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Baseline body weight and platelet counts were early predictors for future AE-related dose modifications for niraparib (Zejula) in women with platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Mansoor Raza Mirza, MD
Baseline body weight and platelet counts were early predictors for future adverse event (AE)-related dose modifications for niraparib (Zejula) in women with platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer, according to an analysis of the phase III ENGOT-OV16/NOVA trial presented during the 2018 Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancers.1
The retrospective analysis showed that just 17% of patients with body weight <77 kg or platelet counts <150,000/µL could remain at the 300-mg starting dose. A greater incidence of grade 3/4 treatment-emergent AEs (TEAEs) in this group resulted in dose reduction or treatment discontinuation for the FDA-approved PARP inhibitor. The median daily dose in this group for the first 2 months of treatment was 207 mg.
“Findings from the analysis concluded that body weight and baseline platelet counts are two significant predictors of early dose modification. An alternative starting dose of 200 mg of niraparib may be considered for frail patients,” said lead investigator Mansoor Raza Mirza, MD, chief oncologist in the Department of Oncology in Rigshospitalet, Copenhagen University Hospital, Denmark. “This analysis is being submitted to regulatory authorities to support consideration of a starting dose of 200 mg for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/µL.”
The phase III trial randomized patients to receive niraparib at 300 mg (n = 367) or placebo (n = 179). All patients had recurrent ovarian cancer and were either in complete or partial response to their last platinum-based therapy. Weight categories were based on quartiles, with the lowest quartile containing those <58 kg and the highest quartile being those ≥77 kg.
Overall, patients <58 kg had greater incidence of grade ≥3 TEAEs compared with patients ≥77 kg. In month 1, thrombocytopenia events were seen in 45% of patients <58 kg compared with 16% in patients ≥77 kg, leading to a dose reduction for 40.3% in the <58 kg group versus 0.6% in the ≥77 kg patients. Other hematologic TEAEs leading to dose reduction were also more common in the <58 kg group compared with ≥77 kg, specifically anemia (18.5% vs 0% dose reduction rates, respectively) and neutropenia (8.7% vs 1.1%).
Of those with a baseline platelet count of ≤180,000 at baseline, 42% had a grade 3/4 thrombocytopenia event compared with 25% for those with counts between 180,000 and 215,000, 31% for those betweeen 215,000 and 273,000, and 20% for those with counts ≥273,000.
“In this case, if you had 3 or more hematological toxicities, the treatment was paused and restarted at a lower dose,” said Mirza. “If thrombocyte count was under 100,000, the dose was paused and patients restarted at a lower level.”
After 12 months across the full trial, 40% of patients were receiving niraparib at 200 mg, 37% at 100 mg, and 23% at 300 mg. With these dose reductions, there were marked decreases in grade 3/4 AEs. Thrombocytopenia events decreased from 33.2% at 300 mg to 5.9% at 200 mg and 2.3% at 100 mg. For those who discontinued treatment, thrombocytopenia events were seen for 3.3% of patients. A similar trend was observed for anemia (15.3% at 300 mg, 16.1% at 200 mg, and 6.3% at 100 mg) and neutropenia (18%, 8.3%, and 2.3%, respectively).
In an analysis completed from 4 months and beyond, there was not a difference seen in progression-free survival between the 300-mg and the 200-mg dose (HR, 1.01; 95% CI, 0.69-1.48). Additionally, a difference was not seen between the 300-mg and the 100-mg doses (HR, 1.05; 95% CI, 0.84-1.31).
“Dose reduction from 300 mg did not appear to compromise efficacy in this retrospective analysis,” Mirza noted. “To look at the efficacy we could not start the analysis from day 1 because then most of the patients were at 300 mg, so we had to have a cut off and we chose the cut off when the dose was reduced after month 3 and looked at different cohorts to see, and this is a retrospective exploratory analysis, telling us that probably the efficacy is not affected by 3 different dosage levels.”
In findings from the trial, which were published in the New England Journal of Medicine,2 niraparib reduced the risk of progression or death by 73% compared with placebo for patients with germline BRCA-mutant platinum-sensitive, recurrent ovarian cancer (HR, 0.27; 95% CI, 0.173-0.410; P <.0001). In patients with non-germline mutant BRCA, there was a 55% reduction in the risk of progression or death with niraparib (HR, 0.45; 95% CI, 0.338-0.607; P <.0001).
Based on these findings, the FDA approved niraparib in March 2017 for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.