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PARP Inhibitors: Which One Should We Use?

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona and Creighton University; Michael J. Birrer, MD, PhD The University of Alabama at Birmingham; Ursula A. Matulonis, MD, Harvard Medical School
Published: Thursday, Jan 03, 2019



Transcript: 

Bradley J. Monk, MD: So we talked a lot about olaparib [Lynparza] moving into frontline in the BRCA-mutated patients. We’ve talked a little bit about niraparib [Zejula] and how, at this meeting, it shows that in the patient [who] weighs less than 170 pounds and who in the beginning has a platelet count of less than 150, you really need to start at the 200-[mg] dose rather than 300-[mg] dose. We’ve not talked about rucaparib [Rubraca]. Rucaparib, on April 6, 2018, was the third PARP [poly (ADP ribose) polymerase] inhibitor to get approved in maintenance, in the second line. Tell us about ARIEL3.

Ursula A. Matulonis, MD: So ARIEL3 had a very similar design, such as the NOVA trial, [in which] all comers were enrolled.

Bradley J. Monk, MD: NOVA being niraparib.

Ursula A. Matulonis, MD: NOVA being niraparib, correct. And really remarkably—and we talked about this—is that the results of the ARIEL3 really mirror the NOVA trial, with niraparib around that non-BRCA group. And I think Mike [has] already alluded to it, that when you’re looking at the HRD [homologous recombination deficiency] population, that pulls out a subset of patients who are going to be more sensitive to the PARP inhibitor. And then that BRCA-negative, HRD-negative setting—there was some benefit in ARIEL3, but even a little bit less so than in NOVA. So ARIEL3, rucaparib, FDA approved for maintenance and a very good PARP tracker. We haven’t talked about PARP tracking, but that’s another mechanism how PARP inhibitors work very similar to olaparib and niraparib.

Bradley J. Monk, MD: You know I like to put things into historical perspective. If you recall, a long time ago, we compared PLD [pegylated liposomal doxorubicin] to topotecan [Hycamtin]. And PLD in the Gordon study was better….[For] that comparative trial, topotecan was fine when we had it. Now we have had Gordon PLD, and it was fine. Then, in 2006, we got carboplatin [and] gemcitabine versus carboplatin alone. It was fine, so you had a carboplatin-gemcitabine option. Platin, what we called then platin-resistant, that was easy. And then we only had one angiogenic, bevacizumab, that was easy. Now we have 3 PARP-inhibitors in the same indication.

Ursula A. Matulonis, MD: That’s right.

Bradley J. Monk, MD: So it was all very compartmentalized and very easy to educate. And now we have to decide PARP versus bevacizumab, and you helped us. Now you’ve got to decide which PARP.

Ursula A. Matulonis, MD: Yeah.

Bradley J. Monk, MD: How in the world do I decide, Professor Birrer: niraparib (Zejula), olaparib (Lynparza), or rucaparib (Rubraca) in my patient? Do I decide [if] you need a PARP, and you’re responding to second-line platinum-based chemotherapy? And I’m going to give which one? It’s not so funny. It’s a common practice, and I think we all agree that observation is not a good idea.

Ursula A. Matulonis, MD: I’m glad Mike [is] getting that question before I am. Thank you for doing it.

Michael J. Birrer, MD, PhD: Well, I’m laughing because it is funny in a sense that we spent years talking about IV [intravenous] versus IP [intraperitoneal injection] or docetaxel (Taxotere) versus [pactilaxel] (Taxol). Those were challenging [but] not boring questions. We really now have choices. And as you point out, you’ve got—you’re sitting in front of a patient, [and] you have to make the choice.

I think for the PARPs it is very difficult, at least for me, based [on] all those randomized phase III trials. The hazard ratio there is so impressive, and [it’s] completely consistent to argue that there’s an efficacious major difference in the efficacy between the three agents. So I think the choice comes down to sort of toxicity profiles, which are different, and convenience for the patient. So there are a class of—so let’s just talk about that.

There are class effects for PARP inhibitors—fatigue, some GI [gastrointestinal] toxicities—[but] they’re usually manageable. There are class effects; you see them in all the agents. The major difference that we can point to is the thrombocytopenia issue with niraparib.

Bradley J. Monk, MD: But that goes away.

