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Difference Among PARP Inhibitors for Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University; Robert L. Coleman, MD, MD Anderson Cancer Center; Gottfried E. Konecny, MD, University of California, Los Angeles; Katie Moore, MD, University of Oklahoma; Matthew A. Powell, MD, Washington University in St. Louis
Published: Wednesday, Aug 23, 2017



Transcript:

Bradley J. Monk, MD: I think with the recent approval of rucaparib, we’ve learned that there are some subtle differences between olaparib and rucaparib. I get that there are some similarities, as you outlined. But, Katie, what are some of the differences in the toxicities between rucaparib and olaparib?

Katie Moore, MD: So, there are differences, and why they’re happening, we don’t quite understand. But they’re really different drugs. They’re metabolized through different CYP pathways, so that’s one important thing to know. The drug-drug interactions between the 2 drugs and niraparib actually should be paid attention to, because you can have toxicities there that differ from PARP to PARP. Specifically for rucaparib and olaparib, you see effects on liver and renal transport molecules. So, you have displacement of creatinine by MATE1, MATE2, and OCT in rucaparib, and a little bit in olaparib.

Robert L. Coleman, MD: Yes, you do see that.

Katie Moore, MD: A little bit. And so, that translates in the rucaparib program into about a 21% grade 1 through 4 increase in creatinine that really tends to be clinically not all that relevant.

Bradley J. Monk, MD: Is that your experience, Rob, it’s not that clinically relevant?

Robert L. Coleman, MD: Absolutely, because during the conduct of these trials, we were concerned about acute kidney injury. And so, what we started to do was send patients for renal scans, and we would realize they would come back with GFR estimates of 90.

Bradley J. Monk, MD: They didn’t use creatinine as an estimate.

Robert L. Coleman, MD: They didn’t use creatinine as an estimate, yes, she’s absolutely right.

Katie Moore, MD: And then you also see an elevation in transaminases, which really is predictable right around cycle 1 on day 15. They can bump pretty high. The bilirubin doesn’t tend to go up as much, and truthfully, we don’t know why that’s happening. But as long as you follow Hy’s law, which is this combination of how high the transaminases are with the bilirubin—as long as you don’t have elevated bilirubin or really high grade 4s—you just treat through it. It comes back down, and it does not happen again. That’s really unique to rucaparib. And as long as you know how to manage it, it’s not this rate-limiting step, but you have to know it’s going to happen, potentially.

Bradley J. Monk, MD: Let’s spend a few minutes and talk about the side effect profile of niraparib. Gottfried, tell us about what the label says and what your experience is with the toxicities associated with niraparib.

Gottfried E. Konecny, MD: I think what sets niraparib a little bit apart is the hematologic toxicity regarding platelets, that there is a higher chance of thrombocytopenia, especially in the early phase—the first 2 to 4 weeks. So, the guidelines are to watch that closely. I do a weekly CBC, and if the platelets drop, I address that, hold the drug, and re-escalate when they normalize. Depending on the degree of the drop, you may even just reduce the dose. Other than that, it’s not a problem that persists throughout the trial. So, it’s really an initial finding.

Bradley J. Monk, MD: So, weekly CBC just for the first month?

Gottfried E. Konecny, MD: Weekly CBC for the first month, and then beyond that, when you’re out a month, you can go on to regular checks every 4 weeks. That’s not seen for olaparib and also not seen for rucaparib. All other things—like the anemia around 20% being severe, grade 3 or 4—are very similar. Also, the neutropenia is very comparable. It’s really unique, and I think that we have to monitor platelets more closely when treating with niraparib.

Robert L. Coleman, MD: And I think the only other kind of nuance we saw was a little bit more hypertension.

Bradley J. Monk, MD: On the label, it says that niraparib interferes with the metabolism, norepinephrine and dopamine, which is idiosyncratic and off-target. That’s, again, unique. You talked about the unique things that happen for rucaparib. This is something that’s unique for niraparib, and it’s associated also with some tachycardia, which is also very rare. Like you said, the LFTs are probably not clinically relevant. This is also probably not going to be relevant.

