November 21, 2020 — Maintenance niraparib, when administered at an individualized starting dose, led to a 70% reduction in the risk of disease progression or death compared with placebo in Chinese patients with recurrent ovarian cancer who were in a complete or partial response to platinum-based chemotherapy.
Maintenance niraparib (Zejula), when administered at an individualized starting dose (ISD), led to a 70% reduction in the risk of disease progression or death compared with placebo in Chinese patients with recurrent ovarian cancer who were in a complete response (CR) or partial response (PR) to platinum-based chemotherapy, according to a subanalysis of the phase 3 NORA trial that was presented at the ESMO Asia Virtual Congress 2020.1
Results showed that the median progression-free survival (PFS) with niraparib in this patient population was 18.3 months vs 5.4 months with placebo (HR, 0.30; 95% CI, 0.21-0.43; P <.0001).
“This is the first [randomized, controlled study] to demonstrate the efficacy and safety of niraparib in Chinese patients with platinum-sensitive, recurrent ovarian cancer,” lead study author Jianqing Zhu, MD, of the Department of Gynecologic Oncology, Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China, said in a virtual presentation of the data during the meeting.
“Consistent with the [intent-to-treat] population in NORA, the individualized starting dosing of niraparib is effective and safe. It should be considered as the standard clinical practice in platinum-sensitive and -refractory ovarian cancer patients,” said Zhu.
In the double-blind phase 3 NORA study, 265 Chinese patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in a CR or PR to platinum-based chemotherapy were randomized 2:1 to receive maintenance niraparib (n = 160) or placebo (n = 80) until disease progression or unacceptable toxicity.
Initially in the trial design, patients were treated with a fixed starting dose of 300 mg of oral niraparib. However, after the first 16 patients received the fixed starting dose, the study protocol was amended to utilize an ISD; this was based on a retrospective data2 that ISD would maintain efficacy of niraparib while improving safety. The ISD comprised of niraparib at 200 mg orally, except for patients with a bodyweight at baseline of more than 77 kg and a platelet count greater than 150,000/μL, who began at a 300-mg dose.
The patients were from 32 hospitals in China, and those eligible for enrollment were aged 18 years or older and had either a germline BRCA mutation or high-grade serous or high-grade predominantly serous histology, and had achieved a CR or PR after completing the last round of platinum-based therapy. Patients also must have completed at least 2 prior lines of platinum-containing therapy.
Stratification factors also included germline BRCA mutations (yes or no), response to last chemotherapy (CR or PR), and time to progression after penultimate platinum-based regimen (6-12 months or longer than 12 months).
The primary end point was PFS in the intent-to-treat (ITT) population, as assessed by blinded independent central review; secondary end points were safety, chemotherapy-free interval, time to first subsequent therapy, and overall survival (OS).
Prior NORA data, which were presented during the 2020 ESMO Virtual Congress, showed that niraparib improved PFS and safety in the ITT population.3 At the 2020 ESMO Asia Virtual Congress, investigators presented findings from those who received niraparib or placebo at ISD.
Of the ITT efficacy population (n = 265), 249 patients with a median body weight of 61 kg received the ISD of niraparib (n = 166) or placebo (n = 83). After the protocol amendment, the niraparib arm comprised 155 patients on the 200-mg dose and 11 on the 300-mg dose; on the placebo arm, 80 patients and 3 patients were on the 200-mg and 300-mg doses, respectively. Forty-four percent (n = 73) of patients were still receiving ISD niraparib at the time of data cutoff compared with 10.8% (n = 9) of patients on placebo. Of the 93 patients who discontinued niraparib, reasons included adverse events (AEs; n = 7), disease progression (n = 75; 45.2%), patient request (n = 9), and other (n = 2).
In the ISD population, the median age was 54.0 years (range, 37-78) and median weight was 61.0 kg (range, 39-93). More than half of patients (61.0%) had an ECOG performance status of 1, and the majority of patients (98.4%) had high-grade serous histology. A total 26.1% of patients underwent secondary cytoreduction surgery, 6.4% of patients had prior bevacizumab (Avastin), and all patients received 2 lines of prior chemotherapy per inclusion criteria. Two-thirds of patients (66.7%) had more than 12 months as their time to progression after penultimate platinum therapy. Moreover, 51.0% of patients had a CR as their best response to their last platinum-based chemotherapy, and 36.9% of patients had a germline BRCA mutation.
Results showed that the significant PFS benefit with ISD niraparib was consistent across all prespecified subgroups, including in patients who were at least 65 years old (HR, 0.41).
Additionally, the median PFS in patients with a germline BRCA mutation was not reached in the niraparib arm compared with 5.5 months with placebo (HR, 0.18; 95% CI, 0.10-0.34; P <.0001). In those without a germline BRCA mutation, the median PFS was 11.1 months and 3.8 months, respectively (HR, 0.39; 95% CI, 0.25-0.60).
When evaluating secondary end points in the ISD population, the median chemotherapy-free interval was 19.4 months with niraparib compared with 9.7 months with placebo (HR, 0.33; 95% CI, 0.23-0.47; P <.0001). Niraparib also led to an improvement in time to first subsequent therapy at a median 16.7 months vs 7.7 months with placebo (HR, 0.35; 95% CI, 0.25-0.50; P <.0001).
Moreover, Zhu noted that the OS data are immature, with 15 and 10 events occurring in the niraparib and placebo arms, respectively. The median OS was not reached in both arms, with a trend toward improvement with niraparib (HR, 0.61; 95% CI, 0.27-1.36; P = .2176).
The efficacy results were found to be consistent with the ITT population, Zhu added, in which the median PFS was also 18.3 months and 5.4 months with niraparib and placebo, respectively (HR, 0.32; 95% CI, 0.23-0.45). Results were also similar in the patients with a germline BRCA mutation (HR, 0.22; 95% CI, 0.12-0.39) and without (HR, 0.40; 95% CI, 0.26-0.61).
Regarding safety, all patients in the niraparib arm experienced a treatment-emergent adverse event (TEAE); 48.8% of patients experienced grade 3 or higher TEAEs, and 16.3% experienced serious TEAEs. There were 57.8% of patients on niraparib who had dose reductions due to a TEAE vs 14.5% on placebo, and 4.2% and 6.0% of patients, respectively, discontinued treatment due to TEAEs. No TEAEs led to death on the niraparib arm vs 1 on placebo.
More patients on niraparib, in the ISD population, experienced grade 3/4 hematologic TEAEs compared with placebo, such as decreased white blood cell count (7.2% with niraparib vs 2.4% with placebo), decreased neutrophil count (20.5% vs 8.4%, respectively), decreased platelet count (9.6% vs 1.2%) and anemia (13.9% vs 2.4%).
The NORA findings were consistent with the data previously reported in the global phase 3 NOVA study, which were the basis for the March 2017 FDA approval of niraparib as a maintenance treatment for adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
The NOVA results showed that the median PFS with maintenance niraparib was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations (HR, 0.26; 95% CI, 0.17-0.41; P <.0001).4 These findings remained consistent across subgroups of patients, including those without BRCA mutations.