Oliver Sartor: Hi, Oliver Sartor here with UroToday and always a pleasure to welcome Rana McKay, who's well known in the field to all. And Rana is Professor of Medicine and Urology at University of California San Diego, an amazing accomplishment in and of itself. Congratulations, Professor McKay.

Rana McKay: Thank you.

Oliver Sartor: And you presented a really fascinating study at ASCO this year on interactions between olaparib and radium. And I wonder if you might give us, first of all, a little bit of a synopsis on that, and then I'm going to shoot you a question or two about some interesting aspects of the study, at least to me. So Rana, tell us about the COMRADE study.

Rana McKay: Wonderful. So the COMRADE study is a study that was a phase I/II trial testing the combination of radium-223 with olaparib for patients with mCRPC with bone-predominant disease. And really, the rationale for this trial is predicated on how we can improve the efficacy of radium-223 with additional DNA-damaging agent, building upon complementary mechanisms of the way that these drugs work. So I think leveraging the synthetic lethality with PARP inhibitors and the DNA damage that's produced by radium, which can then not be repaired with the use of a PARP inhibitor, arresting the cells in the G2/M cell cycle state, which is the most radio-sensitive state, there's chromatin remodeling, these also reduce tumor hypoxia. So there's a lot of rationale for actually combining a PARP inhibitor with radium-223.

So we designed this study as a phase I/II trial. Actually, the phase I has already been published and we identified the recommended phase II dose, which is reduced dose continuous olaparib at 200 milligrams twice daily, which is different than the standard monotherapy dose at 300 milligrams twice daily, with fixed dose radium-223 at standard dosing. And that was published a couple of years ago and we went on to do the randomized phase II, which looked at the combination compared to radium-223 alone with a primary endpoint of rPFS. This was a positive trial that demonstrated a statistically significant improvement in rPFS with the combination compared to radium-223 alone. And we also had various stratified subgroup analysis based off of extent of bony disease and docetaxel utilization and demonstrated improvements in those various subsets.

Oliver Sartor: Yeah. So Rana, help our listeners understand the context a little better. Who are these patients? What have they been pretreated with? Yes, they had bone-dominant disease, but a little more about the patient population. I think it's going to be important, particularly the fact that docetaxel was kind of 50/50.

Rana McKay: Yeah. No, absolutely. So I think this was a population, probably a little bit more late-stage patients that were actually enrolled on this trial. Average age, as you would expect for patients in this population, around 69, 71. A predominantly white population, about 85% of patients were white. Good performance status. I think we had a eligibility criteria of 0 to 1 PS. There was no stipulation around underlying baseline symptoms, so we did enroll patients that had symptomatic disease and asymptomatic disease. We will be presenting the quality of life at a later time point.

We did also allow patients to enroll if they had lymph node metastasis up to 4 centimeters, and all patients actually underwent a baseline bone biopsy. So about 30% of patients or so had measurable disease, most of which was lymph node disease or soft tissue component associated with a bone met. We did have stratification by extent of bony disease, about 50% of patients had more than 20 mets on bone scan. Nearly all patients had received a prior ARPi, about half had received prior docetaxel, and close to 90% had received a bone-protecting agent. So a fair bit of prior treatment utilization in this cohort.

Oliver Sartor: Yeah, absolutely. So you mentioned the top one, that rPFS was better, but now I'm going to ask you to drill down on two components. Number one is differences by docetaxel and differences by the number of bone mets greater than 20, yes/no.

Rana McKay: Yeah.

Oliver Sartor: So take us through that, because I thought that was quite interesting

Rana McKay: Interestingly enough, I think when we look at the ALSYMPCA data, you led the ALSYMPCA trial, the first radiopharmaceutical to actually improve overall survival in any disease setting. I think the ALSYMPCA study really paved the way for radiopharmaceuticals across solid tumors. And I think, initially from that trial, it was more late-line patients, like patients who had symptomatic disease, they could have received docetaxel, they weren't mandated to receive docetaxel.

But I think over the last decade as we've learned more about radium-223, there's a ton of real-world datasets, the PEACE-3 data that's come out, we're actually learning that probably earlier use, even in an asymptomatic population, may even be beneficial. And I think our trial highlights that the no prior docetaxel group really seemed to derive a dramatic benefit, and there was equal number of patients in both arms that were no prior Doce and prior Doce because we stratified by that. But 13.7 months median rPFS with the combo compared to 5.7 months. And I think for the people who had received prior docetaxel, the rPFS was really quite low with the radium-223 alone arm. It was 3 months. So those patients are really not able to complete all cycles of treatment.

And then similarly, when we looked at the analysis by extent of bony disease, actually lower burden of disease was associated with better outcomes. 13.4 rPFS for that combination. I wonder, what's the distribution? There's not been a lot of dosimetry that's been done in the context of radium, and I'd love to better understand that from you, Oliver, you're an expert in this field. What's the actual amount of radium that's getting delivered to all of the bone metastases when the burden of bone metastases is so high? What's actually the intratumoral distribution? Does it matter or is it not even an issue? I don't know that we really know that. And I wonder if there actually is a difference in intratumoral alpha dose between that. That's just me hypothesizing. But I think for those patients that had lower burden of disease, I think they probably have less issues with marrow failure, less issues with other things going on that were able to discontinue the radium, receive six cycles of radium and discontinue it, and continue doing well on maintenance olaparib thereafter for over a year.

