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Recurrent Ovarian Cancer: PARP Inhibitors Compared

Panelists: Bradley J. Monk, MD, FACS, FACOG, Arizona Oncology Practice of US Oncology; Oliver Dorigo, MD, PhD, Stanford University Medical Center; Thomas Herzog, MD, University of Cincinnati Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center; Leslie M. Randall, MD, MAS, University of California, Irvine
Published: Monday, Sep 17, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: I’ve tried to put context into the question of, PARP—yes or no? Once you’ve decided whether or not to use the PARP, whatever the criteria are, then you have to make a key second decision—which PARP? I’d like to spend a few minutes talking about that. Oliver, what’s the dominant decision, when you make a decision? Which PARP? Is it, “Oh, niraparib is once daily.”? Or, “Oh, I have more experience with olaparib.” Or, “Oh, I like the studies with rucaparib.” And there are other answers.

Oliver Dorigo, MD, PhD: To me, it comes down to the experience with the PARP that I’m using. Every one of the PARPs is slightly different, particularly in their side effect profiles and the way you manage the side effects. Therefore, I have a preference.

Bradley J. Monk, MD, FACS, FACOG: That’s a good answer. Thank you for that. Leslie, what’s the most important factor that resonates in your mind as you choose amongst the 3 PARPs, whose indications are very similar?

Leslie M. Randall, MD, MAS: I think the real or perceived toxicity side effect profile.

Bradley J. Monk, MD, FACS, FACOG: What would be the more toxic PARP inhibitor? Or, let me speak positively rather than negatively. What would be the more tolerable PARP inhibitor?

Leslie M. Randall, MD, MAS: I think you’re asking a really difficult question. I think it’s difficult. I’m glad we have all of them. I’m glad that they all work.

Bradley J. Monk, MD, FACS, FACOG: But, you have to make a decision. Help us. Which one is more tolerable, in your mind?

Leslie M. Randall, MD, MAS: Which one is more tolerable? I can’t answer that question. If you know how to manage them, they’re all tolerable.

Bradley J. Monk, MD, FACS, FACOG: Tom, what’s the main factor in determining which PARP inhibitor to triage to?

Thomas Herzog, MD: Right now, I agree with Leslie that toxicity is probably the thing that’s in the front of mind. However, with niraparib, the thing to worry about is thrombocytopenia. Since they’ve instituted the weights and plates assessment, you’re now seeing much lower rates. My understanding is that this is grade 3 thrombocytopenia. With rucaparib, we talk about liver enzyme elevation. With olaparib, there were gastrointestinal concerns when we were using the capsules. But, what we really see is, if we compare any of these drugs to chemotherapy, all of them have a side effect profile that we can deal with. Now we’re starting to nitpick. For whatever is going on with one of the drugs, you have 2 sales forces out there magnifying the side effects and talking about them, probably making them into bigger deals than they are. We could give any one of these PARPs and could easily manage the side effects.

Bradley J. Monk, MD, FACS, FACOG: That’s right. Patients who are underweight, maybe less than 170 pounds, who have a low baseline platelet count, let’s say less than 150, should probably be started at 200 mg, once daily, rather than 300 mg? Is that what you’re talking about?

Thomas Herzog, MD: Correct.

Bradley J. Monk, MD, FACS, FACOG: Katie, what’s the main factor in determining which PARP inhibitor to use?

Kathleen Moore, MD: I think everyone at the table has used all of them, and I’m very comfortable with all of them. For me, it’s which one I can get for my patient without them having to pay a copay. I’m going to use whichever one I can get for the patient that doesn’t cost her $2000 per month.

Bradley J. Monk, MD, FACS, FACOG: Some people have said that because niraparib is the same strength of capsule, if they dose reduce, they don’t have to pay another copay?

Kathleen Moore, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: The best way to avoid or to have a low copay is to not have one.

Kathleen Moore, MD: Right.

Bradley J. Monk, MD, FACS, FACOG: And if you have other PARP inhibitors, you can use different pill strengths.

