Charles Ryan: Russell, great to see you. You have the honor of being the discussant at the oral abstract presentation here at ASCO in Chicago in 2022 and you're discussing three abstracts in a really important space, metastatic hormone sensitive prostate cancer, which arguably has become the most dynamic space in the field in the last few years. Tell us what you're discussing and your views on it.

Russell Szmulewitz: Yeah, thanks. Good morning, Chuck. So, I'll be discussing three abstracts, all focused in mHSPC and the title is “Making Sense of the Intensified Landscape”. So, as you sort of allude to it's an exciting time in the field, but also a confusing time in the field and so I'll discuss these three abstracts and then try to put them in a larger context.

So, the first is an updated long term survival analysis of the ENZAMET trial, which was a randomized open label study of enzalutamide versus nonsteroidal and only nonsteroidal anti-androgen with testosterone lowering therapy for HSPC and this was their long-term survival data and it was exciting to see and so with much longer follow-up, there was a sustained improvement in an overall survival and what's striking to me is that's despite three quarters of the patients essentially crossing over, getting either enzalutamide or abiraterone acetate upon progression to CRPC. So, it really does confirm to us that earlier is important with these androgen receptor signaling inhibitors.

Charles Ryan: I think we should stop there and pull on that thread a little bit because this is a really important, teachable moment I think for the field, in general, and for people who are out there who may have doubts about intensification of therapy. Because of that large crossover proportion, you are clearly demonstrating, or suggesting, that earlier is better and there are still, I think, patients out there who unfortunately are sort of put on ADT LHRH therapy only with the intent to add later for the reasons of avoiding side effects or cost, but that comes with a survival deficit.

Russell Szmulewitz: Yeah. So I think that assumption that some people falsely make is that, "oh, there's a survival benefit but not everybody really gets to second to the androgen receptor signaling inhibitor down the road, but my patient will, so I'll spare them any potential toxicity”. And I think what we're seeing is with longer follow- up is that even when nearly all the patients make it to the same therapy later on the road, there's still a pretty sizable survival difference. In their analysis, which they show is that at five years, there's a 10% absolute benefit in overall survival. So that's, to me, pretty meaningful.

Charles Ryan: And I think that the other point is that you've shifted this use of intensified therapy, and hormone sensitive disease, has shifted the survival of the population. So, another myth we want to get over is that somebody presenting with metastatic disease has only an expected survival of a couple of years. We're actually seeing survivals now into the six, median survivals six, seven, eight year timeframe and it's actually expanding.

Russell Szmulewitz: Yeah, and in their paper with around five years follow-up, the median wasn't reached.

Charles Ryan: Right.

Russell Szmulewitz: In the ENZAMET enzalutamide intensified arm.

Charles Ryan: Right. So that's a really important point to be made. It applies in this case with ENZAMET to enzalutamide, but we could almost just as easily be talking about abiraterone versus ADT alone.

Russell Szmulewitz: Yeah.

Charles Ryan: Apalutamide, Darolutamide et cetera. So, let's go on to the next abstract that you're discussing.

Russell Szmulewitz: Sure. The next abstract is about a phase three study from China of a new oral agent called SHR3680, which is an oral androgen receptor signaling inhibitor and similar to ENZAMET but in a different patient population, as this was 90% in China. They randomized against bicalutamide, and this is only in a higher risk patient population, and I think what they saw is a similar hazard ratio for overall survival of about 0.6, a little bit less, and it was actually quite well tolerated. So, we're now seeing in multiple patient populations across the world that even with an active control in bicalutamide, in a high-risk population, you're seeing a survival advantage to early.

Charles Ryan: And this study done entirely in China.

Russell Szmulewitz: 90%.

Charles Ryan: Yeah. Looking at an Asian population, which, some argue, they have been underrepresented in many studies and may represent an area where we just don't have complete data on correct natural history in that genetic background.

Russell Szmulewitz: Correct. It's also notable as around 20% of the patients in that study had visceral disease, and that's a pretty high risk population and that's another population we're not entirely sure that the benefit but I think we're seeing it pretty clearly with this study.

Charles Ryan: So, what would you think about a new drug in this space? We have so many now and is there a reason to think that this would be something different or is it probably a parallel development in a different country?

Russell Szmulewitz: I think the latter. I think it's a parallel development and tolerability is tough to compare cross trials.

Charles Ryan: Mm-hmm (affirmative).

Russell Szmulewitz: I think that what we need to do is move beyond ADT, or ADT in a nonsteroidal as the control, and really start to build on the platform, might've been an intensified.

Charles Ryan: Right.

Russell Szmulewitz: Landscape and then add drugs or use precision medicine to figure out the population to give something else to.

Charles Ryan: Right.

Russell Szmulewitz: And then all else being equal, I think we have to look at cost and we should really be in a competitive market where these drugs having multiple options has to be beneficial from an economic standpoint. It hasn't been but hopefully with more options, it will drive down the cost of society.

Charles Ryan: Yeah. We certainly hope that would be the case and any unique toxicities from that therapy that we should be aware of?

Russell Szmulewitz: You know, not really. It was a little bit worse from a fatigue standpoint and so forth, as you would expect compared to bicalutamide, but really quite well tolerated.

Charles Ryan: And so no reemergence of seizures or anything like that?

Russell Szmulewitz: No.

Charles Ryan: Great. So the final abstract you're discussing is one from professor Susan Halabi of Duke, which is a statistical analysis, which is really helping to look at outcomes and intermediate endpoints in clinical trials. Discuss that one for us.

Russell Szmulewitz: Sure. So for forever, overall survival is really the benchmark that studies need to hit in the phase three setting and in castration resistant disease, an analysis similar to this several years ago, cross studies really showed that radiographic progression free survival was an established intermediate surrogate for overall survival. Meaning that if a large study showed that there was an improvement in radiographic progression-free survival, we could be confident that would track with overall survival. And so, this analysis is in similar, but in hormone sensitive metastatic prostate cancer, she took multiple studies, with tens and thousands of patient level data, and really showed robustly, with fancier statistics, than I understand that both clinical progression-free survival as in stampede or radiographic progression-free survival were established surrogate, intermediate endpoints for overall survival.

So, it allows us to really think about the next studies we can use either clinical or radiographic progression free survival, which happens a couple, three years before overall survival, get our answers sooner and accelerate innovation.

Charles Ryan: Right. I think that's a really important point and that will help many companies get many new drugs launched. It'll help many patients live longer. It'll help many studies get done faster. If we get to the point where we only have to design a study to look at our PFS, or to look at PFS. This also recapitulates what we did in CRPC, right? Which we created correlation studies looking at PFS and overall survival and I think her work has to be celebrated and having an oral presentation in this venue is certainly I think, a good way to do that.

Russell Szmulewitz: Yeah. Exactly. She'll have to dumb it down for the rest of us from a statistical standpoint, but it's really powerful work.

Charles Ryan: Right.

Russell Szmulewitz: And it needs to be highlighted.

Charles Ryan: Right. Well, congratulations on...

Russell Szmulewitz: Thank you.

Charles Ryan: On your selection as the oral presenter. That's quite an honor in and of itself and great talking to you.

Russell Szmulewitz: Great. Thanks very much, Chuck.