An individualized starting dose of niraparib (Zejula) reduces the risk of hematologic toxicities compared with the 300-mg fixed starting dose while maintaining efficacy as first-line maintenance treatment of patients with recurrent ovarian cancer.
The individualized starting dose, based on baseline body weight and platelet count, performed no differently than the fixed starting dose on the end point of progression-free survival, and was associated with fewer dose interruptions and reductions, in the phase 3 PRIMA study. Niraparib is approved by the US Food and Drug Administration at a fixed starting dose of 300 mg daily for maintenance treatment.
The data were presented by investigators in a poster during the 2020 American Society of Clinical Oncology Virtual Scientific Program.
“Based on these results, an individualized starting dose is recommended for first-line maintenance treatment of patients with ovarian cancer,” the investigators, led by Mansoor Raza Mirza, MD, Medical Director, Nordic Society of Gynecological Oncology-Clinical Trial Unit, and Chief Oncologist, Rigshospitalet Copenhagen University Hospital, Denmark, concluded in their poster.
PRIMA is a randomized double-blind study of niraparib compared with placebo in patients with newly diagnosed advanced ovarian cancer who responded to first-line, platinum-based chemotherapy. A total of 733 patients who had a complete or partial response to first-line, platinum-based chemotherapy were randomized in a 2:1 ratio to niraparib at 300 mg/day or placebo. The study protocol was amended when a post hoc analysis of the phase 3 ENGOT-OV16/NOVA clinical trial identified baseline body weight and platelet count as predictors of high-grade thrombocytopenia and niraparib dose reductions.
“Most thrombocytopenia events and dose adjustments occurred in the first 3 months, after which 200 mg was the most common dose,” said Dr Mirza and colleagues. “Retrospective analysis showed no impact of dose change on efficacy.”
In PRIMA, following the amendment, patients randomized to niraparib were assigned to either 200 mg or 300 mg based on baseline body weight and platelet count. Those with body weight ≥77 kg and a platelet count ≥150,000/µL were assigned to 300 mg daily of niraparib or placebo, while those with a body weight <77 kg or a platelet count <150,000/µL were assigned to 200 mg daily of niraparib or placebo. Approximately 35% of the patients were enrolled after the protocol amendment.
“The hazard ratio for efficacy for the 2 groups was similar at 0.59 for fixed starting dose and 0.69 for the individualized starting dose,” Dr Mirza said. “To determine if these results were statistically different, an interaction test was performed at the prespecified alpha of 0.1. The interaction was not statistically significant, which suggests that starting dose does not affect efficacy.”
Kaplan-Meier progression-free survival curves showed no relationship between improved response in the niraparib arm and increased dose exposure, said Dr Mirza.
Implementation of the individualized starting dose reduced the rate of hematologic events by more than 50%. The rate of thrombocytopenia was reduced from 48.3% in patients who received the fixed starting dose versus 21.3% in those who received an individualized starting dose. Similar trends were observed with anemia and neutropenia. The incidence of any grade ≥3 treatment-emergent adverse events was reduced from 75.9% to 60.4%.