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Sequencing PARP Inhibitors in Advanced Ovarian Cancer

Insights From: Michael Birrer, MD, ONeal Comprehensive Cancer Center; Ursula A. Matulonis, MD, Dana-Farber Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center
Published: Thursday, Jun 20, 2019



Transcript: 

Kathleen Moore, MD: Sequencing of agents in ovarian cancer is a big question. We talk about it all the time, it’s been just very hard to study because on a clinical trial, you can’t dictate what the patient is going to get next necessarily. Because it’s often individualized to her prior toxicity and schedule. There are so many things that factor in to what you pick next. So these studies of trying to find what the optimal sequence is have been talked about, but have been hard to do. So you have to take a little bit of almost a pragmatic approach. In a patient who has a BRCA mutation now, they’re going to get chemotherapy and they’re going to get PARP [poly (ADP) ribose polymerase] inhibitor maintenance, and I hope she never recurs but some of them are going to recur.

And, if they recur and they’re still appropriate for platinum, at this point they should still get a platinum. And, if they recur again, the question will be what you use next. Do you use a PARP again or do you use bevacizumab because she hasn’t had bevacizumab yet? And we know from subset analysis from GOG 218, Barbara Norquist, MD, did these data, that patients with BRCA mutations don’t benefit more from bevacizumab than non-BRCA but they benefit the same. So you get the same benefit as with everyone else, so why wouldn’t you use it? So it’s a good drug. So you could do either thing. In a patient who got 2 years of olaparib and didn’t recur for two more years and recurs again to platinum-based antineoplastic drugs, why wouldn’t you use a PARP inhibitor again there? If someone who progressed on a PARP inhibitor but then gets a platinum-based drug and responds again, are you not going to use a PARP inhibitor? We don’t know that yet. So how do you sequence PARP after PARP? We don’t know that yet. So there is going to be some guessing.

There are studies going on. There’s a study called the OReO trial going on, and there are others coming that are very close to launching that are going to help us answer that question and probably develop some predictive biomarkers, at least for patients who carry a BRCA mutation, to identify those who probably won’t respond to a PARP inhibitor again. So that will be helpful. But, until that time, it’s going to be a little bit empiric. We’re going to be guessing. If I had someone who stopped a PARP inhibitor and then didn’t recur for many years and responds to a platinum drug again, I’m probably going to put her right back on a PARP. In the other scenario, I’m going to weigh a PARP versus bevacizumab.

In a patient with BRCA wild-type who’s gotten frontline chemotherapy with bevacizumab or frontline chemotherapy with observation, now she’s recurred eligible for platinum again. It’s the same sort of discussion we’re having now where that patient could get bevacizumab, which will optimize her response over chemotherapy alone, and be followed by bevacizumab maintenance with a modest but statistically significant overall survival advantage; or they can get chemotherapy and then switch maintenance PARP inhibitor regardless of their biomarker.

And this is clinical equipoise right there. We can put 10 gyn-oncologists in the room and they’ll probably give you 5 different variations on what they would do. And I don’t think any of them are wrong. I tend to use PARP in that setting, only from a very pragmatic standpoint, only because the only way that a patient with BRCA wild-type right now can get a PARP inhibitor is in that setting. And if I don’t use it in that setting and I assume she’s going to be sensitive again, the next line I’m going to lose probably 40% of my potential patients who can get a PARP inhibitor because she’s not going to be sensitive again. And she can’t get PARP as a single agent as a BRCA wild-type at this point.

So, if you believe that every patient should have the opportunity to see if a PARP is effective for them, then I use it there. You could easily make the argument to start with bevacizumab there. So that study has never been done and that choice is one such that again, you have to have with the patient and the physician and sort of what is most important to her.

Given the discussion about whether to use PARP alone is coming, those studies have been completed and will be presented this year. One of them is SOLO-3, which took patients that had three lines of therapy and were still platinum sensitive and randomized them to single-agent olaparib versus chemotherapy, which interestingly did not include a platinum. So it will probably be on the discussion of this talk, but that’s going to be presented this year. And then a study called NRG 004, which is a National Cancer Institute study, took first recurrence platinum-sensitive patients and randomized them to platinum-based chemotherapy versus olaparib or olaparib plus a tyrosine kinase inhibitor called cediranib. And the SOLO-3 is only on patients with BRCA. This one is all-comers, so chemotherapy versus not chemotherapy, and that should result this year as well, we’re expecting. And I don’t know when, but we’re expecting that.

So that may or may not open up opportunities to replace chemotherapy in certain populations with a PARP inhibitor. ARIEL2 would speak to that, but that was a single-arm study in a platinum-sensitive population that used rucaparib with very high response rates and a 9-month duration of response. So it’s nice signal but single arm. It didn’t have a comparator. So I don’t think you could say that’s necessarily the standard of care yet, but it’s an option for patients and we’ll see where that fits in. But how you sequence that in when patients have had a PARP inhibitor in the front line—would you use it as a single agent—I think we’re going to have to figure that out.

There’s a lot of big questions on the table right now in terms of sequencing, and they’re going to get more complicated potentially because we have three frontline ovarian cancer trials resulting this year—it should be this year or early next year—all of which include patients with BRCA but all of which include patients that are non-BRCA importantly as key primary endpoint populations. So, if those are positive, then potentially everybody is getting a PARP in the frontline and then what do you do? So my prediction is that those are going to be positive. I don’t know, I really don’t. But I think it’s about to get complicated.

