Rana McKay: Absolutely. It's my pleasure.
Zachary Klaassen: As always, there's another meeting around the corner with just practice changing data. And so we're going to go through several of those trials. Of course, we haven't seen the data yet, but we're going to just pontificate about what this may lead for practice as we go through the meeting and as we get back into our clinics over the summer.
Rana McKay: Love that.
Zachary Klaassen: Basically, we're setting the stage for this discussion. I'm just going to go through a quick intro of each study and then we'll talk about them. So the first one we're going to talk about is PROTEUS, which is perioperative apalutamide plus ADT versus placebo plus ADT in men that are undergoing radical prostatectomy for high risk disease. This is the PROTEUS study. We've been waiting a while for this study. This is going to be presented by Dr. Mary-Ellen Taplin on Sunday as a plenary at ASCO. And so just to level set for our listeners, this is high risk patients, you can see them on the left, that have agreed to undergo surgery. They're going to get six months of APA plus ADT versus placebo plus ADT. They're all going to undergo a radical prostatectomy. They undergo six more months of whatever treatment they were having in their pre-surgical part of the trial.
And then the key endpoints here, pathological complete response, metastasis-free survival, secondary endpoints, PSA-free survival, progression-free survival. So we've been waiting a long time for this, Rana. What are your initial thoughts? It's a plenary, which is good. There's only seven trials in the plenary. What are your initial thoughts on PROTEUS in being presented?
Rana McKay: I think this is going to be an incredibly informative study and, if positive, will absolutely be practice changing.
Zachary Klaassen: Yeah.
Rana McKay: I think it's going to change the paradigm for people that have high-risk localized disease that elect to undergo surgery. There may be some candidates who, not to say may not have been surgical, but it may open up the window into people who could potentially be surgical candidates. The other really important thing about this trial that is going to be incredibly impactful for the field is the co-primary endpoint of pathologic response in MFS. Because by doing that and establishing in the context of a greater than 2,000 patient trial, that there could be a correlation between those two things will open up the door into leveraging the neoadjuvant window to identify a go, no-go signal for advancing a therapeutic into a larger study in this context.
And we are actually designing the ADAPT study. This study is being kicked off as a neoadjuvant platform trial that builds on the backbone of ADT apalutamide, testing novel therapeutics in this very high risk population. And I think what's so cool about that trial is we're targeting a population of patients that, with any one modality, have a very, very high relapse rate, close to 70 to 80%. So really it's focused on how can we enhance cure. So this is going to be really... I can't wait to see the results.
Zachary Klaassen: It's going to be great. I think, from just a surgeon perspective, I think I'm excited to see, hopefully to do some subgroup analyses with the really high risk patients, those Gleason 9s and 10s. I think those are the ones from a surgical standpoint where we haven't had data to suggest that surgery may or may not be the right thing to do. So I think, like you said, we'll all be tuned in on Sunday for that.
Rana McKay: Absolutely.
Zachary Klaassen: So let's move to the second trial, which is also exciting. TALAPRO-3. This is talazoparib plus enza compared with placebo plus enza for metastatic castrate-sensitive prostate cancer among men with HRR gene alterations. Our good friend, Neeraj Agarwal, will be presenting this on Saturday at the oral abstract session. So this is a pretty straightforward trial. All men, metastatic castrate-sensitive prostate cancer, HRR mutations, nearly 600 patients, one-to-one randomization, tala plus enza versus placebo plus enza.
And then the primary endpoint here, radiographic progression-free survival by investigator assessment. Key secondary endpoint, overall survival. So we've started to see TALAPRO-2 in the mCRPC first-line setting. Now we're moving it into the mCSPC setting. mCSPC is going to get busy if this is a positive trial as well, isn't it?
Rana McKay: Yeah, absolutely. I mean, I think we already see the data from AMPLITUDE as you've alluded to.
Zachary Klaassen: Yeah.
Rana McKay: And also an FDA approval of niraparib plus abiraterone only for BRCA-2 mutated mHSPC. So very, very narrow indication. So I think it's going to be really interesting to see this data, to see the data for the BRCA mutated group, the non-BRCA mutated group, and looking at the TOCs data, the performance of the control arm. I think we've all been eagerly awaiting. I do think that for those select individuals that have an addiction to the HR pathway, those tumors, the pathogenesis is being driven by those underlying derangements, I think the hope is that we can see a positive impact with early PARP inhibition.
Zachary Klaassen: Yeah, absolutely. I think too, another shadow, as always on UroToday for genetic testing and genomic testing, I think we all have to be doing it.
Rana McKay: Yeah.
Zachary Klaassen: Okay. Let's move to trial three. So this is the DREAM/Alliance A032101 trial. Interesting study. I'm excited to see this too. Phase two trial ADT interruption in patients that are responding to androgen receptor pathway inhibitors in mHSPC. This will be presented by Atish Choudhury on Saturday in the oral abstract session as well. And so this is a very simple phase two mHSPC on ADT plus ARPI. Great response. PSA less than 0.2 after 18 to 24 months of ADT and at least 12 months of ARPI. 75 patients. All these patients will then interrupt their ADT and their ARPI. They'll get three-month PSA testosterone checks, imaging every six months or as needed every three months with a rising PSA.
Reinitiation triggers, you can see here. PSA greater than five, radiographic progression-free survival or symptoms. Primary endpoint here, treatment-free at 18 months with a eugonadal testosterone. So when we look at this... I mean, we've done intermittent ADT for years. Now we're doing potentially intermittent ADT plus ARPIs. This is the first of a bunch of these deescalation trials coming down the pipe. What are your thoughts on this trial, Rana?