Michael J. Birrer, MD, PhD: [A dose of] 200 mg is probably going to solve it. And we know we can identify the patients who had the problem with it. So there are even ways you can finesse that. So if you have a patient who’s real thin, you might think of a different PARP inhibitor, or you might use the reduced dose.

Rucaparib has some interesting profile issues. So it has elevations in transaminases, which is not liver toxicity but nevertheless happens, and people need to be aware of that. And a similar phenomenon with [creatinine], which is a pump problem; it’s not a toxicity for the kidney.

Dosing is interesting. I actually think niraparib is pretty convenient. As you say, once a day; you can dose reduce very easy. [As you would for] rucaparib, you have to write a new script for docetaxel; it’s a little challenging.

So that’s where I am right now in terms of trying to make [that choice]. It may be made for you. So in some hospitals, the formularies won’t even put multiple on, whoever gets the first. And then finally, [cost is] something we don’t like to talk about but is reality. It’s not clear to me there’s a substantial difference in cost, [however].

Ursula A. Matulonis, MD: There might be a different co-pay—absolutely.

Michael J. Birrer, MD, PhD: Well co-pay, and although if we go to routinely 200-mg niraparib, it’s actually two-thirds of the original dose.

Ursula A. Matulonis, MD: Yes.

Bradley J. Monk, MD: So let me kind of go through my scorecard here. So olaparib was the first one. We have long-term data; we have familiarity. We even have a breast indication in olaparib, right? And then you go, well, NOVA [niraparib] was the first one approved in maintenance. It really [has] the most formal data because it has a non-BRCA and a BRCA randomized. You said it was once daily. Probably the best PARP tracker. It’s lipophilic; it crosses the blood-brain barrier. And then the new kid on the block is rucaparib. It’s kind of fun and sexy because it’s the new guy. You talk about dose reductions. Rucaparib has lots of options: 6, 5, 4, 3. When you dose reduce niraparib, you go down a third. But we know the exposure on that is probably sufficient.


Bradley J. Monk, MD: Also, maybe the toxicity issues for rucaparib are favorable…because the transaminases are not really important. So when I talk about the 3 PARP inhibitors, I ask to say, just tell me which of those things [is] important. And if once-daily dosing is really important, it’s really easy. You know first to market, familiarity, long-term data; that’s really easy. Or it’s the dose options and so on.

Ursula A. Matulonis, MD: And I think the other issue. Sure, I think it is important to go through the toxicities with patients, but then you can already kind of free superimpose.

Bradley J. Monk, MD: Supportive care.

Ursula A. Matulonis, MD: Supportive care, but also understand which drug is not going to be appropriate for that patient. So I think, for example, if the patient has significant hypertension, she’s already hypertensive because you’ve given her [bevacizumab] (Avastin). And maybe her blood pressure is 160/90 [mm Hg], and it’s hard to keep down.

Bradley J. Monk, MD: Niraparib...syncretic hypertension.

Ursula A. Matulonis, MD: That’s because of the interaction with norepinephrine transport. So that’s right. So then you have to tell her; actually, I don’t think I’d give it to somebody who’s baseline hypertensive. And even someone who is normotensive, I think they have to understand, you’ve got to watch your blood pressure. You know more often than not [that] you’re going to be fine.

Bradley J. Monk, MD: But it’s not common, you measure it at home and...

Ursula A. Matulonis, MD: Yeah, yeah, yeah. Or a patient who’s got brain metastases or some kind of central nervous system metastases.

Bradley J. Monk, MD: So then, niraparib.

Ursula A. Matulonis, MD: It’s 4 niraparib, 4 olaparib; whereas rucaparib does not cross the blood-brain barrier sufficiently.

Bradley J. Monk, MD: Right, interesting. So unprecedented times. And I’m not here to tell our audience or even to argue for one PARP inhibitor over another. I’m not even here to argue PARP versus bevacizumab. But I’ll fight you hard versus placebo.

Bradley J. Monk, MD: Absolutely.

Ursula A. Matulonis, MD: Yeah. I mean, there are situations [in which] maybe the patient can’t. I mean, there are situations unfortunately where cost comes in. The patient is having a hard time paying for the PARP inhibitor, and BEV [bevacizumab] is just not appropriate. So I think there are going to be a few patients who slip through, but they are the minority.

