Data from the phase 3 PRIME trial show improved survival outcomes with frontline niraparib maintenance therapy among patients with advanced ovarian cancer.
Niraparib (Zejula) maintenance therapy delivered at an individualized starting dose (ISD) improved survival outcomes vs placebo in the frontline treatment of patients with advanced ovarian cancer regardless of residual disease or biomarker status, according to findings from the phase 3 PRIME trial (NCT03709316) published in JAMA Oncology.1
Median progression-free survival (PFS) was 24.8 months (95% CI, 19.2-not estimable [NE]) with niraparib vs 8.3 months (95% CI, 7.3-11.1) with placebo (HR, 0.45; 95% CI, 0.34-0.60; P <.001) in the intention-to-treat (ITT) population after a median follow-up of 27.5 months (95% CI, 25.3-27.6) in the niraparib group and 27.6 months (95% CI, 24.9-30.3) in the placebo group. The median time to first subsequent anticancer therapy (TFST) was 29.2 months (95% CI, 22.4-NE) and 11.9 months (95% CI, 8.8-14.8) with niraparib and placebo, respectively (HR, 0.45; 95% CI, 0.34-0.59; P <.001).
Similarly, median PFS in patients with germline BRCA variants was not reached with niraparib vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) with placebo, The corresponding figures for those without BRCA variants were 19.3 and 8.3 months, respectively (HR, 0.48; 95% CI, 0.34-0.67).
In those with homologous recombination deficient disease, the median PFS was not reached (95% CI, 22.3-NE) vs 11.0 months (95% CI, 8.3-13.8) with niraparib and placebo, respectively (HR, 0.48; 95% CI, 0.34-0.68). In those with homologous recombination proficient disease, median PFS was 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75), respectively.
Moreover, patients with optimal debulking had a median PFS of 24.8 months with niraparib vs 8.3 months with placebo (HR, 0.44; 95% CI, 0.32-0.61). The corresponding figures for those with suboptimal debulking were 16.5 and 8.3 months (HR, 0.27; 95% CI, 0.10-0.72), respectively.
The estimated overall survival (OS) rate at 24 months was 87.3% in the niraparib group vs 82.7% in the placebo group.
“[Patients] with advanced ovarian cancer have a poor prognosis, with a global 5-year survival rate of less than 50% and a recurrence rate of approximately 75%,” Rafael G. Amado, MD, president and head of global oncology research and development at Zai Lab Limited, said in a press release on the PRIME study’s findings.2 “The positive results from the PRIME study, which show a substantial reduction in risk of disease progression or death with [niraparib] maintenance, offer insights into the potential to delay the progression of this devastating disease in a broad group of patients.”
As part of the multicenter, double-blind PRIME study, investigators enrolled 384 patients from 29 hospitals in China between June 2018 and November 2019. Patients were randomly assigned 2:1 to receive either niraparib or placebo.
The median patient age was 54 years (range, 32-77). The median patient weight was 59.0 kg (range, 39.5-100.00) in the niraparib group and 57.0 kg (range, 37.0-97.0) in the control group. Most patients in both groups had an ECOG performance status of 1.
Overall, 28.1% of patients had had stage IV disease. Additionally, 46.9% of patients received neoadjuvant chemotherapy, 18.0% had a partial response to platinum-based chemotherapy, and 13.0% had experienced suboptimal debulking. Germline BRCA variants were present in 32.6% of patients, and 66.9%, 22.1%, and 10.9% had homologous recombination deficient, proficient, and indeterminate disease, respectively.
For patients with a body weight lower than 77 kg or a platelet count lower than 150×103/μL at baseline, treatment consisted of either niraparib at a dose of 200 mg, delivered through 2 capsules of 100 mg each, or a matched placebo once daily. All other patients received niraparib at a dose of 300 mg, delivered through 3 such capsules, or matched placebo once daily. Treatment proceeded in 28-day cycles for a maximum of 36 months.
“The complexity of ovarian cancer demands multiple, innovative treatment options,” study author Lingying Wu, MD, PhD, said in the press release. “These data from the PRIME study prospectively demonstrate that an ISD of 200 or 300 mg of [niraparib] based on baseline bodyweight and platelet count can bring significant benefit to patients with an improved safety and tolerability profile of [niraparib] compared to a fixed 300 mg starting dose in previous studies, and further support the use of an ISD to improve patient outcomes in clinical practice.”
Wu is the director of the department of gynecologic oncology in the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College.
The primary end point of the PRIME trial was PFS in the ITT population according to blinded independent central review. OS and TFST in the ITT population were among the trial’s secondary end points.
Treatment-emergent adverse effects (TEAEs) of grade 3 or higher occurred in 54.5% of patients treated with niraparib and 17.8% of those treated with placebo. The most common grade 3 or higher TEAEs in the niraparib group included anemia (18.0%), decreased neutrophil count (17.3%), decreased platelet count (14.1%), and decreased white blood cell count (6.7%). Serious TEAEs affected 18.8% of those in the niraparib group. There was a single instance each of myelodysplastic syndrome and acute myeloid leukemia in this group, the latter of which proved fatal.
Dose reductions due to TEAEs occurred in 40.4% and 6.2% of patients in the niraparib and placebo groups, respectively. The treatment discontinuation rate was 6.7% with niraparib vs 5.4% with placebo.
Investigators noted several limitations to these findings, including the use of a laboratory-developed, unvalidated homologous recombination deficiency assay.