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Maintenance treatment with niraparib produced a sustained and durable progression-free survival benefit in patients with primary advanced ovarian cancer who responded to first-line platinum-based chemotherapy, spanning biomarker subgroups.
Maintenance treatment with niraparib (Zejula) produced a sustained and durable progression-free survival (PFS) benefit in patients with primary advanced ovarian cancer who responded to first-line platinum-based chemotherapy, spanning biomarker subgroups, according to updated data from the phase 3 PRIMA trial (ENGOT-OV26/GOG-3012; NCT02655016).1
Data presented during the 2022 ESMO Congress showed that at a median follow-up of 3.5 years, which had a data cutoff date of November 17, 2021, the median progression-free survival (PFS) with niraparib was 24.5 months per investigator assessment vs 11.2 months with placebo in the homologous recombination deficiency (HRD) population (n = 373; HR, 0.52; 95% CI, 0.40-0.68; P < .001).
In the overall population (n = 733), the median investigator-assessed PFS with niraparib was 13.8 months vs 8.2 months with placebo (HR, 0.66; 95% CI, 0.56-0.79; P < .001).
Treatment with niraparib boosted the duration of PFS vs placebo across the biomarker subgroups examined. The greatest benefit was observed in those with HRD tumors that were BRCA mutated (HR, 0.45; 95% CI, 0.32-0.64).
“Sustained benefit was observed with long-term follow-up, with hazard ratios that were consistent with the primary analysis regardless of biomarker status,” lead study author Antonio González-Martin, of Medical Oncology Department, Clinica Universidad de Navarra, and colleagues, wrote in a poster on the data. “In the HRD and homologous recombination–proficient [HRp] populations, respectively, a clinically meaningful 48% and 35% reduction of the risk of progression or death was observed.”
The randomized, double-blind, placebo-controlled, phase 3 trial enrolled patients with newly diagnosed ovarian cancer who were at high risk for recurrence following response to frontline platinum-based chemotherapy.
Study participants were randomly assigned to 2:1 to receive niraparib (n = 487) or placebo (n = 246). They underwent randomization within 12 weeks of receiving the last cycle of chemotherapy. At the start of the study, the PARP inhibitor was administered at a fixed dose of 300 mg. For those who weighed less than 77 kg or who had platelet counts that were below 150L/μL, the dose was reduced to 200 mg. Treatment was given for 36 months or until progressive disease.
Stratification factors included best response to frontline chemotherapy treatment (complete response [CR] vs partial response [PR]), receipt of neoadjuvant chemotherapy (yes vs no), and HRD status (HRD vs HTp/homologous recombination not determined).
The primary end point of the trial was PFS by blinded independent central review (BICR) in the HRD population and the overall population. Overall survival (OS) represents a key secondary end point. Additional secondary end points include time to second disease progression, time to first subsequent therapy, patient-reported outcomes, and safety.
Data from the primary analysis of the trial showed that maintenance niraparib significantly improved PFS over placebo per BICR, at 21.9 months vs 10.4 months, respectively (HR, 0.43; 95% CI, 0.31-0.59; P < .001); in the overall population, the median PFS in the investigative and control arms were 13.8 months and 8.2 months, respectively (HR, 0.62; 95% CI, 0.50-0.76; P < .001).
These data supported the April 2020 FDA approval of niraparib for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to frontline platinum-based chemotherapy, irrespective of biomarker status.2
Additional updated data shared at the 2022 ESMO Congress showed that in the HRD population, the 1-year PFS rate with niraparib was 70% vs 47% with placebo; the 2-year rates were 51% and 29%, respectively; the 3-year rates were 44% vs 23%, respectively; and the 4-year rates were 38% and 17%, respectively.
In the overall population, the 1-year PFS rate achieved with niraparib vs placebo were 54% and 39%, respectively; at 2 years, these rates were 36% vs 22%, respectively; at 3 years, these rates were 29% vs 18%, respectively; and the 4-year rates were 24% vs 14%, respectively.
The hazard ratio (HR) for PFS in those with HRD tumors that are BRCA wild-type was 0.66 (95% CI, 0.44-1.00). In those with HRp tumors, the HR for PFS was 0.65 (95% CI, 0.49-0.87).
For the overall population, data remained immature at 41.2%.
In those who received niraparib vs placebo, 9.2% and 33.3%, respectively, received subsequent PARP inhibitor therapy in follow-up.
No new safety signals were observed with the long-term follow-up.
Long-term treatment with single-agent niraparib was linked with a low rate of treatment discontinuations because of toxicity vs what was observed in the primary analysis. A total of 11 additional patients discontinued the PARP inhibitor because of a treatment-emergent adverse effects (TEAEs).
TEAEs that resulted in dose interruptions and reductions were both reduced with individualized starting dose implementation. TEAEs that resulted in death were not determined to be related to the study treatment.
Within those who received niraparib in the overall population (n = 484), the most common toxicities included thrombocytopenia (any grade, 67.1%; grade ≥3, 39.7%), anemia (any grade, 65.1%; grade ≥3, 31.6%), nausea (any grade, 58.3%; grade ≥3, 1.2%), neutropenia (any grade, 43.2%; grade ≥3, 21.3%), constipation (any grade, 41.7%; grade ≥3, 0.4%), fatigue (any grade, 36.6%; grade ≥3, 2.3%), headache (any grade, 27.5%; grade ≥3, 0.4%), insomnia (any grade, 25.6%; grade ≥3, 1.0%), abdominal pain (any grade, 24.6%; grade ≥3, 2.1%), vomiting (any grade, 24.4%; grade ≥3, 0.8%), arthralgia (any grade, 20.7%; grade ≥3, 0.6%), hypertension (any grade, 20.5%; grade ≥3, 7.2%), and diarrhea (any grade, 19.6%; grade ≥3, 0.8%).
Those who received the individualized starting dose generally experienced a lower incidence of TEAEs, with the largest reductions observed in any grade or grade 3 or higher anemia, thrombocytopenia, and neutropenia.
Myelodysplastic syndrome or acute myeloid leukemia events were experienced by 1.2% of those who received niraparib and 1.2% of those who received placebo. Known risk factors for these events include platinum-based chemotherapy and PARP inhibitor use.
Of those who experienced these events, all received frontline platinum-based chemotherapy; 3 of the 6 patients who received niraparib and all 3 of those who received placebo went on to receive subsequent chemotherapy. All the 3 patients on the placebo arm went on to receive treatment with PARP inhibitors.