Michael J. Birrer, MD, PhD: And there’s frequently an argument that I hear about: Well, once they get finished with their chemo, they don’t want to come back and see you and see the hospital. I find it’s the opposite…once they finish, the patients are highly motivated to take something. Because you’ve already told them, look, most likely this tumor is going to come back. They want something that will keep the tumor away forever.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD: So we talked a lot about olaparib [Lynparza] moving into frontline in the BRCA-mutated patients. We’ve talked a little bit about niraparib [Zejula] and how, at this meeting, it shows that in the patient [who] weighs less than 170 pounds and who in the beginning has a platelet count of less than 150, you really need to start at the 200-[mg] dose rather than 300-[mg] dose. We’ve not talked about rucaparib [Rubraca]. Rucaparib, on April 6, 2018, was the third PARP [poly (ADP ribose) polymerase] inhibitor to get approved in maintenance, in the second line. Tell us about ARIEL3.

Ursula A. Matulonis, MD: So ARIEL3 had a very similar design, such as the NOVA trial, [in which] all comers were enrolled.

Bradley J. Monk, MD: NOVA being niraparib.

Ursula A. Matulonis, MD: NOVA being niraparib, correct. And really remarkably—and we talked about this—is that the results of the ARIEL3 really mirror the NOVA trial, with niraparib around that non-BRCA group. And I think Mike [has] already alluded to it, that when you’re looking at the HRD [homologous recombination deficiency] population, that pulls out a subset of patients who are going to be more sensitive to the PARP inhibitor. And then that BRCA-negative, HRD-negative setting—there was some benefit in ARIEL3, but even a little bit less so than in NOVA. So ARIEL3, rucaparib, FDA approved for maintenance and a very good PARP tracker. We haven’t talked about PARP tracking, but that’s another mechanism how PARP inhibitors work very similar to olaparib and niraparib.

Bradley J. Monk, MD: You know I like to put things into historical perspective. If you recall, a long time ago, we compared PLD [pegylated liposomal doxorubicin] to topotecan [Hycamtin]. And PLD in the Gordon study was better….[For] that comparative trial, topotecan was fine when we had it. Now we have had Gordon PLD, and it was fine. Then, in 2006, we got carboplatin [and] gemcitabine versus carboplatin alone. It was fine, so you had a carboplatin-gemcitabine option. Platin, what we called then platin-resistant, that was easy. And then we only had one angiogenic, bevacizumab, that was easy. Now we have 3 PARP-inhibitors in the same indication.

Ursula A. Matulonis, MD: That’s right.

Bradley J. Monk, MD: So it was all very compartmentalized and very easy to educate. And now we have to decide PARP versus bevacizumab, and you helped us. Now you’ve got to decide which PARP.

Ursula A. Matulonis, MD: Yeah.

Bradley J. Monk, MD: How in the world do I decide, Professor Birrer: niraparib (Zejula), olaparib (Lynparza), or rucaparib (Rubraca) in my patient? Do I decide [if] you need a PARP, and you’re responding to second-line platinum-based chemotherapy? And I’m going to give which one? It’s not so funny. It’s a common practice, and I think we all agree that observation is not a good idea.

Ursula A. Matulonis, MD: I’m glad Mike [is] getting that question before I am. Thank you for doing it.

Michael J. Birrer, MD, PhD: Well, I’m laughing because it is funny in a sense that we spent years talking about IV [intravenous] versus IP [intraperitoneal injection] or docetaxel (Taxotere) versus [pactilaxel] (Taxol). Those were challenging [but] not boring questions. We really now have choices. And as you point out, you’ve got—you’re sitting in front of a patient, [and] you have to make the choice.

I think for the PARPs it is very difficult, at least for me, based [on] all those randomized phase III trials. The hazard ratio there is so impressive, and [it’s] completely consistent to argue that there’s an efficacious major difference in the efficacy between the three agents. So I think the choice comes down to sort of toxicity profiles, which are different, and convenience for the patient. So there are a class of—so let’s just talk about that.

There are class effects for PARP inhibitors—fatigue, some GI [gastrointestinal] toxicities—[but] they’re usually manageable. There are class effects; you see them in all the agents. The major difference that we can point to is the thrombocytopenia issue with niraparib.

Bradley J. Monk, MD: But that goes away.

Michael J. Birrer, MD, PhD: [A dose of] 200 mg is probably going to solve it. And we know we can identify the patients who had the problem with it. So there are even ways you can finesse that. So if you have a patient who’s real thin, you might think of a different PARP inhibitor, or you might use the reduced dose.

