Case 2: Monitoring Adverse Reactions With Niraparib Maintenance in Ovarian Cancer
Cecelia H. Boardman, MD, John K. Chan, MD, and Thomas C. Krivak, MD, share strategies for monitoring adverse events and the optimal duration for niraparib maintenance therapy for a patient with advanced ovarian cancer.
Thomas C. Krivak, MD: Very good points. How about anemia or with fatigue we always think, as you said, what strategies can we do? With this patient, she got started on with niraparib 300 mg once a day [QD] and her hemoglobin [HbA1C] fell to 7. We always want to think is there an underlying cause for hemoglobin that falls to 7? She received a blood transfusion. How are we going to manage that? To me, blood transfusion, dose reduction, dose interruption, how would you guys manage that toxicity and how do you look at dose holds, reduction, and then back to escalation with respect to anemia, as well as thrombocytopenia? I’m just curious on your thoughts with that. Go ahead, Cecilia?
Cecelia H. Boardman, MD: To me, dose interruption is key. Certainly, a hemoglobin of 7, that’s a pretty big drop so I might get iron indices and then I would also look and see, check folate and B12. I’d look at their MCV, [mean corpuscular volume] get the appropriate vitamin markers to see if we’re missing anything. But, if it is just drug induced, dose interruption and then dose reduction once they recover their counts and then I’ll keep them at that dose. And I always have a few patients that have a little anxiety. Am I going to have a lower efficacy? But you alluded to earlier that there is some post hoc data that looks at response based on dose, and we think we don’t lose efficacy with that dose mod in order to make it more tolerable from a hematologic standpoint. This patient, if she had started at 300 mg, I would hold her for a week or 2, check her counts weekly, and then restart her at a 100 mg dose lower than her initial starting dose.
John K. Chan, MD: For patients with severe anemia, it’s important at that point to work her up for other cause of anemia. Most likely it is due to niraparib, and for these patients, dose holding them and then wait until their toxicity recovers up to at least a grade 1 level before reinitiation. And with that, the reinitiation I generally start them at a modified dose which is a slower ramp-up of the 200 mg. Let’s say they were at a baseline of 200 mg I may start them at 100 mg every other day and then next week start them at 100 mg every day and then slowly work them up to the 200 mg level and of course monitor their lab tests closely.
Thomas C. Krivak, MD: What would you guys say is the optimal duration of treatment for this patient, would you say 2 years, 3 years, or until progression, or TBD?
Cecelia H. Boardman, MD: John, what do you think?
John K. Chan, MD: The maintenance indication is for 3 years for these patients. I generally try to stick with the label, and, if the patients can get through these, the benefit was seen in the patients who went on the trial and took the drug for 3 years as indicated. I try to push to get them through the 3 year period.
Cecelia H. Boardman, MD: I’m generally going to have a conversation with them at that 3 year mark. This was the duration of therapy in the clinical trial. This is what the FDA [Food and Drug Administration] approval is. The recommendation would be if you’re in a sustained clinical remission, to come off drug. Now, for the patient with evaluable disease who still has disease but is stable in terms of her response, then that patient you could continue. But a CR [complete remission] patient, you should have a conversation about whether they come off. Then a subtlety too is, will insurance pay for it beyond 3 years? Is the third party payor savvy enough to realize we’ve approved this drug 3 years in a row and we’re not going to pay for it anymore because that’s what the label says is they should come off.
Thomas C. Krivak, MD: Yes, I agree with both what you guys are saying. 3 years is probably the way to go if they have partial response, stable disease continuing, but those are difficult conversations because again, just like Ashley was saying early on, some of these patients have comfort in taking the medication, they feel like they’re doing something. Obviously, to talk about dosing, we talked about dose reductions. We start at 300 mg, we can go to 200 mg and then the 100 mg if we start at the body weight of 200 lb they go 200 mg to 100 mg. John, you’ve said eloquently throughout how you go from 100 mg to 200 mg modify to go up. You have some nice creative ways that you’re doing some of that dosing. Again, it’s creative because the ultimate goal is to keep these patients on treatment for that 2 to 3 year period and to get them out to their 3 years with respect to, because it’s the duration of exposure to this medication that’s going to be important.
