Ovarian Cancer: Best Practices for Managing PARP Inhibitor Side Effects

Oncologists treating ovarian cancer need to be proactive to prevent or reduce the likelihood of adverse effects associated with poly (ADP-ribose) polymerase (PARP) inhibitors, noted authors of a review in the ASCO Educational Book.

William Tew, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues discuss strategies to improve tolerance to the treatments. The review also covers the key adverse effects reported in the pivotal ovarian cancer clinical trials that led to the regulatory approvals for olaparib, niraparib, and rucaparib, along with safety data and post-marketing reporting of adverse drug reactions (ADRs) that have emerged from real-world experience.

The following Q&A discusses the details of the review. (The authors did not respond to requests for comment, and the answers here are from the text of the paper.)

What are the common adverse effects associated with the three approved PARP inhibitors?

There have not been any head-to-head comparisons of PARP inhibitors in randomized trials, and we can only perform cross-comparisons on the basis of the reported literature. The three approved PARP inhibitors for ovarian cancer share several common adverse effects because of a class effect. These include nausea, fatigue, and anemia, but there are also some notable differences, likely due to variations in the poly-pharmacology and off-target effects.

Rucaparib appears to be associated with a higher incidence of ADRs. There is inter-individual variability in pharmacokinetic exposure levels observed with olaparib, rucaparib, and niraparib, which could also account for some of the variability in adverse effects observed between patients as higher levels of exposure appear to be associated with greater toxicity, particularly hematologic.

Which safe prescribing strategies can reduce the likelihood of adverse effects?

There are several factors to take into consideration before starting a patient on maintenance treatment with a PARP inhibitor, including the choice of PARP inhibitor, the initial dose, and when to start maintenance therapy. Ideally, the patient should have recovered as much as possible from chemotherapy and should not start treatment less than 28 days after the last cycle of chemotherapy to allow bone marrow recovery.

Doses may also need to be modified on the basis of the PARP inhibitor being prescribed, depending on renal and hepatic function and concomitant medications. For example, in patients with moderate renal impairment, olaparib should be started at a reduced dose of 200 mg twice a day, but dose reduction is not required for niraparib or rucaparib.

Olaparib and rucaparib appear to be safe in patients with moderate hepatic impairment, but it is recommended that the dose of niraparib be reduced to 200 mg once daily. There are no data in patients with severe hepatic impairment, so it is advisable to avoid PARP inhibitors for that group.

It is particularly important to take note of all concomitant medications as there may be important drug-drug interactions, particularly with olaparib.

How do you manage nausea and vomiting?

Nausea and, to a lesser extent, vomiting are among the most common adverse effects associated with all three FDA-approved PARP inhibitors. First and foremost, supportive treatment including antiemetics for prophylaxis and treatment are usually effective. Antiemetics such as metoclopramide or domperidone or olanzapine are usually sufficient in most patients, whereas serotonin 5-hydroxytryptamine-3 receptor antagonists may be of value in selected patients for a short duration, but are commonly associated with constipation.

Anecdotally, advising patients to take the PARP inhibitor with food or shortly after eating and administering a prokinetic agent such as metoclopramide 30-60 minutes before the PARP inhibitor can help prevent or reduce nausea, which is prevalent in the first few weeks of starting treatment.

What hematologic events are often seen with PARP inhibitors?

Hematologic adverse effects, including anemia, neutropenia, and thrombocytopenia, are common with all PARP inhibitors. Close monitoring of patients, particularly in the first 12 weeks after commencing a PARP inhibitor, is required as hematologic adverse effects usually occur early, but not invariably, and regular blood counts should continue while patients are on treatment.

Anemia is the most common hematologic toxicity observed with PARP inhibitors and typically is macrocytic. Anemia should be managed with dose interruptions and reductions if dose interruption for symptomatic anemia is required. Transfusions should be used if the hemoglobin level falls to less than 7 g/dL accompanied by a dose reduction.

How significant are myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with PARP inhibitors?

Treatment-related myeloid neoplasms, myelodysplastic syndromes, and AML are the most significant and clinically important adverse effects that have been associated with PARP inhibitors. A recent meta-analysis that included 5,693 patients treated with a PARP inhibitor and 3,406 with placebo reported that PARP inhibitors increased the risk of MDS and AML with an overall risk of 2.63.

The incidence of MDS/AML was 0.73% across all PARP inhibitors compared with 0.47% in controls. The risk is related in part to the number of previous lines of chemotherapy, with a lower incidence of MDS/AML observed in the first-line maintenance trials compared with the recurrent setting.

What is the main take-home message for practicing oncologists?

Awareness of the potential for drug-drug interactions as well as identifying those patients at greater risk of adverse effects are important and affect the choice of PARP inhibitor, the starting dose, and intensity of follow-up. Meticulous attention to all these factors is likely to improve tolerability and permit patients to continue treatment.

Read the review here and expert commentary about it here.