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PARP Inhibitor Selection in Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona, Creighton University, & Arizona Oncology Practice of US Oncology; Ursula Matulonis, MD, Dana-Farber Cancer Institute; David OMalley, MD, The Ohio State University; Matthew Powell, MD, Washington University; Shannon N. Westin, MD, MPH, MD Anderson Cancer Center
Published: Thursday, Apr 26, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: We’re now going to begin a discussion on which poly (ADP-ribose) polymerase inhibitor to use. When a clinician considers a PARP inhibitor, the first decision starts with, is this patient appropriate for a PARP inhibitor? And soon, the labels are going to be exactly the same, or at least similar enough. So, that’s unprecedented for us. If you remember, in 2005, we had pegylated liposomal doxorubicin approved. That was easy because it just beat topotecan. We didn’t have to keep talking about topotecan because there was a randomized comparative trial. And there was no such thing as the PARP inhibitors. And then, when we got gemcitabine approved in 2006, well, that was sensitive disease. So, again, we could still talk about pegylated liposomal doxorubicin and carboplatin/gemcitabine in the same setting. There was no controversy. You said we’re going to get bevacizumab approved. We’ve got 5 chemotherapy backbones, and there’s no competitor to antiangiogenesis in ovarian cancer. So, this is an unprecedented era.

David O’Malley, MD: But after 10 to 15 years of using bevacizumab, we still don’t know exactly where to use it. I think we’re figuring that out.

Bradley J. Monk, MD, FACS, FACOG: But, these are different questions. The first question is when to use it. We will continue to debate that—whether it’s for frontline, or second-line, or in combination. But, once you make that decision, which PARP inhibitor? Shannon, Ursula talked about the dose reduction and the formulation. The good news is, niraparib is given once a day. Publicly, I’ve said that if birth control pills were given twice a day, there would be a lot of unintended pregnancies. There is resonance in once-a-day dosing. But she also said, “Well, maybe we should dose reduce.”

So, when they dose reduce, they dose reduce from 300 mg to 200 mg. That is a 33% dose reduction. That’s generally not what we do. We generally do 20% or less. In rucaparib, the dose reduction is from 600 mg to 500 mg. There’s a lot of flexibility in the tweaking. But you can’t just cut the niraparib capsule up. But it’s a once-a-day option. So, as we isolate this one issue, the dose, which is probably never going to change, at least not without a large trial, does this resonate—this 600 mg to 500 mg dose reduction versus the once-a-day option of niraparib?

Shannon N. Westin, MD, MPH: Ultimately, we don’t know.

Bradley J. Monk, MD, FACS, FACOG: In your practice, next week, does that mean anything to you?

Shannon N. Westin, MD, MPH: It does. But, the subanalyses of the NOVA data indicated that there weren’t any differences in efficacy with those dose reductions. In fact, the majority of the patients were dose reduced, but they still saw a beautiful impact on progression-free survival.

Bradley J. Monk, MD, FACS, FACOG: Hypothesis-generating and non–hypothesis-generating.

Shannon N. Westin, MD, MPH: That’s certainly reassuring to me. I do think you bring up a great point. Can you tease out that efficacy, at those different dose levels? Does it matter? Is that less than 20% dose reduction made up? Or, is that something that we really should be kind of sticking to?

Bradley J. Monk, MD, FACS, FACOG: Dave?

David O’Malley, MD: I think the even larger concern, in some regards, is the next dose reduction is now a two-thirds dose reduction. You don’t have the opportunity to go lower than that. We went from 300 mg. Now, we’re going to start at 200 mg, with certain criteria. And now, the next dose reduction is 100 mg. We’ve taken two-thirds of our delivered drug and are now in a different territory. I do think the once-a-day dosing is very interesting for our patients, and is clearly more compliant across all diseases, from blood pressure to anything else. But, the ability to more easily dose reduce—we know the majority of these patients are going to recover. That’s across drugs. The majority of patients, or nearly the majority of them, will require a dose reduction.

Bradley J. Monk, MD, FACS, FACOG: So, don’t feel defeated if you need to dose reduce, because two-thirds need it. These are fixed doses. Bioavailability, and patient metabolism, and size changes, obviously. I get it.

Ursula Matulonis, MD: On that phase I trial that was published a number of years ago, there was an indication of response at that 100-mg dose.

Matthew Powell, MD: Maybe we’re holding on to old concepts? This platelet toxicity with niraparib is early. It goes away. As a practicing clinician, I might start at 200 mg and go to 300 mg at the next month, if there’s not a problem. We don’t have any guidance on that, but that may alleviate some of that need for dose reduction and this efficacy concern.