This is a nice slide that as we’re doing things differently but similar, we’re using that phase 4 data of how we’re going to manage these things. What you can see is when do you do dose reductions. Again, if you have platelet count go under 100,000 [mcL] with niraparib, you need to hold. Once it recovers, you can go back to the same dose or dose reduce. Any time that I have thrombocytopenia, I almost always dose reduce once it goes under 100,000 [mcL]. It says here if it’s 75,000 [mcL] you want to use reduced dose or if it goes under 10,000, [mcL] those patients may need a blood transfusion and then resume niraparib at a lower dose. At the second recurrence of having thrombocytopenia, you want to hold the medication obviously and then resume niraparib at a reduced dose. We talked about how we may be able to escalate at a later time to see how patients do. There are many different nuances that, as we gain an understanding of how to modify some of these doses, it seems like patients are doing very well.
I haven’t had too many problems with neutrophils with respect to niraparib that patient with the hemoglobin, but, again, if you have to hold the drug for over 28 days, you should most likely stop the medication, but again you can resume niraparib at a reduced dose if their hemoglobin goes below 8 or ANC [Absolute Neutrophil Count] goes below 1,000. In this patient, you would hold the dose, transfuse, wait till they recover and then start at a lower dose. I like how you were thinking, John, where you said you may go ahead and alter the dose and try to dose escalate as well.
Is there any clinical pearls or advice to share with oncologists, related to the use of single-agent PARP as primary maintenance therapy, that you guys have at this time as we’ve gone through these 2 cases?
Cecelia H. Boardman, MD: There’s 2 things that I would offer as advice for the medical oncologists. One is that I almost see maintenance not just as the word maintenance, I see maintenance as part of their treatment. I see maintenance as the second component of their treatment, just like surgery and chemotherapy is a component. For your medical therapy, maintenance strategy is a benefit that we should help these medical oncologists understand that it should be incorporated into their treatment strategy; 4 months of chemotherapy, 2 or 3 years of maintenance strategy to get them that magnitude of benefit that we’re able to see, particularly in patients who have the biomarker to guide that treatment.
The second pearl that I would offer these medical oncologists with respects to the maintenance strategy is even in a small proportion of the patients, particularly related to patients who actually went on the PRIMA trial, they had persistent disease even after 6 lines of treatment, 6 cycles of treatment. For those patients, that second PARPof the medical treatment, even though we call it maintenance, is really not maintenance. That’s basically switch therapy. You switch from chemotherapy to PARP therapy, and PARPs like niraparib is indicated for treatment. Same dose, same treatment. These drugs are active. And knowing that these are drugs, and this is not just a maintenance tamoxifen, these drugs have toxicities. Having the ability to help these patients manage through these toxicities is also important.
Thomas C. Krivak, MD: Good points.
Cecelia H. Boardman, MD: Tom, you have underscored multiple times the importance of compliance with treatment and duration of therapy. And we really stress that with our patients. But it’s hard when you’re a busy surgeon and you’re in the OR [operating room] every other day, you are not necessarily there to hold that patient’s hand and answer their questions and answer their phone calls. And, in my practice, we’ve designated one of our chemotherapy nurses as a PARP champion. And having somebody who the patients can talk to about their adverse effects, about actively managing their adverse effects, supporting them through that wash-in period, really stressing dose interruption in order to manage those adverse effects, we’ve been able to help patients stay on treatment and stay on treatment long term. But, having somebody in the office who supports the patient and is their cheerleader to getting through that wash-in period we have found to be very beneficial.
Thomas C. Krivak, MD: The points that both you guys make are absolutely outstanding and to me are very beneficial to the patients to keep them on long term. Ashley, any thoughts?
Ashley Farione, PA-C: It’s important how Dr Boardman was saying about the patients and the compliance. Because a lot of the times you’re telling them how to take it and they’ll come back in and you’ll ask them. They’re like, “oh well, I skipped a day here, I skipped a day there but I haven’t been doing it twice a day, I’ve only been doing it maybe once a day.” It’s important to urge them the importance that if you don’t take it correctly or if you’re modifying the dose it’s not going to work the right way. Educating the patient and making sure they understand that is key as well.
Thomas C. Krivak, MD: All excellent points. Thank you.
Transcript Edited for Clarity
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