I think some of this will start to really begin to bubble up with the advent of these three new approved agents in the non-metastatic CRPC arena.

Alicia Morgans: Absolutely. So I wanted to commend the FDA also for thinking about this MFS intermediate endpoint on the way to an OS endpoint. We had some information from ICECaP and different populations that this endpoint may be meaningfully tied to survival. And we thankfully have seen that we are by earlier treatment shifting the trajectory of disease and helping patients live longer.

So I do want to acknowledge that and recognize that the FDA I think is trying to do everything they can to support patients receiving these drugs as early as possible. But now we really do know that we're shifting that trajectory and overall survival is not something that we can quibble over. You're either alive or you're dead, and that's important. But what's also important is exactly what you're saying. How are your days? Is your time quality time? And more often than not, I have patients tell me that what is most valuable to them is quality time, not just time.

And so I think understanding the patient-reported outcomes, the side effect profiles become really important. And they are a little bit different between all of the agents that we have at our disposal. So the patient-reported outcomes actually look quite similar that all of these agents from a patient-reported perspective seem to maintain quality of life. Most of the patients in the non-metastatic CRPC setting are asymptomatic to start with very little pain and very little loss of function.

It does beg the question are the measures that we are using actually sensitive enough to understand patients that are generally feeling pretty well because the ceiling effect I think is probably coming into play? But these are the measures that we have. Measures that were incorporated into these studies years ago when they were started. And hopefully, future studies will perhaps be a little more sensitive around things like fatigue and cognitive function in particular. But when we think about the side effect profiles of all of these agents, although they're all generally quite well-tolerated, there are some differences. How do you think about some of the differences in adverse events? For example, between darolutamide, enzalutamide, and apalutamide, the three drugs that are available to us?

Neal Shore: Yeah, so it's a really important question. And so the first caveat statement is that we don't yet have any reported direct comparator trials. Very important to say that. So all we can say is what has been stated in the presentations in the public domain, and what has been published. The SPARTAN, PROSPER, ARAMIS have all been published in the New England Journal. And so folks can really look through the AE event tables, the side effect profiles from Grade 1 to Grade 4, and they can glean what they can from that.

So to your point earlier, even though there's sort of what we call the MedDRA a dictionary or the lexicon on how we describe AEs, the way the AEs are actually reported in the trials varied a lot. And what was actually reported varied too. The clinical endpoints are really pretty consistent. The harmony around PSA doubling time of 10 months or less, consistent. The lack of use of bone health agents, pretty consistent. SPARTAN and PROSPER, about 10% of patients. Only 3% in ARAMIS. There were some differences.

So one of the things that I've been working on is this kind of an analytical methodology with some very smart statisticians to basically look at what's called match-adjusted indirect comparisons where you're trying to take variables where you take trials that are similar in their study schema, but that have cross differences in terms of heterogeneity and how things were reported. And try to find what was adjusted in terms of the data that was within the trials, yet albeit not completely harmonious. And so come up with some signals. And you're going to start to see in some early reports on this and different analyses, that may be helpful.

I think it will be helpful until we start to get more head-to-head prospective comparator trials. But just kind of in a nutshell, what was reported in PROSPER was a slight increase in the treatment arm versus the control arm of some cardiovascular effects. We also saw some increase in falls and fractures. And in the SPARTAN trial, we similarly saw some increase in falls and fractures. As well as all the three trials inclusive of ARAMIS have some increase in fatigue.

Additionally in ARAMIS, we see an incidence of rash. And what was interesting in ARAMIS, the way that trial came out, an increase in fatigue like within SPARTAN and PROSPER. But really within its label and based upon what they reported, we're not required to state an increase in falls and fractures. And so I think really, for now, we have this collection of really well-done studies, globally conducted, prospectively performed now all approved. And it's really, we can look at these match-adjusted indirect comparison analyses until we get additional prospective direct comparator studies as well. And then most importantly for most of our colleagues, it's probably their real-world experience in using these drugs.

Alicia Morgans: Absolutely. And talking to patients about, what are your risks for this or that? What are your preferences around rash, or blood pressure control, or thyroid monitoring? And patients can help to guide us too. But I think the bottom line and the way I am happy to close this conversation, is to say that we have three approved agents. We can make a difference for patients. We are prolonging metastasis-free survival for sure. And now two of these studies have shown us that we're actually shifting the curve and we're prolonging survival.

I have a feeling the third will show us the same when that data is mature. So that's still to come, of course. But it is a good day for patients and an important thing for clinicians to understand, that earlier treatment of these patients in the non-metastatic CRPC setting can actually not just prevent metastatic disease but can help all of our patients who have this condition live longer.

Neal Shore: Yeah.

Alicia Morgans: Absolutely. Well, thank you for your time.

Neal Shore: Thank you.