Oliver Sartor: Yeah, it was really fascinating. And just maybe to summarize that with the docetaxel stratification, no prior docetaxel did dramatically better than docetaxel pretreated with the combination of olaparib and radium. And for the bony mets, if you had fewer than 20, it was dramatically distinct from if you had greater than 20, so I'm sort of thinking more about a little earlier use, which is quite fascinating.

Now, the cynic might say, "Oh, now wait a minute. You're just using olaparib and all these HRR-mutated patients are really going to be explaining the difference in the two groups." But you looked at that, and what did you find when you looked at the HRR distribution and the findings from the response? Because I thought that was also very cool.

Rana McKay: Yeah. So I think we're still dissecting all of the biomarker data. What we presented was the ctDNA data. And we have the tissue data as well, and this is going to be complimentary to the ctDNA just because of the sheer fact that all these patients had bone metastases and doing those baseline biopsies proved to be challenging. So not 100% of patients were in the ctDNA cohort. It was about 85% of patients that actually had evaluable ctDNA that actually had a cycle one day 1 drawn. And of the patients that had a cycle one day 1 drawn, 70% had a detectable tumor fraction. So that also speaks to the aggressiveness of this population. The bulk of patients had detectable ctDNA at the time of study entry.

But the percentage of patients that actually were HRR positive by our definition, which was a priori defined, and we did actually use a research algorithm to account for clonal hematopoiesis, which we can see in this population, we only had 23 patients who were HRR positive. So I think really being able to understand and dissect that group, we're limited by the sample size, but the number that were BRCA1/2, bona fide BRCA1/2, was only 9. So I don't think that those 9 patients are really driving this, especially if you think about the size of the trial and so forth.

We're still dissecting the data and we saw the greatest benefit in the HRR-negative group, but I think that's also because of the size of that group. That was almost 70-some odd patients, 80-some odd patients in that group, and it was only 23 in the HRR group.

Oliver Sartor: Yeah. But to me, the bottom line was if you did not detect an HRR mutation at baseline, you still very clearly had a benefit.

Rana McKay: Yeah.

Oliver Sartor: And you could not explain away the overall findings by some sort of hidden HRR mutation population that sort of predicated the better response when you gave the olaparib here. Anyway, interesting to me that HRR negative was quite positive. Now, one more point and that is the PSA. Now, we all know about the limitations of PSA, and you noted it again here. So when you began to look at distinctions between the groups, you really didn't find much in the way of PSA. And I'm wondering if you might speculate or just comment on the lack of PSA effect that you saw with the combination here.

Rana McKay: Yeah. And I think this actually gets to the underlying rationale for the trial. I think we're basically utilizing the PARP inhibitor as a radiosensitizer to the radium that's targeting the tumor microenvironment. So we're not changing that modality, and so that's why I don't think we're seeing the PSA responses. And I think if it was driven by the BRCA-mutated patients with a tumoral effect, we'd actually see more PSA responses. So I think this kind of drives the underlying biology. But we did not see differences in PSA.

What's interesting, and we're going to report on this at a subsequent meeting, but it actually seemed that ctDNA response was a better marker of predicting how somebody was going to do than PSA. And actually, in this context, you're probably better tracking ctDNA tumor fraction than you are tracking PSA, because we are very limited in the clinic for what we can do to monitor patients who are on radium. We have alk phos response, which is a little bit crude. We didn't see differences in alk phos response between the two arms. Quite interesting. We utilize the threshold set in ALSYMPCA at 30%. But we did see dramatic declines with tumor fraction.

Oliver Sartor: Very interesting. Well, Alex Wyatt might have demonstrated something similar to that in another setting, but we won't go there now. Rana, we're going to wrap up. Any final comments? And by the way, let me make a final comment. I love your allusion to the microenvironment because I think that's where radium exerts its activity. It's not a direct antitumor in the usual killing the tumor cells sense, it's more of a microenvironmental effect, and that's something that has taken so many people such a long time to come to terms with. But I think you've demonstrated, yet again, that the microenvironmental effect is more likely more important than the tumoricidal thing. I'm sorry, that's my editorial. But any final comments before we wrap up?

Rana McKay: I have to say this study has been a labor of love. This was an investigator-initiated trial that was supported through the NCI, through the ETCTN, which is the Experimental Therapeutics Clinical Trials Network. It's the phase I/II arm of the NCI. This was supported through a PCF Young Investigator Award, through a Curebound award here, and UC San Diego with Padres Pedal the Cause. There's been multiple people that really were involved in this. All of the site investigators. I think this was one of the first studies that the ETCTN had done with an IP that was a radiopharmaceutical in prostate, and I almost want to say in any disease, because the ETCTN just doesn't do radiopharmaceutical studies, or historically has not.

So it's been a labor of love and there's a lot of biomarker work to be done. All patients underwent a baseline biopsy. We isolated DNA at the NCI, we taught them how to work with the bone specimens, we worked with Foundation on the ctDNA platform. So it's just been a really awesome experience. I have to thank Mary Ellen Taplin, Phil Kantoff, Geoff Shapiro, Toni, all the team that kind of helped design this trial. This was one of the first studies that I think I designed when I was at the Farber with the team there, and it's amazing to see it come to fruition.

Oliver Sartor: Well, congratulations, Rana. You do beautiful work. And thank you so much for sharing your thoughts and your insights today from the COMRADE trial. Helps our field move forward. Thank you.

Rana McKay: Thanks, Oliver.