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Ovarian Cancer: Comparisons Between PARP Inhibitors

Insights From: Oliver Dorigo, MD, PhD, Stanford University Medical Center; Whitney Graybill, MD, MS, Medical University of South Carolina; Matthew Powell, MD, Washington University School of Medicine
Published: Friday, Jan 26, 2018



Transcript: 

Oliver Dorigo, MD, PhD: There are 3 PARP inhibitors approved for ovarian cancer at this point: olaparib, rucaparib, and niraparib. The dosing is different between those PARP inhibitors. Rucaparib is dosed at 600 mg by mouth bid [twice daily]. Olaparib is given at 300 mg PO bid. Those are 150-mg tablets. They were just approved by the FDA for the treatment of both BRCA1 and BRCA2-mutation carriers with ovarian cancer in the maintenance setting. Niraparib is the only PARP inhibitor that is dosed only once a day, and we dose it initially at 300 mg/day. That’s the recommended starting dose, to be taken at about the same time on a daily basis. The dosing at this point is continuous.

We don’t have any data that suggests we can stop PARP inhibitors unless patients have side effects that are not tolerable or patients progress with the disease. We do have dose modification recommendations that can easily be obtained by the package inserts. The initial administration has to be monitored very carefully by the providers, by the physicians, or by the nurse practitioners, whoever is involved in the care. It’s important to inform the patients about potential side effects and about the likelihood of having to dose modify any of these PARP inhibitors.

Matthew Powell, MD: The mechanisms of action of the 3 different PARP inhibitors are notably different as far as how they interact with the different PARP molecules. Clinically, this is not overly relevant. There may be differences in PARP trapping and some theoretic differences in mechanism. This may be borne out more in the side effect profile and toxicity, perhaps slightly also in efficacy, with differences in potency. This may also lead to a slightly different need for dose reductions and dosing strategy. I think if we look at olaparib, it’s probably complicated by the fact we had capsules initially. Now we have tablets. Those tablets are a more potent mg-to-mg difference than the capsules, so we want to be sure not to substitute on a 1-to-1 basis with the capsules to the tablets. Tablets are what most people are using. In fact, the capsules are mostly disappearing from the market at this point.

With olaparib itself, when we look at the mechanism of action, we see really standard side effects. It has a unique side effect in slightly elevating the creatine, which does not seem to cause a detriment in renal function, but it’s a definite lab abnormality. This is a unique feature. We’ve also mentioned niraparib having that effect on the platelet count. It is probably that the dose is a bit high in that we have a large amount of those patients, at least a third of the patients, end up with dose reduction until they ultimately end up on their final dose. With rucaparib we do have some unique side effects and elevation of the transaminases. But as far as clinically meaningful differences, they typically all have side effects like anemia and fatigue and nausea, which are things that we can fight. Niraparib does have a little bit of unique increased risk of elevation of the blood pressure, where patients can actually sometimes feel palpitations, and that is borne out in the mechanism of that drug having a few betamimetic effects.

Whitney S. Graybill, MD, MS: All of the PARP inhibitors have different toxicities. Olaparib is known to increase creatinine in about 44% of patients who receive the drug. Rucaparib has been shown to increase creatinine in about 92%, and also tends to increase AST and ALT in approximately 75% of patients. Now the increase in creatinine for both olaparib and rucaparib is thought to occur through inhibition of MATE1, MATE2, and OCT1.

The increase in creatinine does not tend to have a clinical significance. It does improve over time, and the estimated GFR [glomerular filtration rate] remains high. The increase in ALT and AST that occurs with rucaparib is also not thought to have clinical significance. It tends to normalize as you continue to treat with the drug, and we don’t typically see an increase in total bilirubin or ACT1 phosphatase with this.

With niraparib, the thing that we think about most is the 30% increase in grade 3 thrombocytopenia. There’s also about a 9% increase in grade 3 hypertension. Now the thrombocytopenia tends to occur early. It occurs usually around cycle 1, day 23, and there is a very good treatment algorithm as to how to manage thrombocytopenia with dose interruption and dose reduction. And through the mechanism of interrupting and reducing the dose of the drug, patients’ platelets recover back to normal and there does not seem to be any further problems with thrombocytopenia as you continue treatment.

The different PARP inhibitors are metabolized in different ways. Rucaparib and olaparib are metabolized by the cytochrome p450 system. Rucaparib is metabolized by CYP2D6, and it also induces and inhibits other CYP enzymes, but there are no known drug-drug interactions at this time. For olaparib, the drug is metabolized by the CYP3A4 and CYP3A5 enzymes. It’s really important with this drug to recognize that other drugs a patient might take that are either CYP3A inducers or inhibitors can interact with olaparib. So, olaparib needs to be dose-adjusted in this setting. Niraparib is actually metabolized by carboxylesterases, and is not affected by the CYP3 system, so there are no drug-drug interactions that are known.

