Impact of dose modifications due to treatment-emergent adverse events (TEAEs) on the efficacy of niraparib maintenance treatment with an individualized starting dose in patients (Pts) with newly diagnosed advanced ovarian cancer (aOC) (1266)

Progression-free survival (PFS) was significantly extended with niraparib maintenance treatment versus placebo in patients (pts) with newly diagnosed advanced ovarian cancer (aOC) in the phase III PRIME study (NCT03709316), but 40.4% of pts. required dose modifications due to treatment-emergent adverse events (TEAEs) and the impact of these modifications is still unknown. This study aimed to compare the efficacy of niraparib with TEAE-caused dose reductions or no dose reductions in the first-line maintenance setting. This was a post hoc analysis of niraparib-treated pts. from PRIME, which randomized adult pts. with newly diagnosed aOC 2:1 to receive niraparib or placebo after a response to first-line platinum-based chemotherapy. The starting daily dose was 200 mg for pts. with a body weight of <77 kg and/or a platelet count of <150,000/μL at baseline and 300 mg for all others. With no dose interruption or reduction in the first two cycles, the daily dose for pts. starting at 200 mg could be increased to 300 mg at the investigators' discretion. The daily dose could be reduced stepwise by 100 mg to manage treatment-related adverse events, and if tolerability improved following reductions, it could be escalated stepwise by 100 mg without exceeding the initial level. The primary endpoint was PFS (BICR). Subgroups comprised niraparib-treated pts. who experienced TEAE-caused dose reductions or had no dose reductions. Dose reductions included reductions following interruptions as specified in the protocol and direct reductions. Of 255 niraparib-treated pts., 103 (40.4%) experienced dose reductions, including direct reductions in 6, due to TEAEs (Fig. 1A), most commonly, platelet count decreased (24.3%), anemia (10.2%), and neutrophil count decreased (9.8%). The median time from randomization to first dose interruption or direct reduction, whichever came earlier, due to TEAEs was 29 days (range: 8–397), and the median time from first dose interruption to the resumption of treatment was 15.5 days (range: 1–28). The distribution of daily dose levels at each cycle is presented in Fig. 1B. Key baseline characteristics were overall balanced between subgroups with TEAE-caused reductions and no reductions. In pts. with TEAE-caused reductions and no reductions, the median total exposure time was 21.9 (range: 1.1–37.8) and 17.5 (range: 0.1–38.5) months (mo), and median relative dose intensity (average actual daily dose/planned starting daily dose) was 58% (range: 26%–106%) and 100% (range: 98%–147%), respectively. Median PFS (95% CI) with TEAE-caused reductions versus no reductions was 27.6 (16.6-not estimable [NE]) versus 24.8 (16.6–NE) mo (HR: 0.89, 95% CI: 0.61–1.30), with not reached versus 24.8 mo in pts. carrying germline BRCA mutations (HR: 0.60, 95% CI: 0.29–1.25) and 16.6 versus 24.8 mo in pts. carrying no germline BRCA mutations (HR: 1.02, 95% CI: 0.66–1.60). The efficacy of niraparib maintenance treatment with an individualized starting dose in pts. with newly diagnosed aOC was not impacted by dose modifications due to TEAEs, regardless of germline BRCA mutation status.