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PARP Inhibitor Toxicity Management

Panelists: Bradley Monk, MD, FACOG, FACS, St. Joseph's Hospital and Medical Center; Michael J. Birrer, MD, PhD, O'Neal Comprehensive Cancer Center; Jubilee Brown, MD, Levine Cancer Institute; Thomas Herzog, MD, UC College of Medicine; Krishnansu S. Tewari, MD, University of California, Irvine
Published: Wednesday, Aug 21, 2019



Transcript:

Bradley Monk, MD, FACOG, FACS: All right, let’s talk a little about the toxicities, because all our enthusiasm has to be balanced with toxicity. Jubilee, give us a very high-level summary of what the toxicities of PARP [poly ADP ribose polymerase] inhibitors are.

Jubilee Brown, MD: We see toxicities with all 3 PARP inhibitors, and those range from nausea that typically goes away with time to thrombocytopenia and anemia. But much of these can be managed, and we’ve learned a lot with your excellent work. We’ve learned a lot about how to manage those and mitigate those. Even the information on niraparib compared with placebo, in terms of how patients tolerate this—the so-called TWiST [time without symptoms or toxicities] data, TWiST analysis—looking at how patients are able to tolerate therapy, and that leads into their quality of life. We know that we can manage with, as you’ve shown, weight and platelet count-based therapy, dose change. And that works for patients, it looks like, across multiple studies.

Bradley Monk, MD, FACOG, FACS: The trick is you have to keep the patient asymptomatic from her treatment and asymptomatic from her cancer, so you can be wrong twice. If the treatment hurts her or the cancer hurts her, there’s a concern. Tom, tell us about this TWiST analysis, in which you know there’s an opportunity to look at that as an aggregate endpoint.

Thomas Herzog, MD: I understand it almost as well as I do the SUCRA [surface under the cumulative ranking curve]. Basically, what you’re trying to do with TWiST is account for the toxicity. This gets into: can we do composite endpoints? This brings in the idea of a composite endpoint where you can subtract the PFS [progression-free survival] gains with significant toxicity. You get a score, if you will, that represents the patient experience in a more comprehensive manner.

Bradley Monk, MD, FACOG, FACS: I like that. That’s the global sort of patient-reported outcomes, this quality-of-life analysis, these questionnaires. But let’s take the 3 that you talked about: GI [gastrointestinal], and that’s nausea and also diarrhea. Michael, tell me how you handle the GI toxicity associated with PARP inhibitors.

Michael J. Birrer, MD, PhD: Well, I’ll preface my comments by saying this class of drugs is exceedingly well tolerated. I know we focus on this, but these drugs are actually very well tolerated. For GI, I know some of my colleagues will preemptively treat with Zofran. I do not do that. Partly because it’s only a subset that get nausea and, as Julie says, tachyphylaxis, so it sort of disappears on its own over a period of time. That’s the way I approach it. If the patient is really bothered by it, of course we’ll use antiemetics.

Bradley Monk, MD, FACOG, FACS: So proactive supportive care. Obviously if it’s too toxic, then stop, recover, and dose reduce.

Michael J. Birrer, MD, PhD: That’s right.

Bradley Monk, MD, FACOG, FACS: That’s GI, and also diarrhea is handled the same way with supportive care: stop, recover, dose reduction. Krish, the second one is bone marrow suppression. Jubilee called out thrombocytopenia. Niraparib is probably the most vulnerable for thrombocytopenia. Tell us how we handle that.
Krishnansu S. Tewari, MD: With niraparib, the starting dosage or the label is 300 mg daily, once-daily dosing. You could definitely start your patients on that dosage and see how they do. If they do have hematologic toxicity, consider dose reducing, especially if it resolved and happens again. Or you can use data from what’s called the RADAR [results of adverse reactions] analysis. And that analysis allows us to predict with some certainty, at least on the NOVA trial, which patients need to have early dose modifications. Patients with a body weight under 77 kg, or 170 lb, or a baseline platelet count under 150,000 mm3. If a patient meets either of those criteria, they can be started at 200 mg.

Bradley Monk, MD, FACOG, FACS: I like the way you put it. You said, “Look, Brad, most patients get to 200 mg anyway, so you can either let them have toxicity and then get there.” Or you can say, “Look, this patient is underweight or has a low baseline platelet count,” and then preemptively, proactively, start a subset of them at 200 mg. I like that.

