Building off of findings from the phase 3 NOVA study, this study revealed that an individualized starting dose of niraparib based on baseline bodyweight and platelet count could improve the tolerability of niraparib without affecting treatment outcomes.
Data from the randomized, double-blind, placebo-controlled phase 3 NORA trial (NCT03705156) indicated that niraparib (Zejula) maintenance treatment reduced the risk of disease progression or death and prolonged progression-free survival (PFS) in Chinese patients with platinum-sensitive, recurrent ovarian cancer when compared with placebo.1
The study, published in Annals of Oncology, also indicated that an individualized starting dose (ISD) of niraparib based on baseline bodyweight and platelet count could improve the tolerability of niraparib without affecting treatment outcomes, and should therefore be considered standard practice in this patient setting.
“This is the first trial of PARP inhibitor maintenance therapy for ovarian cancer conducted in an Asian patient population and will support a change in clinical practice,” wrote the study authors, who were led by Xiaohua Wu, MD, PhD.
The study, which was conducted at 30 centers across China, randomized adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy in a 2:1 fashion to receive either oral niraparib at a dose of 300 mg daily or matched placebo until disease progression or unacceptable toxicity. Shortly after initiation, a protocol amendment was added so that patients with bodyweight less than 77 kg or platelet count less than 150 x 103/μL received 200 mg daily, while all other patients received the original 300 mg, as an ISD.
The study’s primary end point was PFS, determined by blinded independent central review using RECIST v1.1, defined as the time from randomization to disease progression or death, whichever occurred first. Key secondary end points included chemotherapy-free interval (CFI), time-to-first-subsequent-treatment (TFST), and overall survival (OS).
Between September 26, 2017 and February 2, 2019, 177 patients were randomized to niraparib and 88 to placebo; of the 265 patients randomized, 249 received an ISD (300 mg, n = 14; 200 mg, n = 235) per protocol. At the data cut-off of February 1, 2020, 76 (43%) and 11 (13%) patients were still receiving niraparib or placebo, respectively, and the overall median follow-up time was 15.8 months.
Among those in the ITT population, patients who were assigned to niraparib experienced a 68% reduction in the risk of disease progression or death, equating to a longer median PFS of 18.3 months (95% CI, 10.9-not evaluable) versus 5.4 months with placebo (95% CI, 3.7-5.7; HR, 0.32; 95% CI, 0.23-0.45; P < .0001). Moreover, regardless of BRCA mutation status, a similar PFS benefit was observed in patients receiving an ISD.
Additionally, secondary end point analyses demonstrated that patients receiving niraparib maintenance therapy achieved a significantly longer median CFI (18.5 vs 9.7 months; HR, 0.34; 95% CI, 0.24-0.48; P < .0001) and median TFST (16.7 vs 7.7 months; HR, 0.35; 95% CI, 0.25-0.49; P < .0001) when compared with patients receiving placebo. At the time of the data cutoff, a total of 16 patients (9.0%) in the niraparib arm and 10 (11.4%) in the placebo arm had died. However, median OS had not been reached in either group and treatment remains ongoing.
Regarding safety, treatment with niraparib was generally well tolerated with no new safety signals identified. Grade 3 or higher treatment-emergent adverse events (AEs) were reported in 50.8% and 19.3% of patients who received niraparib and placebo, respectively. The most commonly observed AEs were a decrease in neutrophil count (20.3% vs 8.0%) and anemia (14.7% vs 2.3%).
“These findings are in line with results from the NOVA study of niraparib in the same setting, and findings from the phase 3 studies of olaparib and rucaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer, all of which showed maintenance therapy with PARP inhibitors to be effective across patient subgroups,” the authors noted.2-4
Notably, the randomized, placebo-controlled, phase 3 NOVA trial (NCT01847274) served as the basis for the current study design in Chinese patients. The NOVA trial categorized patients according to the presence or absence of a germline BRCA mutation and the type of non-gBRCA mutation, randomizing participants 2:1 to receive either niraparib at a dose of 300 mg or placebo once daily.
Ultimately, the study revealed that among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of PFS was significantly longer for those who received niraparib compared with those who received placebo, regardless of the presence or absence of germline BRCA mutations or homologous recombination deficiency (HRD) status, with moderate bone marrow toxicity.
The retrospective RADAR analysis of the NOVA trial later revealed that patients with a baseline bodyweight less than 77 kg or platelet count less than 150 x 103/μL received an average reduced niraparib dose of 207 mg per day without compromising treatment efficacy, thus leading to the addition of the protocol amendment.
According to investigators, the current findings “provide prospective validation of similar findings reported for the predominantly Caucasian patients included in the NOVA study.”
1. Wu XH, Zhu JQ, Yin RT, et al. Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase 3 trial. Ann Oncol. January 14, 2021. doi: 10.1016/j.annonc.2020.12.018
2. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310
3. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. doi: 10.1016/S1470-2045(14)70228-1
4. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6