PARP Inhibitors in Ovarian Cancer: Choice May Depend on Treatment Setting, Mutation Status, and Side-Effect Profile

Improving outcomes in ovarian cancer through treatment with poly (ADP-ribose) polymerase (PARP) inhibitors requires knowledge of their efficacy in the different treatment settings—upfront maintenance, recurrent maintenance, and treatment—as well as potential adverse events that may be unique to each PARP inhibitor, said Amy Ly Indorf, PharmD, Clinical Oncology Pharmacist, Seattle Cancer Care Alliance, WA, during a recent webinar.

The 3 approved PARP inhibitors have different indications in ovarian cancer based on treatment setting and mutation status.

The upfront maintenance setting is treatment after upfront surgery and adjuvant platinum-based chemotherapy. Olaparib (Lynparza) and niraparib (Zejula) are approved in the upfront maintenance setting; olaparib monotherapy is approved in this setting only for patients with BRCA-mutated disease. As upfront maintenance, olaparib and niraparib decreased the risk for progression by 60% to 70% in patients with the homologous recombination deficiency (HRD) phenotype. For patients without the HRD phenotype, niraparib decreased the risk for progression by approximately 30%.

The recurrent maintenance setting is treatment after disease relapse, with the goal of delaying progression. All 3 PARP inhibitors are approved in this setting regardless of HRD status. In reflecting on the 3 clinical trials of PARP inhibitors in the recurrent maintenance setting—SOLO-2 (olaparib), ARIEL3 (rucaparib), and NOVA (niraparib)—“all 3 trials showed a progression-free survival [PFS] benefit for PARP inhibitor maintenance therapy after platinum-sensitive recurrence,” said Dr Indorf, with the greatest benefit in patients with BRCA mutations or the HRD phenotype. The use of PARP inhibitors in the recurrent maintenance setting reduced the risk for progression by 60% to 70% in patients with the HRD phenotype in the ARIEL3 and NOVA clinical trials. For patients without the HRD phenotype, risk for progression was reduced with the use of niraparib and rucaparib.

Study 19 with olaparib capsules in the recurrent maintenance setting demonstrated an improvement in PFS with olaparib compared with placebo, with a statistically significant improvement in overall survival only in those patients with BRCA mutations, consistent with other trials of PARP inhibitors in this setting. Time to first and second subsequent therapy was also extended in the olaparib arm, which was also more pronounced in the BRCA-mutated population.

The treatment setting is defined as therapy after relapse of disease or progression and may not immediately follow a response to platinum-based chemotherapy, said Dr Indorf. All 3 PARP inhibitors are approved in this setting, with the superior response rates driven by patients with the HRD phenotype and patients who are platinum sensitive.

“Diagnostic tests that evaluate for the HRD phenotype are varied, and there’s no standard test across all trials for PARP inhibitors,” said Dr Indorf. The companion diagnostics are the BRACAnalysis (Myriad Genetics) for the use of olaparib, the Foundation Focus CDxBRCA (Foundation Medicine) for the use of rucaparib, and the myChoice HRD CDx (Myriad Genetics) for the use of niraparib.

Quality of life is important when using an agent in the maintenance setting, she noted. Both olaparib and niraparib have data (TWiST analyses) to support maintenance of quality of life.

Class-wide nonhematologic adverse effects of PARP inhibitors are fatigue, nausea, and diarrhea. The incidences of grade 3 fatigue, all-grade and severe nausea, and all-grade and severe diarrhea are similar across the PARP inhibitors. Management of side effects within the first 4 to 8 weeks is crucial, and these side effects can be managed symptomatically without dose reduction.

Hematologic adverse effects are anemia, neutropenia, and thrombocytopenia. The incidence of anemia is similar across all 3 PARP inhibitors; niraparib is associated with higher rates of thrombocytopenia and neutropenia. With hematologic toxicities, the PARP inhibitor should be discontinued if the toxicity is not resolved by 28 days, with consideration of a hematology consult.

The risk for secondary malignancy, particularly myelodysplastic syndrome or acute myeloid leukemia, is increased with the PARP inhibitors, with an incidence up to 2%.

Asymptomatic elevation in serum creatinine is possible with olaparib. The risk of pneumonitis with olaparib is <1%. “With olaparib, you want to avoid CYP3A/4 inhibitors including foods like grapefruit juice, Seville oranges, and pomegranates,” she said.

Unique adverse drug reactions with rucaparib are transaminitis, which is usually self-resolving, an asymptomatic increase in serum creatinine, reflux disease, dysgeusia, hypomagnesemia, hypercholesterolemia, photosensitivity, and rash. Rucaparib inhibits CYP2C9 so it should be used with caution in patients taking warfarin.

Distribution of the PARP inhibitors is limited to specialty pharmacies. A challenge for patients taking PARP inhibitors is that with the exception of niraparib, dose reductions require multiple tablet strengths. This can be confusing for patients, and instructions must be very clear for the patient. This can also cause a delay in care as dose reduction may require reauthorization with insurance, and the acquisition of a different tablet strength from a mail-order pharmacy may cause delays in care.

All 3 manufacturers of the PARP inhibitors have patient assistance programs to help offset patient out-of-pocket costs, which can be substantial, depending on their health insurance coverage.

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