Transcript Edited for Clarity 
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Transcript: 

Oliver Dorigo, MD, PhD: There are 3 PARP inhibitors approved for ovarian cancer at this point: olaparib, rucaparib, and niraparib. The dosing is different between those PARP inhibitors. Rucaparib is dosed at 600 mg by mouth bid [twice daily]. Olaparib is given at 300 mg PO bid. Those are 150-mg tablets. They were just approved by the FDA for the treatment of both BRCA1 and BRCA2-mutation carriers with ovarian cancer in the maintenance setting. Niraparib is the only PARP inhibitor that is dosed only once a day, and we dose it initially at 300 mg/day. That’s the recommended starting dose, to be taken at about the same time on a daily basis. The dosing at this point is continuous.

We don’t have any data that suggests we can stop PARP inhibitors unless patients have side effects that are not tolerable or patients progress with the disease. We do have dose modification recommendations that can easily be obtained by the package inserts. The initial administration has to be monitored very carefully by the providers, by the physicians, or by the nurse practitioners, whoever is involved in the care. It’s important to inform the patients about potential side effects and about the likelihood of having to dose modify any of these PARP inhibitors.

Matthew Powell, MD: The mechanisms of action of the 3 different PARP inhibitors are notably different as far as how they interact with the different PARP molecules. Clinically, this is not overly relevant. There may be differences in PARP trapping and some theoretic differences in mechanism. This may be borne out more in the side effect profile and toxicity, perhaps slightly also in efficacy, with differences in potency. This may also lead to a slightly different need for dose reductions and dosing strategy. I think if we look at olaparib, it’s probably complicated by the fact we had capsules initially. Now we have tablets. Those tablets are a more potent mg-to-mg difference than the capsules, so we want to be sure not to substitute on a 1-to-1 basis with the capsules to the tablets. Tablets are what most people are using. In fact, the capsules are mostly disappearing from the market at this point.

With olaparib itself, when we look at the mechanism of action, we see really standard side effects. It has a unique side effect in slightly elevating the creatine, which does not seem to cause a detriment in renal function, but it’s a definite lab abnormality. This is a unique feature. We’ve also mentioned niraparib having that effect on the platelet count. It is probably that the dose is a bit high in that we have a large amount of those patients, at least a third of the patients, end up with dose reduction until they ultimately end up on their final dose. With rucaparib we do have some unique side effects and elevation of the transaminases. But as far as clinically meaningful differences, they typically all have side effects like anemia and fatigue and nausea, which are things that we can fight. Niraparib does have a little bit of unique increased risk of elevation of the blood pressure, where patients can actually sometimes feel palpitations, and that is borne out in the mechanism of that drug having a few betamimetic effects.

Whitney S. Graybill, MD, MS: All of the PARP inhibitors have different toxicities. Olaparib is known to increase creatinine in about 44% of patients who receive the drug. Rucaparib has been shown to increase creatinine in about 92%, and also tends to increase AST and ALT in approximately 75% of patients. Now the increase in creatinine for both olaparib and rucaparib is thought to occur through inhibition of MATE1, MATE2, and OCT1.

The increase in creatinine does not tend to have a clinical significance. It does improve over time, and the estimated GFR [glomerular filtration rate] remains high. The increase in ALT and AST that occurs with rucaparib is also not thought to have clinical significance. It tends to normalize as you continue to treat with the drug, and we don’t typically see an increase in total bilirubin or ACT1 phosphatase with this.

With niraparib, the thing that we think about most is the 30% increase in grade 3 thrombocytopenia. There’s also about a 9% increase in grade 3 hypertension. Now the thrombocytopenia tends to occur early. It occurs usually around cycle 1, day 23, and there is a very good treatment algorithm as to how to manage thrombocytopenia with dose interruption and dose reduction. And through the mechanism of interrupting and reducing the dose of the drug, patients’ platelets recover back to normal and there does not seem to be any further problems with thrombocytopenia as you continue treatment.

The different PARP inhibitors are metabolized in different ways. Rucaparib and olaparib are metabolized by the cytochrome p450 system. Rucaparib is metabolized by CYP2D6, and it also induces and inhibits other CYP enzymes, but there are no known drug-drug interactions at this time. For olaparib, the drug is metabolized by the CYP3A4 and CYP3A5 enzymes. It’s really important with this drug to recognize that other drugs a patient might take that are either CYP3A inducers or inhibitors can interact with olaparib. So, olaparib needs to be dose-adjusted in this setting. Niraparib is actually metabolized by carboxylesterases, and is not affected by the CYP3 system, so there are no drug-drug interactions that are known.

Transcript Edited for Clarity 
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