Bradley J. Monk, MD, FACS, FACOG: Once you move beyond the once-daily dosing, what are the other factors that you consider? Once you’ve decided to use a PARP inhibitor, assuming that the labels are similar, what other factors do you consider, other than the flexibility with dosing and the once-daily formulation?

Matthew Powell, MD: For a patient with preexisting hypertension, especially if they’re having a little bit of trouble controlling it, I would probably avoid niraparib. I think it’s going to be additive, if they get that product.

Bradley J. Monk, MD, FACS, FACOG: Tell us why niraparib causes hypertension?

Matthew Powell, MD: It does have some betamimetic activity. l think it’s about 25%? Is that correct? Again, it is usually controlled.

Bradley J. Monk, MD, FACS, FACOG: That’s the only one? The other 2, olaparib and rucaparib, do not?

Matthew Powell, MD: There are slight differences, but not enough to be something significant. It is really associated with niraparib.

Bradley J. Monk, MD, FACS, FACOG: I think you said toxicity profile, and you singled out the hypertension. You’ve discussed the platelets. Dave, what are the other toxicity differences between the 3 PARP inhibitors that are under consideration?

David O’Malley, MD: It appears that the LFT elevation is unique to rucaparib, as well as some elevation in the creatinine. We have seen it in other PARPs. It was better described in the rucaparib, but I have seen it across other PARPs. There’s a lot, with regards to the creatinine and competing for the receptor. But with regard to the LFTs, it’s interesting—you see these LFT elevations but they have no clinical significance.

Bradley J. Monk, MD, FACS, FACOG: Very good.

David O’Malley, MD: We watch them, and they go down within the next month or 2. You don’t have to do anything. In practice, you just have to watch them to make sure they don’t stay up.

Shannon N. Westin, MD, MPH: The elevated creatinine also typically has no clinical significance. Yes, it’s regarded in the creatinine. You need to calculate a GFR. If you’ve got a normal GFR, you can push through. I agree with you—although it was only really well reported in the rucaparib studies, it is something that we’ve seen across all of the PARP inhibitors. It’s a class effect.

Bradley J. Monk, MD, FACS, FACOG: Shannon, is the mechanism of resistance the same for the PARP inhibitors? Or, if a patient fails on one of the 3 PARP inhibitors, maybe I should just try another one?

Shannon N. Westin, MD, MPH: There are multiple mechanisms of resistance. We’re still, I think, trying to tease those things out. Certainly, BRCA2 reversion mutations are a hot one that we’ve heard about. But, there also could be drug transport, and things like that. So, we don’t know, ultimately. In clinical practice, and maybe in studies, I think that we will see people trying a PARP after a PARP, especially in these cases of maintenance. When you say you have somebody on a PARP inhibitor as maintenance, they’re on it for a year or 2. Ultimately, they progress. Can you add a PARP back, after you get that patient to a response again?

Bradley J. Monk, MD, FACS, FACOG: So, let me rephrase that. A patient who doesn’t progress on a PARP inhibitor may be treated differently than a patient who does progress on a PARP inhibitor. What do you think the chance is for effectiveness, if you switch to another PARP inhibitor following progression on a PARP inhibitor?

Shannon N. Westin, MD, MPH: At this point, I would say it’s probably pretty low. I think that’s where combinations are very interesting. Ursula and I have been involved in multiple trials that look at that question. So, you’ve got a patient who gets a single-agent PARP therapy. They ultimately progress. Can you add something? Can you switch something out, to try to overcome that resistance?

David O’Malley, MD: We have the OReO study, in Europe, which is looking at a PARP after a PARP. Hopefully, we will have data to help answer that question in the near future.
Ursula Matulonis, MD: A number of us are involved in clinical trials where we’re starting to try to define that platinum-free interval. We know it is not great, but we still use it—that 6-month cutoff. But, what is it for a PARP inhibitor? Is it also 6 months? Is it 9 months? Is it a year? I think we’re just starting to incorporate that eligibility criteria, especially for combinations.

David O’Malley, MD: As well as with bevacizumab.

Ursula Matulonis, MD: Yes, absolutely.

Bradley J. Monk, MD, FACS, FACOG: And maybe we need a PARP-refractory, PARP-resistant, PARP-sensitive, just like we have for platinum….

Matthew Powell, MD: One caveat is, in patients who are on an upfront trial with veliparib, I still would consider using an FDA-labeled drug. I would feel comfortable using an FDA-approved PARP inhibitor for that patient.

Ursula Matulonis, MD: Absolutely.

