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PARPi Dosing and Safety
Dosing and Safety of PARP Inhibitors in Ovarian Cancer: Tips From My Clinic

Released: August 27, 2019

Expiration: August 25, 2020

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Recent approvals of PARP inhibitors have expanded the treatment options and improved outcomes for patients with ovarian cancer. For optimal patient management, clinicians need to understand dosing and administration of PARP inhibitors and be familiar with their common adverse events and corresponding management strategies. In this commentary, I share my thoughts on PARP inhibitor dosing and administration, discuss the safety profile of these agents, and review strategies to manage the adverse events associated with this drug class based on my clinical experience.

Dosing and Administration
Currently, 3 PARP inhibitors are approved for the treatment of ovarian cancer—olaparib, rucaparib, and niraparib—all of which are oral medications. Olaparib is dosed at 300 mg twice daily, rucaparib is dosed at 600 mg twice daily, and niraparib is dosed at 300 mg once daily. These medications can be taken with or without food, although we have found that timing the doses to occur 30-60 minutes after a meal or at bedtime may help reduce the risk of nausea. In addition, an important consideration for olaparib is the need for reduced dosing in patients with baseline moderate renal impairment.

Another general consideration for these agents is safe handling. PARP inhibitors are oral chemotherapy agents and they should be treated with caution. Because patients are taking these medications at home, we should remind them to keep the drug out of the reach of other family members, especially children and pets. Moreover, caregivers at home who are administering the medication should use gloves. It is also important to avoid introducing these drugs into the water supply and they should not be flushed down the toilet or sink drain. Extra pills should be returned to the clinic or taken to a safe disposal site. These medications should be stored at room temperature, ideally in the original containers. It is important to inform patients not to keep the medication in their car or refrigerator where it can be subject to extreme temperatures.

Common Adverse Events
Thanks to a large body of clinical trial data, the common classwide adverse events of PARP inhibitors are well documented and include gastrointestinal toxicities, such as nausea and vomiting; fatigue; and hematologic toxicities, particularly anemia. When we speak with patients about how to manage these adverse events, it is important to not only describe the toxicities but also discuss when they might occur during the course of treatment.

Nausea and vomiting typically occur early, within the first 4-8 weeks of PARP inhibitor therapy initiation. Major guidelines classify PARP inhibitors as having a moderate to high risk of emetogenicity. As mentioned earlier, we can instruct patients to take the medication after a meal or at bedtime to help mitigate the risk of nausea. We can also offer patients antiemetic prophylaxis, and most prescribers offer antiemetics such as a serotonin receptor antagonist with “as needed” dosing. However, if patients are experiencing debilitating nausea or if they have had previous issues with nausea during chemotherapy, I recommend instructing them to take a dose of antiemetic 30 minutes prior to their PARP inhibitor dose.

Fatigue also occurs early after beginning therapy with a PARP inhibitor, and the management strategy is dependent on the severity of fatigue. For mild fatigue, we can hold the dose for approximately 1 week until it improves, and the patient can typically resume therapy at the same dose. For moderate to severe fatigue, we can hold the dose followed by dose reduction when the patient resumes therapy. Furthermore, we can encourage patients who are experiencing fatigue to try to maintain their physical activity, including walking around and sitting up in a chair instead of lying down. They should also ensure that they are receiving good nutrition and hydration. For patients who struggle with severe fatigue, there are some limited data suggesting that psychostimulant medications can help, although the findings are not consistent.

The most common hematologic adverse event is anemia, which can occur during the first 2 months of therapy and typically stabilizes or improves after 5-6 months. Similar to managing fatigue, we use dose interruption and dose reduction based on the severity of anemia. For grade 1 anemia, we would hold the dose until anemia improves and then resume at the same dose. For grade 2/3 anemia, we would hold the dose and then may resume at a lower dose. The decision about when and how to resume therapy should entail a discussion between the provider and the patient or their caregivers.

Less frequent adverse events that could occur with PARP inhibitors include diarrhea, dysgeusia, headache, and insomnia. Over-the-counter antidiarrheal medications can alleviate the frequency and discomfort of diarrhea, as can supportive care, hydration, and dietary suggestions. Dysgeusia and headache, which can significantly impair quality of life for some patients, can be managed with dose interruption and possible dose reduction. Insomnia, which can accompany fatigue, is first managed by behavioral interventions. I recommend counseling patients on maintaining good sleep hygiene practices, such as avoiding screen time before bed. If necessary, we can offer pharmaceutical sleep aids.