Michael J. Birrer, MD, PhD: It’s important to note that on the NOVA trial, those who were down to 200 mg did as well.

Bradley Monk, MD, FACOG, FACS: That’s exactly right. So regarding GI toxicity we talked about and bone marrow toxicity. Tom, the third would be fatigue. Tell us how you handle the fatigue-related toxicity associated with PARP inhibition.

Thomas Herzog, MD: Yeah. I think the problem with fatigue is it’s often difficult to get the contribution effect of the medication versus the stress of having cancer, versus the actual disease itself, ovarian cancer.

Bradley Monk, MD, FACOG, FACS: Sleep deprivation.

Thomas Herzog, MD: Yeah, exactly. I’m a big advocate of timed naps, exercise, really trying for general conditioning and nutrition and all those types of things, and trying to build up some type of activity program where there’s progress—you know, like the number of steps or miles that you walk. I found that very helpful.

Bradley Monk, MD, FACOG, FACS: What you just said, and you taught this to me, the fatigue is multifactorial. You’ve got the diagnosis right, and if the diagnosis is anemia, then give blood transfusion. If it’s sleep, they’ve got to have better sleep. Listen, the biggest cause of fatigue in the desert is dehydration. We actually have a proactive hydration, and if you think it’s concomitant medications, the PARP inhibitor, just like GI, stop, recover, and dose reduce.

I think that’s very helpful. I think the take-home message is that maintenance is here to stay in ovarian cancer, that it is a very important opportunity to improve outcomes. What you said, not only living longer and better but being prospectively evaluated over and over again. And thank you, Tom and Michael, for your recent publication that says that these results have to change our practice, and for efforts in trying to promote education.

Thomas Herzog, MD: It’s amazing if you think about it. A couple of years ago, 1 of the hot debate topics was maintenance: should we do it? And it was really easy to take the con side 2 or 3 years ago. Now it’s you would not want that position.

Bradley Monk, MD, FACOG, FACS: I have a partner who says, “Look, Brad, it’s really fun to practice gynecologic oncology today, because I can treat my patients. I can make a difference. I can have things to offer them.”

Michael J. Birrer, MD, PhD: We have options.

Thomas Herzog, MD: We have options.

Transcript Edited for Clarity

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Transcript:

Bradley Monk, MD, FACOG, FACS: All right, let’s talk a little about the toxicities, because all our enthusiasm has to be balanced with toxicity. Jubilee, give us a very high-level summary of what the toxicities of PARP [poly ADP ribose polymerase] inhibitors are.

Jubilee Brown, MD: We see toxicities with all 3 PARP inhibitors, and those range from nausea that typically goes away with time to thrombocytopenia and anemia. But much of these can be managed, and we’ve learned a lot with your excellent work. We’ve learned a lot about how to manage those and mitigate those. Even the information on niraparib compared with placebo, in terms of how patients tolerate this—the so-called TWiST [time without symptoms or toxicities] data, TWiST analysis—looking at how patients are able to tolerate therapy, and that leads into their quality of life. We know that we can manage with, as you’ve shown, weight and platelet count-based therapy, dose change. And that works for patients, it looks like, across multiple studies.

Bradley Monk, MD, FACOG, FACS: The trick is you have to keep the patient asymptomatic from her treatment and asymptomatic from her cancer, so you can be wrong twice. If the treatment hurts her or the cancer hurts her, there’s a concern. Tom, tell us about this TWiST analysis, in which you know there’s an opportunity to look at that as an aggregate endpoint.

Thomas Herzog, MD: I understand it almost as well as I do the SUCRA [surface under the cumulative ranking curve]. Basically, what you’re trying to do with TWiST is account for the toxicity. This gets into: can we do composite endpoints? This brings in the idea of a composite endpoint where you can subtract the PFS [progression-free survival] gains with significant toxicity. You get a score, if you will, that represents the patient experience in a more comprehensive manner.

Bradley Monk, MD, FACOG, FACS: I like that. That’s the global sort of patient-reported outcomes, this quality-of-life analysis, these questionnaires. But let’s take the 3 that you talked about: GI [gastrointestinal], and that’s nausea and also diarrhea. Michael, tell me how you handle the GI toxicity associated with PARP inhibitors.