Bradley J. Monk, MD, FACS, FACOG: Again, we have 2 questions in the clinic. Is this patient suitable for PARP inhibition? And, if yes, I think we’ve addressed that.

Transcript Edited for Clarity 

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: We’re now going to begin a discussion on which poly (ADP-ribose) polymerase inhibitor to use. When a clinician considers a PARP inhibitor, the first decision starts with, is this patient appropriate for a PARP inhibitor? And soon, the labels are going to be exactly the same, or at least similar enough. So, that’s unprecedented for us. If you remember, in 2005, we had pegylated liposomal doxorubicin approved. That was easy because it just beat topotecan. We didn’t have to keep talking about topotecan because there was a randomized comparative trial. And there was no such thing as the PARP inhibitors. And then, when we got gemcitabine approved in 2006, well, that was sensitive disease. So, again, we could still talk about pegylated liposomal doxorubicin and carboplatin/gemcitabine in the same setting. There was no controversy. You said we’re going to get bevacizumab approved. We’ve got 5 chemotherapy backbones, and there’s no competitor to antiangiogenesis in ovarian cancer. So, this is an unprecedented era.

David O’Malley, MD: But after 10 to 15 years of using bevacizumab, we still don’t know exactly where to use it. I think we’re figuring that out.

Bradley J. Monk, MD, FACS, FACOG: But, these are different questions. The first question is when to use it. We will continue to debate that—whether it’s for frontline, or second-line, or in combination. But, once you make that decision, which PARP inhibitor? Shannon, Ursula talked about the dose reduction and the formulation. The good news is, niraparib is given once a day. Publicly, I’ve said that if birth control pills were given twice a day, there would be a lot of unintended pregnancies. There is resonance in once-a-day dosing. But she also said, “Well, maybe we should dose reduce.”

So, when they dose reduce, they dose reduce from 300 mg to 200 mg. That is a 33% dose reduction. That’s generally not what we do. We generally do 20% or less. In rucaparib, the dose reduction is from 600 mg to 500 mg. There’s a lot of flexibility in the tweaking. But you can’t just cut the niraparib capsule up. But it’s a once-a-day option. So, as we isolate this one issue, the dose, which is probably never going to change, at least not without a large trial, does this resonate—this 600 mg to 500 mg dose reduction versus the once-a-day option of niraparib?

Shannon N. Westin, MD, MPH: Ultimately, we don’t know.

Bradley J. Monk, MD, FACS, FACOG: In your practice, next week, does that mean anything to you?

Shannon N. Westin, MD, MPH: It does. But, the subanalyses of the NOVA data indicated that there weren’t any differences in efficacy with those dose reductions. In fact, the majority of the patients were dose reduced, but they still saw a beautiful impact on progression-free survival.

Bradley J. Monk, MD, FACS, FACOG: Hypothesis-generating and non–hypothesis-generating.

Shannon N. Westin, MD, MPH: That’s certainly reassuring to me. I do think you bring up a great point. Can you tease out that efficacy, at those different dose levels? Does it matter? Is that less than 20% dose reduction made up? Or, is that something that we really should be kind of sticking to?

Bradley J. Monk, MD, FACS, FACOG: Dave?

David O’Malley, MD: I think the even larger concern, in some regards, is the next dose reduction is now a two-thirds dose reduction. You don’t have the opportunity to go lower than that. We went from 300 mg. Now, we’re going to start at 200 mg, with certain criteria. And now, the next dose reduction is 100 mg. We’ve taken two-thirds of our delivered drug and are now in a different territory. I do think the once-a-day dosing is very interesting for our patients, and is clearly more compliant across all diseases, from blood pressure to anything else. But, the ability to more easily dose reduce—we know the majority of these patients are going to recover. That’s across drugs. The majority of patients, or nearly the majority of them, will require a dose reduction.

Bradley J. Monk, MD, FACS, FACOG: So, don’t feel defeated if you need to dose reduce, because two-thirds need it. These are fixed doses. Bioavailability, and patient metabolism, and size changes, obviously. I get it.

Ursula Matulonis, MD: On that phase I trial that was published a number of years ago, there was an indication of response at that 100-mg dose.

Matthew Powell, MD: Maybe we’re holding on to old concepts? This platelet toxicity with niraparib is early. It goes away. As a practicing clinician, I might start at 200 mg and go to 300 mg at the next month, if there’s not a problem. We don’t have any guidance on that, but that may alleviate some of that need for dose reduction and this efficacy concern.

Bradley J. Monk, MD, FACS, FACOG: Once you move beyond the once-daily dosing, what are the other factors that you consider? Once you’ve decided to use a PARP inhibitor, assuming that the labels are similar, what other factors do you consider, other than the flexibility with dosing and the once-daily formulation?

