Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today Dr. Oliver Sartor, who's a GU medical oncologist and the medical director of the Tulane Cancer Center. Thank you so much for being here with me today, Oliver.

Oliver Sartor: Thanks, Alicia. Glad to be here.

Alicia Morgans: Wonderful. As an expert in the field, someone who's really seen a lot and helps the rest of us think about how we integrate new data, I'd love to talk with you about three studies that were presented at GU ASCO 2022. Of course, ARASENS, Magnitude, and Propel were really practice-affecting, if not practice-changing. I'd love to hear your thoughts. Let's start with ARASENS. What do you think about this data in metastatic hormone-sensitive disease?

Oliver Sartor: Oh, if you back up just for a moment, I was... Explain what it is, because everybody may not be the same page. But, you take metastatic hormone-sensitive patients, and then the standard was ADT, and then the standard became ADT plus docetaxel. And here, we have the addition of darolutamide, half the patients randomized. ADT, docetaxel, plus or minus darolutamide, overall survival endpoint. That's really key, overall survival endpoint. And here's what happened; they knocked it out of the park. It was a really, really strong overall survival benefit. By the way, published in New England Journal, so if you want to go look at the details, go to New England Journal. You can see it all laid out. And I'll simply say that, for ADT plus docetaxel, there's no doubt about it that there is a benefit to darolutamide, and the adverse event profile looked really, really, really good.

Now, this builds a little bit on the PEACE-1 trial that [inaudible] presented at ESMO 2021. And, in that trial, which I think is important to understand the perspectives of both, was ADT, and the abiraterone was the hormonal thing. And so, ADT, docetaxel, plus or minus abiraterone. And again, strong. Now, with the PEACE-1, the low-volume subset did not really have that much of a benefit, and they probably didn't need more maturation. Here, there was no analysis of the low-volume subset, and so there could be more to learn, but I'm going to say it's a very, very positive trial.

To me, the question for PEACE-1, and the question for the ARASENS is, what does docetaxel really do? And I do believe that the addition of the novel hormones, whether abiraterone or darolutamide, clearly add value, but we didn't have the opposite. We didn't have ADT, darolutamide, plus or minus docetaxel, and I think there is some legitimate question about the triplet and how much it adds. I think there's a good, compelling reason to use it, particularly in the high-volume patients, and I think if you look at the data, you're going to be pleased with the adverse event profile, and I think it is potentially practice-changing. I think particularly for my young high-volume patients, it's probably going to be a go-to regimen. I don't know. That's one way of looking at it. I don't know. You might have a different way.

Alicia Morgans: No, I think it's pretty similar. From my perspective, if a patient is chemo-fit, particularly if he is high-volume, I'm going to consider ADT and docetaxel. I just have always, and always presented that as an option. For any patient where ADT and docetaxel is appropriate, from my perspective, it's a no-brainer to add darolutamide now. That's how I think about it. I actually have already integrated the PEACE-1 data, really thinking about de novo and high-volume patients as the patients that would clearly benefit there, from my perspective, benefit based on the data. This is really just a little bit of a shift in my thinking of how I would integrate a triplet, but I agree. Strongly positive, very well-tolerated, and I really do look forward, as you said, to the upcoming analyses that will, I think, inform us a little bit more about the details of subgroups and how we can think through some of the more nuanced questions that may be sitting in front of us in our clinic room.

Oliver Sartor: One of the things you said that I really like is, "... for those three chemo-fit." And I'm going to say, if you're chemo-fit and you're thinking about ADT/docetaxel, it is absolutely a no-brainer to be adding in one of the novel hormones that have now been proven to have benefit. And overall survival is our goal standard, and they knocked it out of the park. It was really, really positive.

Alicia Morgans: Particularly with the control on arm getting 70 something percent of these patients actually received treatment subsequently, a life prolonging treatment. I think it's not the case that the control arm did poorly because they didn't receive subsequent therapies. They did receive them, and still, we met an overall survival benefit in terms of this data. Very, very interesting. Let's move on. Would love to hear you set the stage and then tell us your thoughts on the Propel trial.

Oliver Sartor: Okay. Propel trial was really interesting. Abiraterone, first-line metastatic CRPC, and abiraterone's been used ever since [inaudible] 3-0-2, and Chuck Ryan, and really showed that was a clearly practice-changing trial. And the question would be, can a PARP inhibitor add in an unselected patient population? And that's the key, unselected patient population. And so, what they did is very simple. Abiraterone plus or minus the olaparib, and it was full-dose olaparib, the 30 milligrams B-I-D, just like it's FDA approved. And that is now widely accepted as a consequence to the profound trial. Taking these two active therapies, put them together, but the profound trial was only a [inaudible] combination repair positive. These are, BROC one, BRCA two, ATM, et cetera, et cetera. And here, it's unselected. What do we find? It turns out that there's a really nice rPFS benefit, and the survival is a little bit too young to be able to say at inadequate maturity, but maybe there's a little positive trend.