Transcript Edited for Clarity.
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Transcript: 

Kathleen Moore, MD: Sequencing of agents in ovarian cancer is a big question. We talk about it all the time, it’s been just very hard to study because on a clinical trial, you can’t dictate what the patient is going to get next necessarily. Because it’s often individualized to her prior toxicity and schedule. There are so many things that factor in to what you pick next. So these studies of trying to find what the optimal sequence is have been talked about, but have been hard to do. So you have to take a little bit of almost a pragmatic approach. In a patient who has a BRCA mutation now, they’re going to get chemotherapy and they’re going to get PARP [poly (ADP) ribose polymerase] inhibitor maintenance, and I hope she never recurs but some of them are going to recur.

And, if they recur and they’re still appropriate for platinum, at this point they should still get a platinum. And, if they recur again, the question will be what you use next. Do you use a PARP again or do you use bevacizumab because she hasn’t had bevacizumab yet? And we know from subset analysis from GOG 218, Barbara Norquist, MD, did these data, that patients with BRCA mutations don’t benefit more from bevacizumab than non-BRCA but they benefit the same. So you get the same benefit as with everyone else, so why wouldn’t you use it? So it’s a good drug. So you could do either thing. In a patient who got 2 years of olaparib and didn’t recur for two more years and recurs again to platinum-based antineoplastic drugs, why wouldn’t you use a PARP inhibitor again there? If someone who progressed on a PARP inhibitor but then gets a platinum-based drug and responds again, are you not going to use a PARP inhibitor? We don’t know that yet. So how do you sequence PARP after PARP? We don’t know that yet. So there is going to be some guessing.

There are studies going on. There’s a study called the OReO trial going on, and there are others coming that are very close to launching that are going to help us answer that question and probably develop some predictive biomarkers, at least for patients who carry a BRCA mutation, to identify those who probably won’t respond to a PARP inhibitor again. So that will be helpful. But, until that time, it’s going to be a little bit empiric. We’re going to be guessing. If I had someone who stopped a PARP inhibitor and then didn’t recur for many years and responds to a platinum drug again, I’m probably going to put her right back on a PARP. In the other scenario, I’m going to weigh a PARP versus bevacizumab.

In a patient with BRCA wild-type who’s gotten frontline chemotherapy with bevacizumab or frontline chemotherapy with observation, now she’s recurred eligible for platinum again. It’s the same sort of discussion we’re having now where that patient could get bevacizumab, which will optimize her response over chemotherapy alone, and be followed by bevacizumab maintenance with a modest but statistically significant overall survival advantage; or they can get chemotherapy and then switch maintenance PARP inhibitor regardless of their biomarker.

And this is clinical equipoise right there. We can put 10 gyn-oncologists in the room and they’ll probably give you 5 different variations on what they would do. And I don’t think any of them are wrong. I tend to use PARP in that setting, only from a very pragmatic standpoint, only because the only way that a patient with BRCA wild-type right now can get a PARP inhibitor is in that setting. And if I don’t use it in that setting and I assume she’s going to be sensitive again, the next line I’m going to lose probably 40% of my potential patients who can get a PARP inhibitor because she’s not going to be sensitive again. And she can’t get PARP as a single agent as a BRCA wild-type at this point.

So, if you believe that every patient should have the opportunity to see if a PARP is effective for them, then I use it there. You could easily make the argument to start with bevacizumab there. So that study has never been done and that choice is one such that again, you have to have with the patient and the physician and sort of what is most important to her.

Given the discussion about whether to use PARP alone is coming, those studies have been completed and will be presented this year. One of them is SOLO-3, which took patients that had three lines of therapy and were still platinum sensitive and randomized them to single-agent olaparib versus chemotherapy, which interestingly did not include a platinum. So it will probably be on the discussion of this talk, but that’s going to be presented this year. And then a study called NRG 004, which is a National Cancer Institute study, took first recurrence platinum-sensitive patients and randomized them to platinum-based chemotherapy versus olaparib or olaparib plus a tyrosine kinase inhibitor called cediranib. And the SOLO-3 is only on patients with BRCA. This one is all-comers, so chemotherapy versus not chemotherapy, and that should result this year as well, we’re expecting. And I don’t know when, but we’re expecting that.

So that may or may not open up opportunities to replace chemotherapy in certain populations with a PARP inhibitor. ARIEL2 would speak to that, but that was a single-arm study in a platinum-sensitive population that used rucaparib with very high response rates and a 9-month duration of response. So it’s nice signal but single arm. It didn’t have a comparator. So I don’t think you could say that’s necessarily the standard of care yet, but it’s an option for patients and we’ll see where that fits in. But how you sequence that in when patients have had a PARP inhibitor in the front line—would you use it as a single agent—I think we’re going to have to figure that out.

There’s a lot of big questions on the table right now in terms of sequencing, and they’re going to get more complicated potentially because we have three frontline ovarian cancer trials resulting this year—it should be this year or early next year—all of which include patients with BRCA but all of which include patients that are non-BRCA importantly as key primary endpoint populations. So, if those are positive, then potentially everybody is getting a PARP in the frontline and then what do you do? So my prediction is that those are going to be positive. I don’t know, I really don’t. But I think it’s about to get complicated.

Transcript Edited for Clarity.
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