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First-Line Therapy for BRCA2-Mutated Metastatic Castration-Resistant Prostate Cancer

This is Part 3 of Updates in Prostate Cancer, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

In this video, Drs. Celestia (Tia) Higano, Julie Graff, and Neal Shore discuss the first-line therapy for BRCA2-mutated metastatic castration-resistant prostate cancer. The patient is a 69-year-old man with new castration-resistant prostate cancer who was previously treated with androgen-deprivation therapy plus docetaxel for metastatic hormone-sensitive prostate cancer and has a known BRCA2 mutation. The faculty discuss their choices for first-line therapy for this patient, reviewing the current NCCN recommendations, the role of PARP inhibitors, and recent data from the PROpel and MAGNITUDE trials.


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Transcript

Dr. Higano: Hi, welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. My name is Tia Higano. I'm a medical oncologist and adjunct professor at the University of British Columbia, formerly University of Washington. And I'm joined today by two of my colleagues. Please introduce yourselves. Dr. Graff: Hi, Tia. Great to be here with you and Neal. My name is Julie Graff. I, too, am a medical oncologist associate professor of medicine at Oregon Health and Science University and the VA Portland Health Care System. Thank you. Dr. Shore: Hi everyone. It’s great to be with both Tia and Julie. I’m Neal Shore, I’m the chief medical officer for GenesisCare in the US for urology and surgical oncology. And I’m the medical director of Carolina Urologic Research Center in Myrtle Beach, South Carolina. Dr. Higano: Great, thank you both. Today we'll be discussing recent updates in prostate cancer and integrating these new developments in for patient case studies. Our third case will focus on treatment for newly diagnosed BRCA2-mutated metastatic castration-resistant prostate cancer. So, let's listen to the details of this case study: a 69-year-old man with new metastatic CRPC. His bone scan shows multiple new lesions because his cat scan is negative for nodal or visceral disease. He was treated with ADT plus docetaxel when he had metastatic hormone-sensitive prostate cancer, and he comes to you with a known BRCA2 mutation. Now there have been a lot of studies recently about BRCA2 mutations. What would be your first line of therapy for this man with metastatic CRPC with a BRCA2 mutation? Julie, you're the medical oncologist. You have to go first. Dr. Graff: Thank you, Tia. You may know in the VA system we're really doing a good job of somatic testing for these veterans and looking for this mutation quite a bit. For the first line metastatic castration-resistant prostate cancer patient, I would not necessarily target the BRCA2 mutation. We use PARP inhibitors to target that mutation, but I would go back and look at the other drugs we have. It looks like he was not treated with the hormonal therapy when he was hormone-sensitive, so that leaves open a few options of probably starting with enzalutamide or abiraterone, and then after progression on one of those, then considering the PARP inhibitor. Dr. Higano: And Neal? Dr. Shore: Julie is spot on. I mean, think back to when the pandemic started. Just a few months afterwards, we saw in May, literally day after day back in May, we saw the approval first of rucaparib based on the TRITON2, which got approval for rucaparib for patients who had progressed, with mCRPC, who had progressed on both an NHA and a taxane exposure for who had BRCA mutations. Then literally the next day, ironically, literally 24 hours, we saw the approval of olaparib and a phase 3 trial known as the PROfound, which demonstrated the benefit for patients who had HRR mutations—14 different genes, inclusive of the BRCA gene alterations—and these patients received the approval that led from PROfound for FDA was for patients to receive olaparib if they had progressed on a novel hormonal agent. It didn't necessarily require that they had to have a taxane. That was a really big deal. I think the key to that in both of those trials is you don't know if you're going to use these therapies unless you're doing genomic testing, and that's really, to Julie's point, doing it at the VA, I think that's fantastic. All of our colleagues, medical oncologists, and urologists, radiation oncologists, especially for our CRPC patients, should be doing testing, and even for our mCSPC patients, should be doing testing. Even our high-risk localized patients who have significant family histories, according to the NCCN, should be getting testing. The key take home of what I'm saying is if you're not doing the testing, then you would not know that you could potentially benefit a patient with a PARP inhibitor, and upwards of 30% of mCRPC patients could benefit from a PARP inhibitor. Dr. Higano: The NCCN guidelines now, just as both of you have said, do not recommend use of a PARP inhibitor upfront for first-line therapy. As Julie mentioned, since this patient was treated initially with docetaxel, he could get either abiraterone or enzalutamide as first-line metastatic CRPC therapy. But then this brings up the presentations at ASCO of two trials: the MAGNITUDE trial and the PROpel trial. I was a discussant for those two, which I know you know, but I just want to point out before we go on much further that the MAGNITUDE trial was very, very different in its underlying population than the PROpel trial. Even though they were both studying first-line therapy for metastatic CRPC. Because the MAGNITUDE trial was made up of 100% patients with HRR mutations after they kicked out the non-HRR mutations with a futility