One approach to help manage or mitigate common toxicities is to start treatment at a slightly lower dose. For example, there are data with niraparib demonstrating benefit from initiating treatment at 200 mg/day in patients who have a lower body weight or those with baseline thrombocytopenia. In my practice, we have used this approach with success.

Finally, we should consider the risk of secondary malignancies with PARP inhibitors. Although these were uncommon in clinical trials and we have yet to see new safety signals, it is important to monitor for secondary malignancies and discuss the risk with our patients who are receiving long-term maintenance therapies with PARP inhibitors.

Specific Adverse Events
Despite similar mechanisms of action, each PARP inhibitor has a unique chemical structure, which introduces slight differences in their safety profiles. In clinical trials, some patients receiving rucaparib experienced elevations in liver function tests (LFTs)—that is, moderate transaminitis, most frequently grade 1/2. These changes were most common during the first 1-2 months of therapy, and LFTs typically returned to baseline within 5-6 months. Fortunately, we can continue normal treatment with PARP inhibitors through these transient, moderate elevations in LFTs. However, severe elevations in LFTs and/or other signs of possible liver dysfunction warrant further workup.

Both rucaparib and olaparib were associated with elevations in serum creatinine levels in clinical trials, and most were low grade and occurred in the first 2 months of therapy. These elevations typically return to baseline within 5-6 months and often do not require dose adjustment of the PARP inhibitor. Of importance, this adverse event is not due to actual renal toxicity or renal dysfunction, but from the drugs’ inhibition of renal transport proteins, which are involved in the process of creatinine secretion. This can lead to a confusing clinical picture in these patients, many of whom have a history of platinum‑based chemotherapy exposure or other baseline comorbidities that could lead to renal dysfunction. Thus, if you observe a significant rise in serum creatinine that is concerning, you should consider other tests of renal function, such as a radionucleotide scan, a 24‑hour urine collection, or checking other renal markers such as cystatin C.

Myelosuppression is common with all the PARP inhibitors, but niraparib is associated with more severe cases, possibly related to a stronger PARP enzyme trapping mechanism. Patients who develop severe thrombocytopenia typically exhibit a significant drop in platelets at approximately week 3 of the first treatment cycle. Dose reduction can stabilize the condition and patients can typically continue therapy with the reduced dose. Neutropenia is also more common with niraparib compared with the other PARP inhibitors. However, this tends not to be as severe and can be managed with dose interruption and dose reduction.

Other distinct adverse events with niraparib are cardiovascular events, including hypertension and tachycardia. Most events are low grade, but they are important to monitor, particularly in patients with baseline hypertension or other comorbidities that can lead to hypertension, such as diabetes, and those who may be receiving antiangiogenic agents, which can also promote hypertension.

Monitoring Strategies
The package inserts for olaparib and rucaparib recommend monitoring patients’ lab values at baseline and then monthly. In clinical practice, we find that more frequent monitoring during the first 1-2 cycles helps identify some of the adverse events earlier. In particular, we will monitor patients at higher risk of experiencing adverse events more frequently. Monitoring instructions for niraparib are to obtain baseline lab values and then recheck weekly for the first month. That schedule is particularly helpful to catch thrombocytopenia that commonly occurs at approximately the third week. It may be helpful to discuss the different monitoring schedules with patients prior to selecting a PARP inhibitor, as the different schedules may influence their adherence, particularly if it is challenging for them to access a local laboratory for testing.

Finally, frequently checking in with patients can be quite important. In my practice, we conduct a baseline counseling session before they start PARP inhibitors. Then we connect with the patient again by phone after the first 7-10 days of therapy, which is when we frequently begin to see some issues with lab tests or nausea and we can try to intervene at that early stage. Ideally, we should speak with our patients monthly while they are receiving therapy to help identify adverse events sooner. This way, we can better manage the toxicities and offer patients supportive care to help them stay on therapy.

Your Thoughts?
What challenges do you face when managing adverse events associated with PARP inhibitors? I encourage you to answer the polling question and post your thoughts in the comments box below.