Robert L. Coleman, MD: But I think a lot of people are, at least what I’m hearing, very nervous about these kinds of potential effects. But I think these are all side effects that we know how to handle, and we have done a great job. They’re something like we’ve seen with bevacizumab, for instance, where we had that hypertension, we were going through multiple lines of agents.

Matthew Powell, MD: But, again, you’re sitting in a room full of experts.

Robert L. Coleman, MD: Yes, that’s true.

Matthew Powell, MD: The average clinician out there hasn’t written for a PARP inhibitor. It’s novel, it’s new. There’s a lot of education that has to happen to feel comfortable with these.

Robert L. Coleman, MD: Absolutely.

Bradley J. Monk, MD: So, are these the same? Are they chocolate, vanilla, and strawberry, but they’re all ice cream?

Matthew Powell, MD: Katie’s points are really that they are different drugs: they have different mechanisms, different amount of PARP trapping perhaps, etc, that lead to some different toxicities and unique pathways of clearance.

Bradley J. Monk, MD: Is the efficacy the same though, at least?

Robert L. Coleman, MD: We talked about it. If you were able to line up all of the studies and had the same patient population, you would probably see pretty close to the same efficacy. But what Matt is talking about is really critical. As we move on—we talked about what’s next—with the PARP, these other nuances and their actions may actually become relevant. PARP trapping may be really relevant for something that we may use in combination with it. I think the other thing I’d add about the side effect profile is that we’re still pretty early in this process.

Bradley J. Monk, MD: Not in olaparib.

Matthew Powell, MD: Of course, switching from capsule to tablet.

Robert L. Coleman, MD: If you think about it, the first report in phase I that was published was only in 2009. So, I wouldn’t say we had long. And what I mean by this is that the relationship between what PARP is actually doing to the adverse event profile is something we’re still learning.

Gottfried E. Konecny, MD: I agree with Rob. I think we’re moving out of the clinical trial setting into the real world, and that applies specifically for a very severe side effect like MDS and secondary leukemias. Now they’re all reported at very low incidences, but it is on the label. It’s a serious complication. And I think we just have to be alert and aware that that may not reflect the true incidence of this, considering that these patients have had multiple lines of platinum and now may be getting a second line of a PARP inhibitor. They’ve been on olaparib. They may be re-treated with rucaparib. So, I think that’s something we have to be alert and watchful for.

Transcript Edited for Clarity

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Transcript:

Bradley J. Monk, MD: I think with the recent approval of rucaparib, we’ve learned that there are some subtle differences between olaparib and rucaparib. I get that there are some similarities, as you outlined. But, Katie, what are some of the differences in the toxicities between rucaparib and olaparib?

Katie Moore, MD: So, there are differences, and why they’re happening, we don’t quite understand. But they’re really different drugs. They’re metabolized through different CYP pathways, so that’s one important thing to know. The drug-drug interactions between the 2 drugs and niraparib actually should be paid attention to, because you can have toxicities there that differ from PARP to PARP. Specifically for rucaparib and olaparib, you see effects on liver and renal transport molecules. So, you have displacement of creatinine by MATE1, MATE2, and OCT in rucaparib, and a little bit in olaparib.

Robert L. Coleman, MD: Yes, you do see that.

Katie Moore, MD: A little bit. And so, that translates in the rucaparib program into about a 21% grade 1 through 4 increase in creatinine that really tends to be clinically not all that relevant.

Bradley J. Monk, MD: Is that your experience, Rob, it’s not that clinically relevant?

Robert L. Coleman, MD: Absolutely, because during the conduct of these trials, we were concerned about acute kidney injury. And so, what we started to do was send patients for renal scans, and we would realize they would come back with GFR estimates of 90.

Bradley J. Monk, MD: They didn’t use creatinine as an estimate.

Robert L. Coleman, MD: They didn’t use creatinine as an estimate, yes, she’s absolutely right.

Katie Moore, MD: And then you also see an elevation in transaminases, which really is predictable right around cycle 1 on day 15. They can bump pretty high. The bilirubin doesn’t tend to go up as much, and truthfully, we don’t know why that’s happening. But as long as you follow Hy’s law, which is this combination of how high the transaminases are with the bilirubin—as long as you don’t have elevated bilirubin or really high grade 4s—you just treat through it. It comes back down, and it does not happen again. That’s really unique to rucaparib. And as long as you know how to manage it, it’s not this rate-limiting step, but you have to know it’s going to happen, potentially.