Kathleen Moore, MD: Yes, you can do a new prescription. I don’t think we can use this against them, but it is true that these are expensive drugs. I take care of an amazing patient population, but I don’t have people walking in with brimming cash to pay for this out-of-pocket. I don’t have any patients who can pay for this out-of-pocket. So, it’s incredibly important. I want to use PARPs. I really want every patient to have access to a PARP, but I don’t want them to go into financial ruin for it.

Bradley J. Monk, MD, FACS, FACOG: As I surveyed the 4 of you, I’m struck by the fact that none of you said, “Oh, I like once-daily dosing for a PARP inhibitor.” I hear that frequently. I’m going to give you my answer, which is different than...

Thomas Herzog, MD: I think it’s label. It’s always label, right? But the labels have become homogenized.

Bradley J. Monk, MD, FACS, FACOG: That’s what I’m saying.

Thomas Herzog, MD: I do think the once-daily option is something that needs to be considered, because it becomes about convenience and compliance.

Bradley J. Monk, MD, FACS, FACOG: That’s also true. The first thing that you said was molecular signature. In the highly sensitive patient, the BRCA patient, all PARPs probably have equal efficacy. OK? They’re so sensitive. In the molecular signature-negative patient, you need the most active PARP. By active I mean the highest intracellular level, and the one that inhibits the PARP trapping and enzymatic inhibition the greatest. As you look at the 3 PARP inhibitors, there are differences in the volume of distribution and how they respond, in vitro, to the HRD-negative genotype.

If you say that one PARP inhibitor isn’t stronger than the other, if you look at the clinical data, you kind of get a hint. Again, it’s an incomplete assessment, but these are the things that I agonize over. Quite frankly, I don’t really care what PARP inhibitor I give to a patient with a BRCA mutation. They’re all going to work, and I know how to use all 3 of them. But in the HRD-negative patient, am I going to use the wrong PARP inhibitor? Then, she’s not going to have a response because I picked the wrong choice. Is that reasonable, or am I just worrying too much?

Oliver Dorigo, MD, PhD: I agree with you. There are some significant pharmacological differences. In vivo preclinical models, you do see increased efficacy with niraparib when you treat xenografts. It doesn’t necessarily relate to increased efficacy in patients, however. I don’t think we have the data, because we have never compared that.

Bradley J. Monk, MD, FACS, FACOG: We’ll never know, right? We’ll never compare them.

Transcript Edited for Clarity 

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: I’ve tried to put context into the question of, PARP—yes or no? Once you’ve decided whether or not to use the PARP, whatever the criteria are, then you have to make a key second decision—which PARP? I’d like to spend a few minutes talking about that. Oliver, what’s the dominant decision, when you make a decision? Which PARP? Is it, “Oh, niraparib is once daily.”? Or, “Oh, I have more experience with olaparib.” Or, “Oh, I like the studies with rucaparib.” And there are other answers.

Oliver Dorigo, MD, PhD: To me, it comes down to the experience with the PARP that I’m using. Every one of the PARPs is slightly different, particularly in their side effect profiles and the way you manage the side effects. Therefore, I have a preference.

Bradley J. Monk, MD, FACS, FACOG: That’s a good answer. Thank you for that. Leslie, what’s the most important factor that resonates in your mind as you choose amongst the 3 PARPs, whose indications are very similar?

Leslie M. Randall, MD, MAS: I think the real or perceived toxicity side effect profile.

Bradley J. Monk, MD, FACS, FACOG: What would be the more toxic PARP inhibitor? Or, let me speak positively rather than negatively. What would be the more tolerable PARP inhibitor?

Leslie M. Randall, MD, MAS: I think you’re asking a really difficult question. I think it’s difficult. I’m glad we have all of them. I’m glad that they all work.

Bradley J. Monk, MD, FACS, FACOG: But, you have to make a decision. Help us. Which one is more tolerable, in your mind?

Leslie M. Randall, MD, MAS: Which one is more tolerable? I can’t answer that question. If you know how to manage them, they’re all tolerable.

Bradley J. Monk, MD, FACS, FACOG: Tom, what’s the main factor in determining which PARP inhibitor to triage to?