Rucaparib has some interesting profile issues. So it has elevations in transaminases, which is not liver toxicity but nevertheless happens, and people need to be aware of that. And a similar phenomenon with [creatinine], which is a pump problem; it’s not a toxicity for the kidney.

Dosing is interesting. I actually think niraparib is pretty convenient. As you say, once a day; you can dose reduce very easy. [As you would for] rucaparib, you have to write a new script for docetaxel; it’s a little challenging.

So that’s where I am right now in terms of trying to make [that choice]. It may be made for you. So in some hospitals, the formularies won’t even put multiple on, whoever gets the first. And then finally, [cost is] something we don’t like to talk about but is reality. It’s not clear to me there’s a substantial difference in cost, [however].

Ursula A. Matulonis, MD: There might be a different co-pay—absolutely.

Michael J. Birrer, MD, PhD: Well co-pay, and although if we go to routinely 200-mg niraparib, it’s actually two-thirds of the original dose.

Ursula A. Matulonis, MD: Yes.

Bradley J. Monk, MD: So let me kind of go through my scorecard here. So olaparib was the first one. We have long-term data; we have familiarity. We even have a breast indication in olaparib, right? And then you go, well, NOVA [niraparib] was the first one approved in maintenance. It really [has] the most formal data because it has a non-BRCA and a BRCA randomized. You said it was once daily. Probably the best PARP tracker. It’s lipophilic; it crosses the blood-brain barrier. And then the new kid on the block is rucaparib. It’s kind of fun and sexy because it’s the new guy. You talk about dose reductions. Rucaparib has lots of options: 6, 5, 4, 3. When you dose reduce niraparib, you go down a third. But we know the exposure on that is probably sufficient.


Bradley J. Monk, MD: Also, maybe the toxicity issues for rucaparib are favorable…because the transaminases are not really important. So when I talk about the 3 PARP inhibitors, I ask to say, just tell me which of those things [is] important. And if once-daily dosing is really important, it’s really easy. You know first to market, familiarity, long-term data; that’s really easy. Or it’s the dose options and so on.

Ursula A. Matulonis, MD: And I think the other issue. Sure, I think it is important to go through the toxicities with patients, but then you can already kind of free superimpose.

Bradley J. Monk, MD: Supportive care.

Ursula A. Matulonis, MD: Supportive care, but also understand which drug is not going to be appropriate for that patient. So I think, for example, if the patient has significant hypertension, she’s already hypertensive because you’ve given her [bevacizumab] (Avastin). And maybe her blood pressure is 160/90 [mm Hg], and it’s hard to keep down.

Bradley J. Monk, MD: Niraparib...syncretic hypertension.

Ursula A. Matulonis, MD: That’s because of the interaction with norepinephrine transport. So that’s right. So then you have to tell her; actually, I don’t think I’d give it to somebody who’s baseline hypertensive. And even someone who is normotensive, I think they have to understand, you’ve got to watch your blood pressure. You know more often than not [that] you’re going to be fine.

Bradley J. Monk, MD: But it’s not common, you measure it at home and...

Ursula A. Matulonis, MD: Yeah, yeah, yeah. Or a patient who’s got brain metastases or some kind of central nervous system metastases.

Bradley J. Monk, MD: So then, niraparib.

Ursula A. Matulonis, MD: It’s 4 niraparib, 4 olaparib; whereas rucaparib does not cross the blood-brain barrier sufficiently.

Bradley J. Monk, MD: Right, interesting. So unprecedented times. And I’m not here to tell our audience or even to argue for one PARP inhibitor over another. I’m not even here to argue PARP versus bevacizumab. But I’ll fight you hard versus placebo.

Bradley J. Monk, MD: Absolutely.

Ursula A. Matulonis, MD: Yeah. I mean, there are situations [in which] maybe the patient can’t. I mean, there are situations unfortunately where cost comes in. The patient is having a hard time paying for the PARP inhibitor, and BEV [bevacizumab] is just not appropriate. So I think there are going to be a few patients who slip through, but they are the minority.

Michael J. Birrer, MD, PhD: And there’s frequently an argument that I hear about: Well, once they get finished with their chemo, they don’t want to come back and see you and see the hospital. I find it’s the opposite…once they finish, the patients are highly motivated to take something. Because you’ve already told them, look, most likely this tumor is going to come back. They want something that will keep the tumor away forever.

Transcript Edited for Clarity
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