Michael J. Birrer, MD, PhD: Well, I’ll preface my comments by saying this class of drugs is exceedingly well tolerated. I know we focus on this, but these drugs are actually very well tolerated. For GI, I know some of my colleagues will preemptively treat with Zofran. I do not do that. Partly because it’s only a subset that get nausea and, as Julie says, tachyphylaxis, so it sort of disappears on its own over a period of time. That’s the way I approach it. If the patient is really bothered by it, of course we’ll use antiemetics.

Bradley Monk, MD, FACOG, FACS: So proactive supportive care. Obviously if it’s too toxic, then stop, recover, and dose reduce.

Michael J. Birrer, MD, PhD: That’s right.

Bradley Monk, MD, FACOG, FACS: That’s GI, and also diarrhea is handled the same way with supportive care: stop, recover, dose reduction. Krish, the second one is bone marrow suppression. Jubilee called out thrombocytopenia. Niraparib is probably the most vulnerable for thrombocytopenia. Tell us how we handle that.
Krishnansu S. Tewari, MD: With niraparib, the starting dosage or the label is 300 mg daily, once-daily dosing. You could definitely start your patients on that dosage and see how they do. If they do have hematologic toxicity, consider dose reducing, especially if it resolved and happens again. Or you can use data from what’s called the RADAR [results of adverse reactions] analysis. And that analysis allows us to predict with some certainty, at least on the NOVA trial, which patients need to have early dose modifications. Patients with a body weight under 77 kg, or 170 lb, or a baseline platelet count under 150,000 mm3. If a patient meets either of those criteria, they can be started at 200 mg.

Bradley Monk, MD, FACOG, FACS: I like the way you put it. You said, “Look, Brad, most patients get to 200 mg anyway, so you can either let them have toxicity and then get there.” Or you can say, “Look, this patient is underweight or has a low baseline platelet count,” and then preemptively, proactively, start a subset of them at 200 mg. I like that.

Michael J. Birrer, MD, PhD: It’s important to note that on the NOVA trial, those who were down to 200 mg did as well.

Bradley Monk, MD, FACOG, FACS: That’s exactly right. So regarding GI toxicity we talked about and bone marrow toxicity. Tom, the third would be fatigue. Tell us how you handle the fatigue-related toxicity associated with PARP inhibition.

Thomas Herzog, MD: Yeah. I think the problem with fatigue is it’s often difficult to get the contribution effect of the medication versus the stress of having cancer, versus the actual disease itself, ovarian cancer.

Bradley Monk, MD, FACOG, FACS: Sleep deprivation.

Thomas Herzog, MD: Yeah, exactly. I’m a big advocate of timed naps, exercise, really trying for general conditioning and nutrition and all those types of things, and trying to build up some type of activity program where there’s progress—you know, like the number of steps or miles that you walk. I found that very helpful.

Bradley Monk, MD, FACOG, FACS: What you just said, and you taught this to me, the fatigue is multifactorial. You’ve got the diagnosis right, and if the diagnosis is anemia, then give blood transfusion. If it’s sleep, they’ve got to have better sleep. Listen, the biggest cause of fatigue in the desert is dehydration. We actually have a proactive hydration, and if you think it’s concomitant medications, the PARP inhibitor, just like GI, stop, recover, and dose reduce.

I think that’s very helpful. I think the take-home message is that maintenance is here to stay in ovarian cancer, that it is a very important opportunity to improve outcomes. What you said, not only living longer and better but being prospectively evaluated over and over again. And thank you, Tom and Michael, for your recent publication that says that these results have to change our practice, and for efforts in trying to promote education.

Thomas Herzog, MD: It’s amazing if you think about it. A couple of years ago, 1 of the hot debate topics was maintenance: should we do it? And it was really easy to take the con side 2 or 3 years ago. Now it’s you would not want that position.

Bradley Monk, MD, FACOG, FACS: I have a partner who says, “Look, Brad, it’s really fun to practice gynecologic oncology today, because I can treat my patients. I can make a difference. I can have things to offer them.”

Michael J. Birrer, MD, PhD: We have options.

Thomas Herzog, MD: We have options.

Transcript Edited for Clarity
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