Niraparib Maintenance Extends PFS in Newly Diagnosed Ovarian Cancer

Maintenance therapy with the PARP inhibitor niraparib (Zejula) prolonged progression-free survival (PFS) vs placebo in patients with newly diagnosed advanced ovarian cancer, according to findings from the phase 3 PRIME trial (NCT03709316) published in JAMA Oncology.­¹

At the September 30, 2021, data cutoff the median PFS among patients in the intention-to-treat population who received niraparib (n = 255) was 24.8 months (95% CI, 19.2-not estimable [NE]) compared with 8.3 months (95% CI, 7.3-11.1) among patients who received placebo (n = 129; HR, 0.45; 95% CI, 0.34-0.60; P < .001). The median follow-up for PFS was 27.5 months (95% CI, 25.3-27.6) and 27.6 months (95% CI, 24.9-30.3), respectively. The median overall survival (OS) was not yet reached in either arm (HR, 0.63; 95% CI, 0.38-1.03), although investigators noted these data are not yet mature. The estimated 24-month OS rates were 87.3% and 82.7%, with niraparib and placebo, respectively.¹

Additionally, the PFS benefit achieved with niraparib maintenance vs placebo was observed across all subgroups. Pronounced benefit was seen in patients who were aged at least 65 years old (HR, 0.24; 95% CI, 0.09-0.66) and in those who received neoadjuvant chemotherapy (HR, 0.32; 95% CI, 0.21-0.48).¹

The exploratory subgroup analysis demonstrated that the median PFS for patients with optimal debulking (R0/R1) was 24.8 months vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and was 16.5 months vs 8.3 months in those with suboptimal debunking (R2; HR, 0.27; 95% CI, 0.10-0.72), with niraparib vs placebo, respectively. Benefit with niraparib was also seen regardless of biomarker status: patients with a germline BRCA variant had a median PFS of not reached (NR) vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68); those without a BRCA germline variant experienced a median PFS of 19.3 months vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67); those who were homologous recombination deficient (HRD) had a median PFS of NR vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68); and the median PFS was 16.6 months vs 5.5 months among those who were homologous recombination proficient (HR, 0.41; 95% CI, 0.22-0.75).¹

Benefit with niraparib vs placebo was also experienced by patients with suboptimal cytoreductive surgery outcomes (HR, 0.27; 95% CI, 0.10-0.72), those who had received neoadjuvant chemotherapy (HR, 0.32; 95% CI, 0.21-0.48), and those who had not received neoadjuvant chemotherapy (HR, 0.63; 95% CI, 0.42-0.94).

Maintenance therapy with niraparib is already approved by the FDA for a population of patients with advanced ovarian cancer. The agency approved the treatment for adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy on April 29, 2020, based on findings from the PRIMA phase 3 trial (NCT02655016).²

Data from the phase 3 trial published in JAMA Oncology was a multicenter double-blind, placebo-controlled, study conducted in China. The study enrolled patients with newly diagnosed advanced ovarian cancer who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. Patients also needed to be at least 18 years old and primary or interval debulking surgery was permitted regardless of cytoreductive surgery outcome.¹

Upon enrollment, patients were randomly assigned 2:1 to received niraparib or placebo. Patients who weighed less than 77 kg and/or had a platelet count of less than 150 x 10³ /μL at baseline received niraprib at a dose of 200 mg orally once daily and all others in this arm were treated at a dose of 300 mg orally once daily. Niraparib was given in 28-day cycles for 36 months or until disease progression, death, intolerable adverse effects (AEs), withdrawal, or loss to follow-up.¹

Most patients (97.7%) received a starting daily dose of 200 mg, 247 of which were in the niraparib arm and 128 were in the placebo arm. The remaining 9 received the 300-mg dose, all but 1 of whom were in the niraparib arm. The median exposure to study drug was 19.3 months (range, 0.1-38.5) and 10.2 months (range, 0.4-38.2) in the niraparib and placebo arms, respectively.¹

The primary end point was PFS by blinded independent central review and secondary end points in the intention-to-treat population included OS and time to first subsequent therapy as well as PFS and OS in the HRD subgroup.¹

The baseline characteristics were well balanced between the 2 arms; the median age was 53 years (range, 32-77) and 54 years (range, 33-77) in the niraparib and placebo arms, respectively. Most patients in both arms had ECOG performance status of 1 (61.6% vs 59.7%), optimal debulking (75.7% vs 81.4%), FIGO stage IIIC disease (60.4% vs 62.0%), a tumor primarily located in the ovaries (89.8% vs 90.7%), serous ovarian cancer (99.2% vs 99.2%), did not undergo neoadjuvant chemotherapy (52.5% vs 54.3%), did not have a germline BRCA variant (66.7% vs 69.0%), and had tumors that were HRD (66.7% vs 67.4%). Following platinum-based chemotherapy, 83.1% of patients in the niraparib arm experienced a CR vs 79.8% in the placebo arm.¹

In terms of safety, most patients in both the niraparib (99.2%) and placebo (93.8%) arms experienced a treatment-emergent AE (TEAE). Treatment-related TEAEs (97.6% vs 86.0%), serious TEAEs (18.8% vs 8.5%), and TEAEs of at least grade 3 severity (54.5% vs 17.8%) were present in both arms. Patients in both arms also experienced TEAEs leading to treatment interruption (62.7% vs 19.4%), dose reduction (40.4% vs 6.2%), and treatment discontinuation (6.7% vs 5.4%). One patient in the niraparib arm died due to a TEAE.¹

The most common any-grade TEAEs in the niraparib arm were decreased neutrophil count (65.5%), decreased white blood cell count (65.1%), and anemia (57.3%). Common TEAEs of at least grade 3 severity consisted of anemia (18.0%), decreased neutrophil count (17.3%), and decreased platelet count (14.1%).¹

Similarly, in the placebo arm, the most common any-grade TEAEs were decreased neutrophil count (39.5%), decreased white blood cell count (37.2%), and anemia (26.4%). Grade 3 or higher TEAEs included hypertriglyceridemia (2.3%), increased γ-Glutamyl transferase (2.3%), and upper respiratory tract infection (1.6%).¹

One-hundred two and 29 patients were still on treatment at the time of data cutoff in the niraparib and placebo arms, respectively. Reasons for discontinuation in the niraparib arm included disease progression (n = 103), AEs (n = 17), withdrawal (n = 27), and other (n = 6). Patients who received placebo discontinued treatment due to disease progression (n = 86), AEs (n = 7), withdrawal (n = 5), and other reasons (n = 2).¹

Investigators noted that their study was limited by the unvalidated assay that was used to determine homologous recombination deficiency and the lack of a dedicated subgroup analysis for patients with R0 resection.¹

References

1. Li N, Zhu J, Yin R, et al. Treatment with niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer: a phase 3 randomized clinical trial. JAMA Oncol. Published online July 13, 2023. doi:10.1001/jamaoncol.2023.2283
2. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA. April 29, 2020. Accessed July 26, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer#:~:text=On%20April%2029%2C%202020%2C%20the,%2Dline%20platinum%2Dbased%20chemotherapy.