analysis, and of those, half of them were BRCA2 patients or BRCA1 or 2 patients. And then the PROpel trial was all comers with metastatic CRPC. We're talking about doublets again in CRPC setting, though. Where do you think that's going to go moving forward, Julie? Dr. Graff: For those of us who are focused on precision oncology doing the somatic testing, matching the tumor and the drug, it was a blow to see the PROpel trial where all that went out the window and we got less precise. We're just treating all patients with the PARP inhibitor. I think neither one of these studies is really going to change my mind at this minute. Neither one of them really has overall survival -- it's not mature enough for the OS data. It is notable that the abi plus niraparib for the people who did not have HRR, that arm is closed, and they did not see any benefit of this combination. I think we just need to learn a little bit more. I know they came up with some reasons for why abi plus olaparib could lead to instability in homologous recombination outside of having the BRCA2 or other mutation. But I think a lot of us in the field are struggling with that mechanism of action there, and is it real? Dr. Higano: Well, I think that brings up the point of there's been all kinds of mechanisms of action proposed for different agents, and they may or may not hold if the question is, does it really work in the clinic? At least that's my thinking on it. Neal, what are your thoughts on those two trials? Do either of those change your practice right now? Dr. Shore: Well, we were fortunate we participated in both of those trials. Is more always better? There's certainly is a signal clearly that the KM curves -- the primary endpoint of PROpel, the primary endpoint was rPFS, and they met their primary endpoint in an all-comers population. We need to get more subanalysis of the breakdown of the HRR-mutated patients versus those who weren't and see how they did. With about 30% were HRR-mutated, biomarker-positive, much like in PROfound. There always will still be in the real-world issues around, still, there's a little bit more added toxicity, and there's no doubt about that. It'll require a little bit more vigilance in management. There may be some additional economic concerns, economic toxicity. Many people still want to see the overall survival benefit. Obviously, that's very, very important. I think you pointed out, and I thought it was absolutely key, these BRCA patients, especially the BRCA2, this is bad biology, and we saw that in the PROpel KM. Again, if you test and you find these patients, you have to be a little bit more aggressive with them. I think these were really important trials. Congratulations, to Kim Chi and Fred Saad for their presentations, and we're going to hear more as more data comes forward. I'm sure we'll hear more at ASCO in June. Dr. Higano: I completely agree. I think we are going to learn more as time goes on. I think the one thing I'd like to point out about the MAGNITUDE trial with respect to this very specialized population HRR-positive, 50% of who were BRCA1 or 2: when you looked at the patients who were treated with abiraterone alone, their median rPFS was 10.9 months, which is quite a bit lower than what we would expect from abiraterone in an unselected population, right? Whereas the combination of niraparib and abiraterone, that actually was the same as what you would expect with abiraterone alone in an unselected population. I mean, there's clear benefit at least as far as rPFS. And that was the one group, this BRCA-positive group was the one where I commented that maybe, you might be influenced to add a PARP inhibitor and abiraterone together. But clearly, it's not in the NCCN guidelines, so I don't want to be promoting that necessarily, but just to be thinking about it. Let me try to wrap up this case. We talked about the fact that men with BRCA mutations definitely have a more aggressive disease with a poor prognosis. As Neal alluded to, the approvals for olaparib and rucaparib, two PARP inhibitors, are the only ones right now that are approved for prostate cancer. The NCCN doesn't recommend first-line use of PARP inhibitors at this time, but we'll have to see how things change as both of these trials mature. There might be some changes to the recommendations. Again, this was talked about: neither the MAGNITUDE nor PROpel trials have gotten to the median OS point. They're just not mature enough. One or both of these trials may actually ultimately change the approach to first-line therapy in patients either with or without BRCA mutations. Other thoughts or takeaways? Dr. Graff: I would love to echo Neal's point about if we're not looking, we're not going to find it, and we're not going to be optimally treating patients with BRCA2 mutations if we're not sequencing with next-gen sequencing. It's important. Dr. Higano: Neal? Dr. Shore: Thanks, Julie. The other thing is we talk about the embarrassment of riches and all the great strides we've made in advanced prostate cancer. And just now looking at PARP inhibitors, we have multiple different PARP inhibitors. Are they all the same? Probably not. We'll need to learn more about their efficacy, and maybe there are some differences. Maybe there are some synergistic differences with other drugs. Remains to be seen. Maybe there are some even nuanced differences in their tolerability and safety profile. So it's a good problem to have, so I certainly encourage all of our colleagues to understand the importance of their role in advanced prostate cancer. Dr. Higano: Great. Thanks, both of you. This brings us to the end of this case. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.
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