Thomas Herzog, MD: Right now, I agree with Leslie that toxicity is probably the thing that’s in the front of mind. However, with niraparib, the thing to worry about is thrombocytopenia. Since they’ve instituted the weights and plates assessment, you’re now seeing much lower rates. My understanding is that this is grade 3 thrombocytopenia. With rucaparib, we talk about liver enzyme elevation. With olaparib, there were gastrointestinal concerns when we were using the capsules. But, what we really see is, if we compare any of these drugs to chemotherapy, all of them have a side effect profile that we can deal with. Now we’re starting to nitpick. For whatever is going on with one of the drugs, you have 2 sales forces out there magnifying the side effects and talking about them, probably making them into bigger deals than they are. We could give any one of these PARPs and could easily manage the side effects.

Bradley J. Monk, MD, FACS, FACOG: That’s right. Patients who are underweight, maybe less than 170 pounds, who have a low baseline platelet count, let’s say less than 150, should probably be started at 200 mg, once daily, rather than 300 mg? Is that what you’re talking about?

Thomas Herzog, MD: Correct.

Bradley J. Monk, MD, FACS, FACOG: Katie, what’s the main factor in determining which PARP inhibitor to use?

Kathleen Moore, MD: I think everyone at the table has used all of them, and I’m very comfortable with all of them. For me, it’s which one I can get for my patient without them having to pay a copay. I’m going to use whichever one I can get for the patient that doesn’t cost her $2000 per month.

Bradley J. Monk, MD, FACS, FACOG: Some people have said that because niraparib is the same strength of capsule, if they dose reduce, they don’t have to pay another copay?

Kathleen Moore, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: The best way to avoid or to have a low copay is to not have one.

Kathleen Moore, MD: Right.

Bradley J. Monk, MD, FACS, FACOG: And if you have other PARP inhibitors, you can use different pill strengths.

Kathleen Moore, MD: Yes, you can do a new prescription. I don’t think we can use this against them, but it is true that these are expensive drugs. I take care of an amazing patient population, but I don’t have people walking in with brimming cash to pay for this out-of-pocket. I don’t have any patients who can pay for this out-of-pocket. So, it’s incredibly important. I want to use PARPs. I really want every patient to have access to a PARP, but I don’t want them to go into financial ruin for it.

Bradley J. Monk, MD, FACS, FACOG: As I surveyed the 4 of you, I’m struck by the fact that none of you said, “Oh, I like once-daily dosing for a PARP inhibitor.” I hear that frequently. I’m going to give you my answer, which is different than...

Thomas Herzog, MD: I think it’s label. It’s always label, right? But the labels have become homogenized.

Bradley J. Monk, MD, FACS, FACOG: That’s what I’m saying.

Thomas Herzog, MD: I do think the once-daily option is something that needs to be considered, because it becomes about convenience and compliance.

Bradley J. Monk, MD, FACS, FACOG: That’s also true. The first thing that you said was molecular signature. In the highly sensitive patient, the BRCA patient, all PARPs probably have equal efficacy. OK? They’re so sensitive. In the molecular signature-negative patient, you need the most active PARP. By active I mean the highest intracellular level, and the one that inhibits the PARP trapping and enzymatic inhibition the greatest. As you look at the 3 PARP inhibitors, there are differences in the volume of distribution and how they respond, in vitro, to the HRD-negative genotype.

If you say that one PARP inhibitor isn’t stronger than the other, if you look at the clinical data, you kind of get a hint. Again, it’s an incomplete assessment, but these are the things that I agonize over. Quite frankly, I don’t really care what PARP inhibitor I give to a patient with a BRCA mutation. They’re all going to work, and I know how to use all 3 of them. But in the HRD-negative patient, am I going to use the wrong PARP inhibitor? Then, she’s not going to have a response because I picked the wrong choice. Is that reasonable, or am I just worrying too much?

Oliver Dorigo, MD, PhD: I agree with you. There are some significant pharmacological differences. In vivo preclinical models, you do see increased efficacy with niraparib when you treat xenografts. It doesn’t necessarily relate to increased efficacy in patients, however. I don’t think we have the data, because we have never compared that.

Bradley J. Monk, MD, FACS, FACOG: We’ll never know, right? We’ll never compare them.

Transcript Edited for Clarity 
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