Bradley J. Monk, MD: Let’s spend a few minutes and talk about the side effect profile of niraparib. Gottfried, tell us about what the label says and what your experience is with the toxicities associated with niraparib.

Gottfried E. Konecny, MD: I think what sets niraparib a little bit apart is the hematologic toxicity regarding platelets, that there is a higher chance of thrombocytopenia, especially in the early phase—the first 2 to 4 weeks. So, the guidelines are to watch that closely. I do a weekly CBC, and if the platelets drop, I address that, hold the drug, and re-escalate when they normalize. Depending on the degree of the drop, you may even just reduce the dose. Other than that, it’s not a problem that persists throughout the trial. So, it’s really an initial finding.

Bradley J. Monk, MD: So, weekly CBC just for the first month?

Gottfried E. Konecny, MD: Weekly CBC for the first month, and then beyond that, when you’re out a month, you can go on to regular checks every 4 weeks. That’s not seen for olaparib and also not seen for rucaparib. All other things—like the anemia around 20% being severe, grade 3 or 4—are very similar. Also, the neutropenia is very comparable. It’s really unique, and I think that we have to monitor platelets more closely when treating with niraparib.

Robert L. Coleman, MD: And I think the only other kind of nuance we saw was a little bit more hypertension.

Bradley J. Monk, MD: On the label, it says that niraparib interferes with the metabolism, norepinephrine and dopamine, which is idiosyncratic and off-target. That’s, again, unique. You talked about the unique things that happen for rucaparib. This is something that’s unique for niraparib, and it’s associated also with some tachycardia, which is also very rare. Like you said, the LFTs are probably not clinically relevant. This is also probably not going to be relevant.

Robert L. Coleman, MD: But I think a lot of people are, at least what I’m hearing, very nervous about these kinds of potential effects. But I think these are all side effects that we know how to handle, and we have done a great job. They’re something like we’ve seen with bevacizumab, for instance, where we had that hypertension, we were going through multiple lines of agents.

Matthew Powell, MD: But, again, you’re sitting in a room full of experts.

Robert L. Coleman, MD: Yes, that’s true.

Matthew Powell, MD: The average clinician out there hasn’t written for a PARP inhibitor. It’s novel, it’s new. There’s a lot of education that has to happen to feel comfortable with these.

Robert L. Coleman, MD: Absolutely.

Bradley J. Monk, MD: So, are these the same? Are they chocolate, vanilla, and strawberry, but they’re all ice cream?

Matthew Powell, MD: Katie’s points are really that they are different drugs: they have different mechanisms, different amount of PARP trapping perhaps, etc, that lead to some different toxicities and unique pathways of clearance.

Bradley J. Monk, MD: Is the efficacy the same though, at least?

Robert L. Coleman, MD: We talked about it. If you were able to line up all of the studies and had the same patient population, you would probably see pretty close to the same efficacy. But what Matt is talking about is really critical. As we move on—we talked about what’s next—with the PARP, these other nuances and their actions may actually become relevant. PARP trapping may be really relevant for something that we may use in combination with it. I think the other thing I’d add about the side effect profile is that we’re still pretty early in this process.

Bradley J. Monk, MD: Not in olaparib.

Matthew Powell, MD: Of course, switching from capsule to tablet.

Robert L. Coleman, MD: If you think about it, the first report in phase I that was published was only in 2009. So, I wouldn’t say we had long. And what I mean by this is that the relationship between what PARP is actually doing to the adverse event profile is something we’re still learning.

Gottfried E. Konecny, MD: I agree with Rob. I think we’re moving out of the clinical trial setting into the real world, and that applies specifically for a very severe side effect like MDS and secondary leukemias. Now they’re all reported at very low incidences, but it is on the label. It’s a serious complication. And I think we just have to be alert and aware that that may not reflect the true incidence of this, considering that these patients have had multiple lines of platinum and now may be getting a second line of a PARP inhibitor. They’ve been on olaparib. They may be re-treated with rucaparib. So, I think that’s something we have to be alert and watchful for.

Transcript Edited for Clarity
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