*3.2.3 Hematologic toxicity*

Hematologic toxicity (or myelosuppression) is a commonly recognized class-effect adverse event of PARPi that is linked to its mechanism of PARP trapping, which appears to drive cytotoxicity in healthy human bone marrow [56, 63]. Emerging

clinical data suggest an inverse relationship between PARPi trapping potency and risks of myelosuppression adverse events [63]. Myelosuppression adverse events tend to occur in the early phase of PARPi maintenance treatment with median time to onset ranging from 22 to 80 days (first 3 treatment cycles) [21, 48, 55, 64]. Although, grade ≥ 3 hematological adverse events tend to have a later onset [21, 55].

Anemia of any grade has been reported in 34–64% of patients receiving PARPi with grade ≥ 3 observed in 20–30% of patients. Permanently discontinuation due to anemia of PARPi was seen in ≤4% of patients in clinical trials [44, 47, 51, 54]. Neutropenia of any grade has been reported in 17–42% of patients receiving PARPi, neutropenia ≥ grade 3 was observed in less than 20% of patients [44, 47, 51, 54]. Dose interruption or reduction may be used to manage anemia or neutropenia adverse events. For patients whose hemoglobin level falls <8 g/dL or if neutrophil count is <1000/mcL, PARPi should be held for a maximum of 28 days and blood counts or neutrophil counts to be monitored weekly until it returns to ≥9 g/dL or ≥ 1500/mcL, respectively. PARPi therapy may be resumed at a reduced dose [47].

Thrombocytopenia of any grade has been reported in 10–30% of patients with a higher incidence of 50–65% seen in patient receiving niraparib therapy [42, 45, 49, 52]. Grade ≥ 3 thrombocytopenia was more common in niraparib ranging from 20–30% compared to olaparib and rucaparib at 1–7% [44, 47, 51, 54]. For platelet count <100,000/mcL, niraparib can be held for a maximum of 28 days, platelet counts to be monitored weekly until recovery to ≥100,000/ mcL. Niraparib may be resumed at the same or reduced dose but if platelet count was <75,000/mcL at the onset of adverse event occurrence, a reduced dose is recommended. If a patient experiences severe thrombocytopenia with a platelet count ≤10,000/mcL or if a patients has other risk factors of anticoagulation or antiplatelet drug use, these drugs should be held, and a platelet transfusion may be considered [47].

Overall, higher incidences of hematologic toxicity have been observed with niraparib, which is consistent with its pharmacologic properties as niraparib has higher PARP trapping potency relative to olaparib and rucaparib [65, 66]. As discussed above in Section 2.2, individualized starting dose of niraparib was evaluated prospectively in 35% of patients in the PRIMA trial. Results showed improved safety and tolerability of niraparib [42].