Okay. We like that. And then, there is a retrospective analysis, because everybody had genotyping, and about 70% had tissue and the other 30% essentially had ctDNA. And, if I'm trying to remember, I think there were 2% that were uncharacterized. Now, they overlay in a retrospective fashion, like, "Who had an HRR and who did not?" And it turns out that the HRR mutant population had a really strong rPFS. It has a ratio like 0.5. And again, remember, we don't have the survival, but really strong rPFS. And now, when we go to the non-HRR patients, haz ratio comes in much higher, above 0.7. And so my conclusion, first of all, is the HRR-positive mutant subset. That is really a strong win. I not really sure that we need to see all the OS if you got a haz ratio like 0.5 on the rPFS, that's super, super, super strong.

On the other hand, if you are running rPFS and it's a 0.75, I don't know if that'll translate into a benefit or not on the survival front, and I probably want to see a little bit more. Adverse events actually better than expected. I have the explanation I think is true, but I'm not sure. These patients are earlier in the treatment cycle. They're better protoplasm, and you just don't have the same degree of anemia. You don't have the same degree of adverse events that you might have seen in the PROFOUND trial, which is post [inaudible] or post-docetaxel in addition to the novel hormones. To me, clear winner in the [inaudible] recombination repair mutant subset, and a little less clear, and not really sure that I would adopt it as my standard of care in the HRR negative subset. But nevertheless, I think it's a practice-changing trial, because you put the two together and you get a win, and it's a significant proportion of the patients, by the way. It's about 29% of the tested patients. 29% of your patients may be benefiting with this combination.

Alicia Morgans: I agree. Lots of points there to comment on. I love that they were able to characterize the population for us, and tell us what the prevalence is of these DNA repair defect alterations in this population, and it's higher than I would've thought. That I think was really, really helpful, and that's before we even get to the therapeutic benefit that clearly occurs when we combine these two agents. One piece that I thought was really bold and was similarly done in another trial we'll talk about in a minute is that, this trial first-line mCRPC, they used Abiraterone and olaparib, but against a very, very good control arm, Abiraterone. We know that this drug works. We know it works in this setting. A very, very effective control arm, and then a therapeutic arm that, like you said, just really demonstrated this rPFS benefit.

A clear winner here, and I think I agree with you. It will be interesting to see how the field sorts out this distinction between those patients with the DNA repair defect alterations and those without, but that hazard ratio... Like you said, we don't know what's going to happen with overall survival, but at least in progression-free survival, there was a statistically significant benefit, even in the HRR-negative population. What we do with that as a field remains to be seen, but very, very intriguing nonetheless. Let's move on to the third study, and I would love to hear your thoughts on Magnitude.

Oliver Sartor: Okay. Again, let's talk about Magnitude for a second. In some ways, it's similar to Propel, but now there's a prospective differentiation between the HRR-positive subset and the HRR-negative subset. And it differences in terms of the drugs. You have abiraterone backbone again, and that first-line metastatic CRPC, but now it's niraparib. Now, it turns out they may have lowered the dose of the niraparib in the combination a little bit, and that may be important. Finding number one, that there was a futility analysis done in that HRR-negative subset. And in that futility analysis, they included PSA, not the radiographic progression-free survival, as part of the endpoint, and guess what? It was futile, so they shut it down after a relatively small number of patients, about 200 patients. Magnitude in the HRR-negative subset with a mixed rPFS PSA endpoint is considered to be futile and no-go. On the other hand, on the HRR-positive, they again had a very nice, good signal on the rPFS front with regard to the combination of abiraterone and niraparib, the PARP inhibitor.

In some ways, it's very analogous to the Propel in the HRR-positive subset. Positive study. Stop there. In the HRR-negative subset, whereas clearly there was statistically significant benefit in rPFS in Propel, now there is no benefit, and it was considered to be futile, and they shut the trial off in the HRR-negative subset. Compare/contrast, if you will. Different agents, different PARP inhibitors, different design. One prospective analysis of the HRRs, one retrospective analysis. One true all-comers. One has been divvied up. But nevertheless, I think the HRR-positive subset similarities drives a certain conclusion, and the conclusion is PARP inhibitors and abiraterone for those with HRR mutants is probably a really good way to go in that first-line of metastatic CRPC setting. I think that's practice changing. Now, we have to wait. FDA and regulatory, and all the insurance regulators, et cetera, et cetera. But nevertheless, this is new data, impactful new data, and really insightful. So nice, by the way, to be here in San Francisco and do a meeting live.

Alicia Morgans: I could not agree more, especially with the last point, but it's also so great to have these oral abstracts at our first in-person meeting with this beautiful positive data. All three of these trials had positive data, and I also commend the Magnitude authors and investigators for identifying when something was futile and shutting it down. I think that that's really important, and clearly those patients who have these DNA repair defects clearly benefit in that combination between abiraterone and niraparib. And so, final thoughts, GU ASCO 2022, these three heavy-hitting abstracts. What would you say?

Oliver Sartor: To me, the fact that you could combine a PARP inhibitor with abiraterone in the HRR-positive subset and come out really positive, I think that's a game changer, and I think the [inaudible] is a game changer. They knocked it out of the park with regard to the overall survival. ADT, docetaxel, darolutamide is going to be a regimen that needs to be considered in the future.

Alicia Morgans: Wonderful. Thank you so much for your time, your insights, and your expertise.

Oliver Sartor: Thanks, Alicia