Rana McKay: I have to say kudos to the cooperative groups, right? For running this very innovative trial. I think this is a question that is at the heart of many individuals, patients and physicians alike, is, "Do I need to continue on therapy? If I have a dramatic response, if I hit a nadir PSA and I'm sustained there, do I have to continue treatment? And if so, what are the risks of that? And what's the likelihood that my T is going to recover if I do stop in this context?" So this trial is really beginning to dissect that and try to understand, is an interruption for those exceptional responders in the mHSPC setting associated with a negative outcome? Can you recover T and buy patient's time off hormone therapy?
So I think it's a very practical study. I think it's a very patient-driven study. So I'm going to be really interested to see the results as these unfold. And I think our patients too, our patient advocates are going to be really interested in this.
Zachary Klaassen: And it'll be nice to see some phase two data. I know there's some phase three trials coming down the pipeline that'll read out in the next several years, but just at least see this will be exciting for sure. All right. So let's move to our fourth trial. This is switching gears now to kidney cancer. This is going to be the ctDNA analysis from the KEYNOTE-564 trial. Obviously a really famous trial now five, six years in the post-initial presentation by Dr. Choueiri, who's going to be presenting this at the oral abstract session.
And so I'll just quickly go through this. This is high risk patients looking at adjuvant therapy. After surgery, you can see the criteria on the left. These patients then had pembro for a year versus placebo. This had DFS. This has overall survival. And so now, this has become routine clinical practice. We know some patients may be overtreated, so we have ctDNA to maybe guide us. What are your thoughts on this trial? This could be really exciting.
Rana McKay: Well, we know the trial is positive for both, improvements in DFS and OS. I think it's all about the assay with regards to ctDNA.
Zachary Klaassen: Sure.
Rana McKay: Because in RCC, yes, there's a risk that this tumor doesn't shed as much as urothelial, for example. But the assays, I mean, every time I turn, there's a newer assay with increased sensitivity and moving beyond just genome methylation and the depth of being able to assess the presence of tumor DNA is increasing. So I think the devil's going to be in the details around the assay and the prevalence of positivity. Like if you are positive, what's the prognosis that's associated with that? I think that the issue with kidney cancer has been, what do you do with the negatives? What's the percentage of people that are negative versus positive? And of the people that are negative, how do you discriminate in that group? And I think it's largely going to be assay dependent.
Zachary Klaassen: Yeah. And I think too, this coming after we saw belzutifan plus pembro versus pembro at GU ASCO. And so this will hopefully help us stratify some of these patients with ctDNA.
Rana McKay: Yeah.
Zachary Klaassen: All right. Last trial is your trial. This is the Alliance A031801 RADICAL trial, a phase two randomized trial of radium-223 and cabo in RCC with bone mets. You'll be presenting this at the same session as Dr. Choueiri, the oral abstracts. And so this trial is... I'm excited for this too because I think this is crossing radium from prostate to kidney cancer. Any RCC histology, greater than one untreated bone met, good performance status, and then randomization one-to-one to cabo plus radium six injections versus cabo alone. Primary endpoint here is symptomatic skeletal event-free survival, which I thought was innovative.
So we're crossing barriers here from prostate to RCC. What are your thoughts on this? I'm sure you obviously have seen the data.
Rana McKay: Yes.
Zachary Klaassen: But just tell us what your thoughts are on the trial design and just the genesis of this trial.
Rana McKay: I think this is a homebred story. Honestly, in the clinic, over a decade ago, seeing that patients with bone metastases do very poorly, we conducted several large database analysis through the IMDC and also through a large clinical trials database of pooled clinical trials data demonstrating that the presence of bone metastasis is associated with negative outcomes. And it was right around the time that radium was actually entering into the clinic for prostate cancer. And it's essentially a tumor agnostic therapy that treats the tumor microenvironment, targeting calcium turnover. And we had demonstrated from our biomarker work that even though RCC tumors can generate a osteolytic reaction, they do have osteoblastic activity and there's dysregulated pathology between osteoblast and osteoclast.
We conducted a small pilot study with VEGF-TKIs plus radium, demonstrated dramatic declines in all markers of bone turnover, demonstrating safety. And that's what led us to conduct this trial. This is the largest trial that I know of any radiopharmaceutical in kidney cancer. It's the largest trial that I know of radium-223 in non-prostate. And I think it's going to really potentially open up the door. There's other radiopharmaceuticals that are being evaluated, most as monotherapy, but I think, thinking about the opportunities for combination therapy is certainly going to be something on the forefront. So I think it's just going to open up a lot of opportunity.
The other thing is, this is the only trial conducted in RCC in a site specific patient population. Only patients with bone metastases. And so I think there's going to be a lot of learnings for the field, and look forward to sharing that with everybody.
Zachary Klaassen: Yeah, it's going to be exciting. I mean, you think back to ALSYMPCA 2013, we have PEACE-3 now, and now we're going to have RADICAL. So we'll look forward to hearing that data in a short amount of time at ASCO. Just a quick reminder before we wrap up. Don't forget to sign up for coverage at ASCO for UroToday. We'll be covering obviously all of these trials and many more abstracts and posters and talks. And so Rana, I know you're busy. Thank you so much for getting us ramped up-
Rana McKay: It's my pleasure. Thanks for having me.
Zachary Klaassen: Thanks for getting us ramped up for ASCO. Thank you.
Rana McKay: Bye-bye.