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Alicia Morgans: Hi, I'm so excited to be here with Dr. Kim Chi where we're talking about challenges, controversies, and opportunities with PARP inhibitor combinations with androgen receptor signaling inhibitors. Very, very frequently discussed, especially with all of the new data at GU ASCO 2023. Thank you so much for talking with me today.

Kim Chi: Pleasure to be here, Alicia.

Alicia Morgans: Wonderful. Well, always a pleasure to talk to you and I'd really love to hear your thoughts on some of the data that has recently been presented. We've got TALAPRO-2, we certainly have PROpel, we have MAGNITUDE, we've got multiple different combinations, some different ways of that that we've seen the data actually turn out in terms of populations that may seem to have a signal and otherwise and signals being rPFS and OS. Just so much to sort through. Can you break it down for us? Start to tell us, if you can, how you think through these trials and these combinations.

Kim Chi: Well, I'll summarize first the trials. Niraparib, or the MAGNITUDE trial, looked at patients with metastatic CRPC for first-line therapy randomized to either ARPI or abiraterone versus abiraterone plus niraparib. Now, what's different of the MAGNITUDE study compared to the other two that have been recently reported now is that it had a prospective selection of the patients, prospective pre-screening for homologous recombination repair mutations. The statistical design also looked at BRCA2 patients first, then it looked at the overall, all patients with a homologous recombination repair mutation, and then there was a second cohort for those that were homologous recombination repair mutant-negative, biomarker-negative.

Now, the MAGNITUDE study showed that the biomarker-negative population, in a futility analysis, they didn't benefit from the combination. And so that arm was closed. But in the BRCA population and the biomarker population overall there was a benefit for radiographic progression-free survival, as well as other secondary endpoints. At the GU ASCO meeting today, we saw a update at the interim analysis confirming the benefit in BRCA patients, as well as patients, overall, that had homologous recombination repair mutation.

Now, this study is different in design from the TALAPRO study as well as PROpel study, which were more all-comers population, with a subsequent analysis that looked at whether patients were mutation-positive or mutation-negative by the analysis. Very different designs, so we have to remember that, because I think the pre-screening selection just creates a bias in the patients. By selecting out the patients, we know that not all patients get through that pre-screening process, so it's a different population. So we have to be careful about comparing across the trials.

Now, I know a lot of the differences are accentuated, but I'm going to actually say that the trials are actually very similar. What are the similarities? In that the patients that are biomarker-positive that were identified as having a mutation really benefited from the combination, particularly those BRCA2 patients. And what we saw in the PROpel data today, looking at the overall survival, it was substantial. Number one, that patients with BRCA alterations do very badly, but the combination allows them to do very much better. We know that radiographic progression-free survival is more than doubled and as well today we learned that their overall survival is also improved.

But we also see, across all three trials, is that if you are mutation-negative, there's much less benefit. We also have to remember, radiographic progression-free survival is not a patient-centered endpoint. It's really something that we find on imaging. It's not what a patient feels, it's what we see on imaging. And then we have to look at the other endpoints. Overall survival, there was no difference. Quality of life was no different, overall quality of life was no different, and then there's actual substantial toxicity or there can be substantial toxicity with these treatments.

So, wrapping it all up, for me, there's no doubt that if a patient has a BRCA mutation or other mutation in homologous recombination repair gene, we really should be thinking about combination therapy of a PARP inhibitor plus the AR pathway inhibitor for first-line therapy. However, if somebody's mutation-negative, I think we need to be very cautious about using a combination. There's financial toxicity, there's toxicity from the drugs, and as well there could be long-term toxicity that we don't realize quite yet. So I think we have to be very careful about recommending patients for that combination therapy.

Alicia Morgans: This has been certainly an area of hot debate and people have talked about the patient perspective, quality of life. What are your thoughts there? What data do we have, at least at this point, because we don't have a ton of data in terms of quality of life, what are your thoughts?

Kim Chi: Well, we know from the PROpel study as well as the MAGNITUDE study that overall quality of life was not different between the two arms. However, in the MAGNITUDE study we did report some of the quality of life data where we saw that if you look at some specific aspects like side effect bother, fatigue, and so on, there is a statistically significant difference.

We also know about the side effects of the drug. There's anemia, substantial grade 3/4 anemia in a substantial number of patients, and in the TALAPRO study today we also saw a very high rate of blood transfusions. So, we're taking a very well tolerated drug, AR pathway inhibitors, be it abiraterone or enzalutamide, and we're adding a drug in that has substantial toxicity. We're taking something that is well tolerated and we're actually making it toxic for a patient. And they would remain on these therapies for quite a while. We're talking a couple of years that they'd be on this treatment for.

Alicia Morgans: Agreed. Are there specific adverse events, other than the cytopenias, that you raise as areas just to be attentive to and to think about when you're thinking about these combinations, whether in a selected population or otherwise?

Kim Chi: Yeah, I think one that we underplay is the nausea. It is a common side effect with PARP inhibitors, but it tends to be low grade. But I know, for me, having a nausea every day from a pill that you're taking can be challenging for patients. So I think nausea is something we need to think about. Fatigue is another one. And then what we saw also in PROpel is that there was a bit of an increase in thromboembolic events, so we also need to be aware of those kinds of side effects. But these are real side effects that patients have to live with every day that we need to be attentive to.

Alicia Morgans: Great. Any concern from your perspective for MDS, AML, other myeloproliferative disorders with the longer exposure to a PARP?

Kim Chi: Yeah, I think we need to be concerned about that. There are some rare cases, but it's hard to say right now. I think when we start thinking about bringing it even earlier in disease, like castration-sensitive setting, where, for example, patients with low volume can live 5, 7, 10 years and more, then that's something we have to be much more aware of, of the risk of this happening.

Alicia Morgans: Great. Well, thank you for talking that through. As we wrap up, we've talked a lot about similarities, we've talked about some differences and populations where you might really think about using this combination even soon, now, perhaps, versus maybe other populations where you're less inclined. What is your closing message? Is this a good thing for prostate cancer? Is it not a good thing? What do we take away from these studies?

Kim Chi: I think it's a good thing. I think it brings us into the precision medicine age, and we shouldn't throw that out. I think all patients should get genomic testing, and there's three reasons I think these studies have accentuated that. One is prognostic. We need to understand these patients who are they are because they have a worse outcome. So number one, we should do genomic testing to understand prognosis. Number two, as we saw, many of these alterations, a third to half, are actually germline in origin. So we also need to do it for the hereditary cancer implications. And number three is around prediction. We know that patients with these alterations do better with a PARP inhibitor. So, even though, yes, perhaps some people will interpret this as, "Maybe I could just treat everybody and I don't need to test." No, I don't think that's the case. We need to still test. We need to test all our patients with metastatic disease or advanced prostate cancer with genomic testing to find these alterations.

Alicia Morgans: I could not agree more. Definitely the message is not stop testing. Keep testing. We can always use that information for this implication or for others. I really appreciate your very, very helpful and balanced discussion of these kinds of controversial-type questions that we have right now about PARP inhibitors in combination with the AR-targeted agents. Thank you so much for your time and expertise.

Kim Chi: Thank you, Alicia.