Matthew Powell, MD: For a patient with preexisting hypertension, especially if they’re having a little bit of trouble controlling it, I would probably avoid niraparib. I think it’s going to be additive, if they get that product.

Bradley J. Monk, MD, FACS, FACOG: Tell us why niraparib causes hypertension?

Matthew Powell, MD: It does have some betamimetic activity. l think it’s about 25%? Is that correct? Again, it is usually controlled.

Bradley J. Monk, MD, FACS, FACOG: That’s the only one? The other 2, olaparib and rucaparib, do not?

Matthew Powell, MD: There are slight differences, but not enough to be something significant. It is really associated with niraparib.

Bradley J. Monk, MD, FACS, FACOG: I think you said toxicity profile, and you singled out the hypertension. You’ve discussed the platelets. Dave, what are the other toxicity differences between the 3 PARP inhibitors that are under consideration?

David O’Malley, MD: It appears that the LFT elevation is unique to rucaparib, as well as some elevation in the creatinine. We have seen it in other PARPs. It was better described in the rucaparib, but I have seen it across other PARPs. There’s a lot, with regards to the creatinine and competing for the receptor. But with regard to the LFTs, it’s interesting—you see these LFT elevations but they have no clinical significance.

Bradley J. Monk, MD, FACS, FACOG: Very good.

David O’Malley, MD: We watch them, and they go down within the next month or 2. You don’t have to do anything. In practice, you just have to watch them to make sure they don’t stay up.

Shannon N. Westin, MD, MPH: The elevated creatinine also typically has no clinical significance. Yes, it’s regarded in the creatinine. You need to calculate a GFR. If you’ve got a normal GFR, you can push through. I agree with you—although it was only really well reported in the rucaparib studies, it is something that we’ve seen across all of the PARP inhibitors. It’s a class effect.

Bradley J. Monk, MD, FACS, FACOG: Shannon, is the mechanism of resistance the same for the PARP inhibitors? Or, if a patient fails on one of the 3 PARP inhibitors, maybe I should just try another one?

Shannon N. Westin, MD, MPH: There are multiple mechanisms of resistance. We’re still, I think, trying to tease those things out. Certainly, BRCA2 reversion mutations are a hot one that we’ve heard about. But, there also could be drug transport, and things like that. So, we don’t know, ultimately. In clinical practice, and maybe in studies, I think that we will see people trying a PARP after a PARP, especially in these cases of maintenance. When you say you have somebody on a PARP inhibitor as maintenance, they’re on it for a year or 2. Ultimately, they progress. Can you add a PARP back, after you get that patient to a response again?

Bradley J. Monk, MD, FACS, FACOG: So, let me rephrase that. A patient who doesn’t progress on a PARP inhibitor may be treated differently than a patient who does progress on a PARP inhibitor. What do you think the chance is for effectiveness, if you switch to another PARP inhibitor following progression on a PARP inhibitor?

Shannon N. Westin, MD, MPH: At this point, I would say it’s probably pretty low. I think that’s where combinations are very interesting. Ursula and I have been involved in multiple trials that look at that question. So, you’ve got a patient who gets a single-agent PARP therapy. They ultimately progress. Can you add something? Can you switch something out, to try to overcome that resistance?

David O’Malley, MD: We have the OReO study, in Europe, which is looking at a PARP after a PARP. Hopefully, we will have data to help answer that question in the near future.
Ursula Matulonis, MD: A number of us are involved in clinical trials where we’re starting to try to define that platinum-free interval. We know it is not great, but we still use it—that 6-month cutoff. But, what is it for a PARP inhibitor? Is it also 6 months? Is it 9 months? Is it a year? I think we’re just starting to incorporate that eligibility criteria, especially for combinations.

David O’Malley, MD: As well as with bevacizumab.

Ursula Matulonis, MD: Yes, absolutely.

Bradley J. Monk, MD, FACS, FACOG: And maybe we need a PARP-refractory, PARP-resistant, PARP-sensitive, just like we have for platinum….

Matthew Powell, MD: One caveat is, in patients who are on an upfront trial with veliparib, I still would consider using an FDA-labeled drug. I would feel comfortable using an FDA-approved PARP inhibitor for that patient.

Ursula Matulonis, MD: Absolutely.

Bradley J. Monk, MD, FACS, FACOG: Again, we have 2 questions in the clinic. Is this patient suitable for PARP inhibition? And, if yes, I think we’ve addressed that.

Transcript Edited for Clarity 
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