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Differences Among PARP Inhibitors in Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University School of Medicine at St. Joseph’s Hospital; Robert L. Coleman, MD, MD Anderson Cancer Center; Thomas Herzog, MD, University of Cincinnati; Kathleen N. Moore, MD, Stephenson Cancer Center; Angeles Alvarez Secord, MD, Duke University School of Medicine
Published: Tuesday, Mar 07, 2017


Transcript:

Bradley J. Monk, MD:
So, we’ve talked about olaparib and the new olaparib, SOLO-2, which we don’t really know. We’ve talked about rucaparib, which is going to be probably the next approval. Now we have niraparib; this mammoth phase III trial, 22 months versus 5 months, 0.27 hazard ratio. Tom, we’re going to have some familiarity with olaparib, although it’s going to probably be even a new and better olaparib. When you go to choose which PARP inhibitor to use, how much does familiarity drive it or is it efficacy? You’re going to do cross-trial comparisons? Is it cost?

Thomas Herzog, MD: Yes. All those things are going to get considered. Certainly, you’re going to look at the different and varied toxicity profiles that you see with these. You see a little more thrombocytopenia with niraparib. Maybe it was like 34% grade 3/4.

Bradley J. Monk, MD: Maybe a few LFT elevations with rucaparib. Maybe that’s not important.

Thomas Herzog, MD: Right, exactly, and a little more, at least from what we saw earlier. There is maybe a little more GI toxicity perhaps with olaparib. We won’t know, that may change, and we’ll have to look at that data carefully. So, I think that that will be part of the puzzle. One of the pieces that you’ll look at it is toxicity profile. You’re going to look at indication and what’s going to be covered. Now these are all catching up to one another as these trials report and as the labels expand and change. It’s a dynamic process. I honestly think cost could certainly play a role.

Bradley J. Monk, MD: So, Katie, am I looking for something that doesn’t exist? Are these drugs really more similar than different? In other words, am I looking for a difference when one doesn’t really exist and looking at more practical things like cost and contracting? What do you think?

Kathleen N. Moore, MD: I think, again, it’s too early to know if one is better than the other. Certainly, they have differences in the petri dish in terms of potency, but even the 3 we’re talking about are all really pretty potent PARP inhibitors and they all work in those studies that they have been tested in. They all work. So, until they’re compared head-to-head—they may never be—I don’t think we’re going to say, “This is the better PARP than this one.” So, I think the market is going to drive selection. I think you have these wonderful niraparib data, which have the potential to be paradigm-shifting. But obviously, what I’m doing in my practice, because I’m waiting for that drug, is switching all my patients who are on platinum right now to cisplatin so I don’t use up all their platelets.

Angeles Alvarez Secord, MD: Oh, but you can just dose reduce the niraparib.

Kathleen N. Moore, MD: But maybe I don’t want to.

Angeles Alvarez Secord, MD: But even in patients with that dose reduction…

Kathleen N. Moore, MD: I know that, but I don’t want to bring them down to 100.

Bradley J. Monk, MD: Is the reason that there’s more thrombocytopenia with niraparib because there’s a higher dose or is it because the agent is different?

Kathleen N. Moore, MD: We don’t know.

Angeles Alvarez Secord, MD: It could be a higher dose. There could be some off-target effects. There are some differences between these drugs and how they bind to the different PARP inhibitors. And there’s actually some other targets that they can bind to as well.

Thomas Herzog, MD: And there are bioavailability differences, too, and that can be affecting things.

Angeles Alvarez Secord, MD: We have the QUADRA trial open right now, and my comfort level with the drug is you have to be very wary of the thrombocytopenia.

Bradley J. Monk, MD: What does that mean, “wary”?

Angeles Alvarez Secord, MD: As soon as those platelets start to go down.

Bradley J. Monk, MD: So, what you’re saying is weekly CBCs in the first cycle?

Angeles Alvarez Secord, MD: Well, I can’t remember the exact. I feel comfortable with that. I can’t remember exact. I think it’s like day 15.

Thomas Herzog, MD: It is. Day 15, cycle 1 is when you see the majority, and it resolves in about 8 days.

Angeles Alvarez Secord, MD: And when I see them start to really drop, I just do a dose reduction. I haven’t gotten into any problems. Now, the first few patients I have on trial, I got into more issues with thrombocytopenia because I wasn’t as comfortable dose-modifying quickly. But I don’t think decreasing the dose affected efficacy.

Robert L. Coleman, MD: I think there’s a couple things here. In the olaparib experience, we learned long ago that there is probably a threshold for where dose is important, but there’s a large therapeutic range. We do the 200 mg versus 400 mg, and if you look at the PFS in that study, it really is about the same. So, I think we have the leeway, but the key to using this in the clinic outside of a clinical trial is just to be mindful of all of these particular things, like even LFT elevations, which we did see in ARIEL2. We need to monitor these things; you can’t just give it and forget it. And that frequent modification was a common element of all of the trials.

Bradley J. Monk, MD: Dose discontinuation was low.

Robert L. Coleman, MD: Right, and that’s what I’m saying.

Bradley J. Monk, MD: So, dose interruption, dose delay high.

Robert L. Coleman, MD: To get to Tom’s point, in the very beginning, you asked him about familiarity. We’ve asked that question to large audiences, and familiarity is a big deal.

Thomas Herzog, MD: It is.

