Niraparib Yields Limited OS in Final Analysis for Ovarian Cancer

Treatment with niraparib (Zejula) maintenance therapy did not produce a statistically significant improvement in overall survival (OS), according to findings from an updated exploratory analysis in the phase 3 ENGOT-OV16/NOVA study (NCT01847274) presented at The Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer.¹

"There remains a considerable amount of missing data for these measures, as well as imbalances in post-progression therapy," according to an expert from Dana-Farber Cancer Institute.

Ursula Matulonis, MD, presented updated OS results from the randomized, double-blind, placebo-controlled phase 3 trial, with a collected survival status of 97.6% of patients involved in the trial (n = 540). The overall OS maturity of the data was 77.9%.

Split amongst the germline (g)BRCA-mutated cohort (n = 203) and non-gBRCA-mutated cohort (n = 350), median OS for niraparib and placebo was 40.9 months vs 38.1 months, respectively (HR, 0.85; 95% CI, 0.61-1.20). In comparison, the median OS with niraparib in the non-gBRCA mutated cohort was 31.0 months vs 34.8 months with placebo (HR, 1.06; 95% CI, 0.81-1.37).

Further exploratory analyses of the homologous recombination-deficient subgroups within the non-gBRCA-mutated cohort showed that while there was still no significant difference between the use of niraparib over placebo, the PARP inhibitor was still favored. In the homologous recombination-deficient group of patients who received niraparib (n = 106), median OS was 35.6 months compared to 41.4 months in the placebo group (n = 56), with an HR of 1.29 (95% CI, 0.85-1.95). Moreover, in the homologous recombination not determined subgroup of patients who received niraparib (n = 36), median OS was 29.8 months vs 20.2 months for patients who received placebo (n = 18), with an HR of 0.62 (95% CI, 0.29-1.35). However, patients who were homologous recombination proficient had the same median OS of 27.9 months in both the niraparib arm (n = 92) and placebo arm (n = 42), with an HR of 0.93 (95% CI, 0.61-1.41).

Secondary end points were re-assessed with the updated data, showing that PFS2 still favored the use of niraparib to placebo in both the gBRCA- and non-gBRCA-mutated cohorts, at a median of 29.9 months vs 22.7 months, respectively(HR, 0.70; 95% CI, 0.50-0.97), and 19.5 months vs 16.1 months (HR, 0.80; 95% CI, 0.63-1.02). Moreover, time to first subsequent therapy was superior with niraprib in both cohorts at a median of 19.1 months vs 8.6 months, respectively (HR, 0.57; 95% CI, 0.41-0.78), and 12.4 months vs 7.4 months (HR, 0.58; 95% CI, 0.45-0.74), respectively.

“While the additional data captured survival outcomes for the overwhelming majority of patients, data on subsequent therapies were not available, in many cases,” explained Matulonis, chief of the Division of Gynecologic Oncology, Brock-Wilson Family Chair, and institute physician at the Dana-Farber Cancer Institute in Boston. “There remains a considerable amount of missing data for these measures, as well as imbalances in post-progression therapy.”

Previous Results

The previously published primary analysis of niraparib as maintenance therapy in this patient population met its primary end point of progression-free survival (PFS) after a median follow up of 16.9 months. The use of niraparib in the gBRCA-mutated cohort led to a median PFS of 21.0 months compared to 5.5 months for patients on placebo (HR, 0.27; 95% CI, 0.17-0.41; P <.001), whereas, in the non-gBRCA cohort, median PFS was lower in both groups but still favored niraparib at a median of 9.3 months vs 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.61; P <.001).²

These results were seen regardless of patients’ homologous recombination deficiency status and, when adjusted for patients who progressed, there was an 81% PFS2 maturity rate among patients in the non-gBRCA cohort (HR, 0.81; 95% CI, 0.632-1.050), compared with a 78% maturity rate among those who had gBRCA-mutated disease (HR, 0.67; 95% CI, 0.479-0.948).

Missing Data

In 2021, the primary analysis³ had been presented with limited OS data and, Matulonis explained that this trial was not powered for OS data, which was still true for the 2023 update. At the time, OS still improved with niraparib at a median of 43.6 months compared with 41.6 months on placebo (HR, 0.93; 95% CI, 0.633-1.355).

In order to acquire the updated OS data, researchers collected further data after the FDA recommended further data retrieval at the time of data cutoff in 2020. They reduced the missing survival status from 17% of patients to 2% after looking for the status of 92 patients that had been missing, which included an outreach effort to 24 sites across 13 countries, explained Matulonis. Moreover, data cutoff was extended by 6 months up to the date of the study unblinding.

Safety

Compared to the primary analysis, the safety profile of niraparib was consistent, including the incidence of grade 3 or greater adverse events (AEs) like thrombocytopenia (35.7%), anemia (27%), neutropenia (20.7%), hypertension (2.2%), fatigue (2.8%), and GI disorders.

As of the new data cutoff at March 31, 2021, 3.8% of patients who were administered niraparib and 1.7% of patients on placebo had developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Moreover, 1 additional case of MDS or AML was reported in the gBRCA cohort since the original 2020 data cutoff, bringing the total count to 10 patients on niraparib vs 2 patients on placebo.

References

1. Matulonis UA, Herrstedt J, Mahner S, et al. Final overall survival and long-term safety in the ENGOT-OV16/NOVA phase III trial of niraparib in patients with recurrent ovarian cancer. Presented at Society of Gynecological Oncology 2023 Virtual Annual Meeting on Women’s Cancer; March 25-28, 2023; Virtual. Abstract LBA.
2. Del Campo JM, Matulonis UA, Malander S, et al. Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial. J Clin Oncol. 2019 Nov 10;37(32):2968-2973. doi: 10.1200/JCO.18.02238Matulonis UA, Herrstedt J, Oza A, et al. Long-term safety and secondary efficacy endpoints in the ENGOT-OV16/NOVA phase 3 trial of niraparib in recurrent ovarian cancer. Presented at: Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021; Virtual. Abstract 37
3. Matulonis UA, Herrstedt J, Oza A, et al. Long-term safety and secondary efficacy endpoints in the ENGOT-OV16/NOVA phase 3 trial of niraparib in recurrent ovarian cancer. Presented at: Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021; Virtual. Abstract 37.