Niraparib has an acceptable safety profile for patients with platinum-sensitive recurrent ovarian cancer, regardless of the dose being adjusted for weight, according to updated results from the phase 3 NORMA trial.
Niraparib (Zejula) has an acceptable safety profile for patients with platinum-sensitive recurrent ovarian cancer (PSROC), regardless of the dose being adjusted for weight, according to updated results from the phase 3 NORMA trial (NCT03705156) presented at the 2021 American Society of Clinical Oncology Annual Meeting.
Approximately 70% of women with advanced ovarian cancer relapse within 2 years of receiving platinum-based chemotherapy, despite high initial response rates. For patients who remain platinum-sensitive, they may undergo multiple lines of retreatment with a platinum-based chemotherapy. However, with each line of therapy, treatment effectiveness diminishes, eventually leading to resistance and toxicity. The poly(ADP-ribose) polymerase (PARP) inhibitor, niraparib, is currently approved as maintenance therapy for newly diagnosed ovarian cancer and/or PSROC in the United States, Europe, and China. However, questions still remain surrounding its efficacy in PSROC at individualized doses.
“A retrospective analysis indicated that an individualized starting dose may improve the safety profile of niraparib without compromising efficacy,” said Jing Wang, MD, a gynecologic oncologist at the Hunan Cancer Hospital in Hunan in China.
The ongoing randomized, double-blind, placebo-controlled phase 3 NORA trial includes 265 participants with PSROC. The primary end point of the study is progression-free survival (PFS). The secondary outcomes include chemotherapy-free interval (CFI), time to first subsequent anti-cancer treatment (TFST), and overall survival (OS).
Patients in the study were randomized 2:1 to receive either oral niraparib at 300 mg/day or 200 mg/day given their body weight was <77 kg or matching placebo. Of the 265 patients, 16 received niraparib or matched placebo at a fixed dose of 300mg/day and 249 received an individualized starting dose of niraparib (n = 166) or matched placebo (n = 83). The baseline characteristics between the 2 groups were similar.
Those enrolled were Chinese patients aged 18 years or older with PSROC who received at least 2 prior line of platinum-based chemotherapy with a complete response or partial response after the first-line and received at least 4 cycles of the second-line therapy. All patients enrolled had an ECOG score of 0 or 1. The study population was assessed for safety through the monitoring of treatment-emergent adverse events (TEAEs) and of the incidence of TEAEs of special interest. Those included hematologic, gastrointestinal, and other symptomatic TEAEs. For the safety analysis, the incidence of TEAEs was reported by the month of first occurrence and then categorized and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
The analysis showed that the majority of the TEAEs associated with niraparib were low grade. These TEAEs occurred early for most patients, mainly in the first month of treatment, and decreased considerably with the help of dose modifications.
“In the niraparib group, the incidence of most TEAEs, except for anemia, were greatest in the first month after treatment initiation and declined sustainably thereafter,” said Wang. “By month 6, the incidence of all TEAEs was similar or lower in the niraparib group versus [the] placebo group.”
Of the 177 patients who received niraparib, the TEAE rate was 100.0% versus 95.5% in the placebo group. The rate of grade 3 or higher TEAEs was 50.8% in the treatment group compared with 19.3% in the placebo group. Serious TEAEs occurred in 17.5% of participants in the niraparib group versus 11.4% in the placebo group. In the niraparib group, 59.9% of patients required dose reductions due to TEAEs, and 4.0% discontinued treatment. In comparison, 13.6% of the placebo arm reduced their dose, and 5.7% discontinued treatment.
The incidence of hematological TEAEs by month of first occurrence showed that in month 1 18.6% of patients in the niraparib arm experienced anemia compared with 17.0% of the placebo arm. By month 6, the rate of anemia decreased to 8.8% in the niraparib arm and 8.0% in the placebo arm. Platelet count decrease was seen in 39.5% of the niaparib arm in month 1 compared with 10.2% of the placebo arm. In month 6, cases of platelet count decrease dropped to 4.8% versus 12.0%, respectively. Finally, neutrophil count decreased in 36.2% of the niraparib arm in month 1 versus 25.0% in the placebo arm. By the 6th month of treatment, these TEAEs decreased to 4.8% versus 8.0%, respectively.
For gastrointestinal TEAEs by month of first occurrence showed that in month 1, approximately 43% of patients in the niraparib arm and 18.8% in the placebo arm experienced nausea. By month 6, the rate of nausea decreased to 4.1% in the niraparib arm and 4.2% in the placebo group. Vomiting was observed in 24.3% of the patients in the niraparib group in month 1 versus 2.3% of the placebo group. By month 6, cases of vomiting decreased to 4.1% in those treated with niraparib but increased to 4.0% in those treated with placebo. Constipation occurred in 19.8% of the niraparib arm at month 1 compared with 6.8% then decreased to 2.7% versus 4/0%, respectively by month 6.
For other symptomatic TEAEs by month of first occurrence in month 1, 18.4% of patients in the niraparib arm experienced insomnia versus 5.7% in the placebo arm. By month 6, the rate of this TEAE was reduced to 2.0% in the niraparib arm and 0 in the placebo arm. Palpitations occurred in month 1 in 10.2% of the niraparib arm versus 4.5% of the placebo arm. By month 6, these cases decreased to 2.0% in each arm. Finally, 6.2% of the niraparib arm developed hypertension in month 1 compared with no patients in the placebo arm. Later, in month 6, the incidence of hypertension decreased to 3.4% in the niraparib arm and increased to 4.0% in the placebo arm.
The most common TEAEs in the niraparib group were hematological, including anemia, reductions in white blood cell count, neutrophil count, and platelet count. The median time to TEAEs occurrence for any grade was shorter in the niraparib group versus the placebo group. In the niraparib group, nausea was the first AE to appear at a median time to onset of 6 days. In the placebo group, it was palpitations at 4 days. The last AE to appear in the niraparib group was anemia at 36 days. In the placebo group, it was hypertension at 228 days.
Wang J, Wu X, Zhu J, et al. Safety assessment of niraparib individualized starting dose in patients with platinum-sensitive recurrent ovarian cancer: A randomized, double-blind, placebo-controlled, phase III NORA trial. J. Clin. Onc.39, 2021 (suppl 15; abstr 5535). doi: 10.1200/JCO.2021.39.15_suppl.5535