Post-hoc analyses from the previously completed NOVA phase 3 study in China, which assessed niraparib versus placebo for patients with platinum-sensitive, recurrent ovarian cancer, revealed that some patients, particularly those with low body weight (<77 kg) or low platelet count (<150,000/μL), could benefit from an initial starting dose of niraparib that was lower than the 300-mg once-daily starting dose initially used for the trial. Because this lower dose, 200 mg once daily, was not associated with reduced efficacy for these specific patients, the NORA trial was conducted to validate the above premise and further evaluate the safety and efficacy of niraparib with an individualized starting dose in Chinese patients. In fact, NORA is the first fully powered phase 3 randomized controlled trial evaluating a poly (ADP-ribose) polymerase (PARP) inhibitor in Chinese patients with ovarian cancer.
The NORA trial included patients with platinum-sensitive, recurrent ovarian cancer being treated at 1 of 32 hospitals in China. Patients had either germline BRCA mutation or high-grade serous histologic features and exhibited complete or partial response after completing their last round of platinum therapy. Patients were randomized (2:1) to receive niraparib (n = 177) or placebo (n = 88) once daily. Progression-free survival (PFS) was the primary end point of the study.
Of the 265 total patients in the study, the first 16 patients received the fixed starting dose of 300 mg. After this, the protocol was amended such that patients who met the criteria for starting at the lower dose (body weight <77 kg or platelet count <150,000/μL) received 200 mg (n = 235), while other patients received 300 mg (n = 14). At data cutoff, 43% of patients taking niraparib and 13% of patients taking placebo were still receiving treatment. The median PFS was significantly longer for niraparib versus placebo at 18.3 months (95% confidence interval [CI], 10.96-not evaluable) versus 5.4 months (95% CI, 3.7-5.7), respectively (hazard ratio [HR], 0.32; 95% CI, 0.23-0.45; P <.0001). In all specified subgroup analyses including a subgroup divided by BRCA status, niraparib showed consistently improved PFS compared with placebo. Consistent with the primary end point, niraparib improved the chemotherapy-free interval (HR, 0.34; 95% CI, 0.24-0.48; P <.0001) and time to first subsequent therapy (HR, 0.35; 95% CI, 0.25-0.50; P <.0001). Overall, the efficacy results from the NORA trial were consistent with those from the NOVA trial.
Overall, most adverse events were grade 1 or 2. Treatment-emergent adverse events (TEAEs) grade ≥3 occurred in 50.8% of patients treated with niraparib versus 19.3% of patients receiving placebo. The most common TEAEs grade ≥3 in the niraparib arm were decreased neutrophil count (20.3% vs 8.0% for placebo), anemia (14.7% vs 2.3% for placebo), decreased platelet count (11.3% vs 1.1% for placebo), and decreased white blood cell count (7.3% vs 2.3% for placebo). When comparing the NOVA study, most hematologic adverse events were less prevalent in the current (NORA) study versus the previous one (NOVA).
The present study (NORA) illustrated that niraparib administered with an individualized starting dose significantly improves outcomes in patients with platinum-sensitive, recurrent ovarian cancer, validating the retrospective analysis from the earlier NOVA study and illustrating an improved safety profile, particularly with regard to hematologic toxicities.
Abstract and Late-Breaking Oral Presentation LBA29. ESMO 2020. September 21, 2020. Individualized starting dose of niraparib in Chinese patients with platinum-sensitive recurrent ovarian cancer (PSROC): a randomized, double-blind, placebo-controlled, phase III trial (NORA).