PARP Inhibition in Ovarian Cancer: Safety Profiles and Dose Adjustment

Focused discussion on the safety profiles of PARP inhibitors in ovarian cancer and how these can be mitigated with proper dose management.


Leslie M. Randall, MD: From a safety standpoint in the PRIMA trial, there were certain side effects giving PARP in the maintenance phase over giving a placebo. The most common side effects were nonhematologic and there were fatigue and nausea, and the hematologic side effects were anemia and thrombocytopenia. Now, niraparib [Zejula] is managed with an individualized starting dose, which helps mitigate the risk of thrombocytopenia and that’s described in the package label for the drug. The 1 consideration for PARP inhibitors is myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML]. That was a signal, a safety signal that came up in the PARP inhibitors as therapy trials where patients have had a lot of prior pretreatment. So in the recurrent setting, the risk of MDS/AML was probably between 5% and 8%. In the frontline, the risk is 1% or less. Again, here is another reason to use PARP as early as possible for patients with ovarian cancer because the earlier you use it, the lower the risk for MDS/AML was. Incidentally, the risk of MDS/AML was similar in the placebo group in PRIMA, which makes us think that potentially, this is an HRD [homologous recombination deficiency] effect, this is a BRCA effect, or this is potentially a platinum effect in addition to the PARP inhibitor. But overall, the safety is very manageable and very favorable.

Dose modifications are really important for PARP inhibitors. It’s really important to get comfortable with those dose modifications. That starts with knowing the starting dose of the drug that you’re using. That starts with knowing the individualized starting dose if you’re using niraparib so that you can mitigate some of these side effects. Most patients will need a dose reduction within the first month of therapy so that’s the time you need to be most in tune with what their symptoms are. Most patients will need reductions for fatigue, nausea, and hematologic side effects so we monitor CBCs [complete blood count] weekly for the first month. Once they’re stable, you can monitor those monthly. Once you get patients on a stable dose that they personally will tolerate, really the side effect profile is very, very, very manageable and they tend to tolerate therapy very well after that point. It’s just that first month that can be involved in the dose modification.

There are different dosing frequencies for different PARP inhibitors. Niraparib is dosed once a day, and olaparib [Lynparza] and rucaparib [Rubraca] are dosed twice daily. And in my mind, in my practice, this is really more of a patient preference and compliance issue. If you think you have a patient who will be more compliant with the once-daily dosing, which I’d say that the bulk of patients are. If we’re honest with ourselves, then you would consider more of a once-daily niraparib dosing. That’s not to say that patients can’t take and be compliant with a twice-daily dose of olaparib or rucaparib but it can be a consideration for patients. I offer and discuss that with my patients, and I get their feedback on what they think is more realistic for them and I incorporate that into my decision-making for what drug I think is best for them.

Back to our patient who will receive niraparib treatment in the maintenance phase, the question that you should be asking is, is that the only option for her? Is she a candidate for olaparib therapy? And the answer to that question is yes. She is a candidate for elaborate therapy based on the SOLO-1 trial. She’s also a candidate for olaparib with bevacizumab [Avastin] based on the PAOLA-1 data. So how do you decide which treatment the patient should get? I’ll share with you my personal bias. We don’t have a trial that compares PARP to PARP/Bev [bevacizumab], only in the BRCA population. And the BRCA population benefits so much from single-agent PARP inhibition that the addition of bevacizumab might not benefit them much more. Especially in the absence of other risk factors that increase the chances of benefit from bevacizumab like continued ascites. This patient had ascites in the beginning but after her treatment, that was completely gone, or stage IV disease, and this patient had earlier stage disease. So she may not benefit as much from bevacizumab. My bias is to treat BRCA mutated patients with PARP alone for toxicity reasons. You don’t want to add toxicity with bevacizumab if you don’t know that you’ll have a benefit. Now having said that, that is still an option to add bevacizumab to the PARP therapy. Now when choosing between PARP inhibitors, it really goes back to that dosing schedule and patient preference and patient compliance questions. Both PARP inhibitors are approved for BRCA1 patients and so you have those options available to you. Also, some practitioners really get comfortable with 1 PARP over another. I personally have experience with all 3 PARP inhibitors and I’m equally comfortable managing all of them. In my case, it really comes down to what my patient preferences and their ability to multidose during the day in a compliant fashion.

Transcript edited for clarity.

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