PARP Inhibitors in Ovarian Cancer

Evidence for Maintenance and Treatment Strategies

Antonio Bahena-González; Alfredo Toledo-Leyva; Dolores Gallardo-Rincón

Disclosures

Chin Clin Oncol. 2020;9(4):51 

In This Article

Toxicities

The toxicity of PARP inhibitors has been widely described in a recently published review.[44] In general, the toxicity profiles of olaparib, niraparib and rucaparib are similar and manageable. Adverse events are usually managed with appropriate delays and dose modifications. Frequency of adverse events leading to olaparib dose interruptions in SOLO2 study was 45% compared to 18% in the placebo group.[20] Olaparib dose reductions following adverse events were 25% vs. 3%. Discontinuations owing to adverse events were 11% and 2%. In the NOVA trial, niraparib dose interruptions were 68.9%, dose reductions were 66.5% and discontinuations were 14.7%.[21] Rucaparib treatment interruptions due to an adverse event occurred in 64% of patients of the ARIEL3 trial, dose reductions in 55% and discontinuations in 13%.[22]

PARP inhibitors class adverse events include hematologic effects, gastrointestinal effects and fatigue (Table 3). Hematologic toxicities typical occur during the first cycles of treatment and are usually transient. Anemia is the prominent hematologic toxicity among PARP inhibitors. Anemia of all grades occurred in 44% of patients that received olaparib in the SOLO2 trial, in 50% of patients treated with niraparib in the NOVA trial, and in 37% that received rucaparib in ARIEL3. Grade 3–4 anemia was documented in 19% of patients with olaparib, 25% of patients with niraparib, and 19% in patients with rucaparib. Thrombocytopenia is the main cause of niraparib hematologic toxicity, occurring in 61% of patients in any grade and in 34% of patients in grades 3–4. Neutropenia is also more prominent in patients with niraparib.

The most common gastrointestinal toxicity is nausea. Nausea of all grades was documented in 76% of patients with olaparib, 74% of patients with niraparib and 75% of patients with rucaparib but grade 3–4 nausea is not common in patients with PARP inhibitors. In most cases, nausea responds to standard oral antiemetics such as metoclopramide. Patients initiating a PARP inhibitor could receive antiemesis primary or secondary prophylaxis to help prevent nausea or vomiting. It should be noted that CYP 3A4/5 enzymes are related to the metabolic clearance of olaparib and concomitant administration with inducers of inhibitors of CYP3A4/5 isoenzymes should be done very cautiously. Neurokinin 1 receptor antagonist aprepitant is a CYP3A inhibitor and should be avoided.[45] Other gastrointestinal effects include vomiting, constipation, diarrhea, dysgeusia, dyspepsia, stomatitis, and hyporexia. Rucaparib is associated with grade 3–4 elevation of hepatic enzymes (10%), but this effect is transient and self-limiting.[22]

Fatigue is another common symptom related to the use of PARP inhibitors. It has been related to 66% of patients using olaparib, 59% of patients with niraparib, and 69% of patients with rucaparib, but grades 3–4 presentation is not common. Some experts suggest that patients should be reassured about the frequency of this symptom and its transitory nature before initiating the drug.[46] In addition, patient should receive guidance on undertaking moderate exercise and ensuring adequate nutrition.

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