Robert L. Coleman, MD: And so, when you have a large database and a familiarity of administering the drug, there is comfort with that. If they say that all this is a push on numbers from the efficacy standpoint, it’s going to be those types of things that are going to drive.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
So, we’ve talked about olaparib and the new olaparib, SOLO-2, which we don’t really know. We’ve talked about rucaparib, which is going to be probably the next approval. Now we have niraparib; this mammoth phase III trial, 22 months versus 5 months, 0.27 hazard ratio. Tom, we’re going to have some familiarity with olaparib, although it’s going to probably be even a new and better olaparib. When you go to choose which PARP inhibitor to use, how much does familiarity drive it or is it efficacy? You’re going to do cross-trial comparisons? Is it cost?

Thomas Herzog, MD: Yes. All those things are going to get considered. Certainly, you’re going to look at the different and varied toxicity profiles that you see with these. You see a little more thrombocytopenia with niraparib. Maybe it was like 34% grade 3/4.

Bradley J. Monk, MD: Maybe a few LFT elevations with rucaparib. Maybe that’s not important.

Thomas Herzog, MD: Right, exactly, and a little more, at least from what we saw earlier. There is maybe a little more GI toxicity perhaps with olaparib. We won’t know, that may change, and we’ll have to look at that data carefully. So, I think that that will be part of the puzzle. One of the pieces that you’ll look at it is toxicity profile. You’re going to look at indication and what’s going to be covered. Now these are all catching up to one another as these trials report and as the labels expand and change. It’s a dynamic process. I honestly think cost could certainly play a role.

Bradley J. Monk, MD: So, Katie, am I looking for something that doesn’t exist? Are these drugs really more similar than different? In other words, am I looking for a difference when one doesn’t really exist and looking at more practical things like cost and contracting? What do you think?

Kathleen N. Moore, MD: I think, again, it’s too early to know if one is better than the other. Certainly, they have differences in the petri dish in terms of potency, but even the 3 we’re talking about are all really pretty potent PARP inhibitors and they all work in those studies that they have been tested in. They all work. So, until they’re compared head-to-head—they may never be—I don’t think we’re going to say, “This is the better PARP than this one.” So, I think the market is going to drive selection. I think you have these wonderful niraparib data, which have the potential to be paradigm-shifting. But obviously, what I’m doing in my practice, because I’m waiting for that drug, is switching all my patients who are on platinum right now to cisplatin so I don’t use up all their platelets.

Angeles Alvarez Secord, MD: Oh, but you can just dose reduce the niraparib.

Kathleen N. Moore, MD: But maybe I don’t want to.

Angeles Alvarez Secord, MD: But even in patients with that dose reduction…

Kathleen N. Moore, MD: I know that, but I don’t want to bring them down to 100.

Bradley J. Monk, MD: Is the reason that there’s more thrombocytopenia with niraparib because there’s a higher dose or is it because the agent is different?

Kathleen N. Moore, MD: We don’t know.

Angeles Alvarez Secord, MD: It could be a higher dose. There could be some off-target effects. There are some differences between these drugs and how they bind to the different PARP inhibitors. And there’s actually some other targets that they can bind to as well.

Thomas Herzog, MD: And there are bioavailability differences, too, and that can be affecting things.

Angeles Alvarez Secord, MD: We have the QUADRA trial open right now, and my comfort level with the drug is you have to be very wary of the thrombocytopenia.

Bradley J. Monk, MD: What does that mean, “wary”?

Angeles Alvarez Secord, MD: As soon as those platelets start to go down.

Bradley J. Monk, MD: So, what you’re saying is weekly CBCs in the first cycle?

Angeles Alvarez Secord, MD: Well, I can’t remember the exact. I feel comfortable with that. I can’t remember exact. I think it’s like day 15.

Thomas Herzog, MD: It is. Day 15, cycle 1 is when you see the majority, and it resolves in about 8 days.

Angeles Alvarez Secord, MD: And when I see them start to really drop, I just do a dose reduction. I haven’t gotten into any problems. Now, the first few patients I have on trial, I got into more issues with thrombocytopenia because I wasn’t as comfortable dose-modifying quickly. But I don’t think decreasing the dose affected efficacy.

Robert L. Coleman, MD: I think there’s a couple things here. In the olaparib experience, we learned long ago that there is probably a threshold for where dose is important, but there’s a large therapeutic range. We do the 200 mg versus 400 mg, and if you look at the PFS in that study, it really is about the same. So, I think we have the leeway, but the key to using this in the clinic outside of a clinical trial is just to be mindful of all of these particular things, like even LFT elevations, which we did see in ARIEL2. We need to monitor these things; you can’t just give it and forget it. And that frequent modification was a common element of all of the trials.

Bradley J. Monk, MD: Dose discontinuation was low.

Robert L. Coleman, MD: Right, and that’s what I’m saying.

Bradley J. Monk, MD: So, dose interruption, dose delay high.

Robert L. Coleman, MD: To get to Tom’s point, in the very beginning, you asked him about familiarity. We’ve asked that question to large audiences, and familiarity is a big deal.

Thomas Herzog, MD: It is.

Robert L. Coleman, MD: And so, when you have a large database and a familiarity of administering the drug, there is comfort with that. If they say that all this is a push on numbers from the efficacy standpoint, it’s going to be those types of things that are going to drive.

Transcript Edited for Clarity
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