Restricted Indication for Maintenance Niraparib Therapy in Recurrent Ovarian Cancer Further Supported by Final Survival Analysis of NOVA Trial

Ursula A. Matulonis, MD

Despite initial problems with data retrieval and imbalances in post-progression therapy, long-term exploratory findings of survival data from the phase 3 ENGOT-OV16/NOVA trial (NCT01847274) more conclusively demonstrate that second-line maintenance niraparib (Zejula) provides a persistent treatment effect specifically for patients with platinum-sensitive, recurrent ovarian cancer who have germline BRCA mutations, according to Ursula A. Matulonis, MD.

Previously reported results from the NOVA trial supported niraparib’s original FDA approval in 2017 for patients with epithelial ovarian cancer who achieved complete or partial response with prior chemotherapy. The trial showed that maintenance niraparib significantly improved progression-free survival (PFS) regardless of a patient’s germline BRCA mutation or homologous recombination deficiency (HRD) status.¹

However, an FDA review of updated overall survival (OS) in 2022 led the regulatory agency to restrict niraparib’s second-line maintenance indication to patients harboring deleterious or suspected deleterious germline BRCA mutations. Notably, this analysis was associated with missing survival status for 17% of enrolled patients.^1,2

Final OS and long-term safety data from the study were presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer. In the germline BRCA-mutant cohort, niraparib maintenance therapy produced a numerically superior median OS of 40.9 months (95% CI, 34.9-52.9) vs 38.1 months (95% CI, 27.6-47.3) with placebo (HR, 0.85; 95% CI, 0.61-1.20). Conversely, median OS was 31.0 months (95% CI, 27.8-35.6) vs 34.8 months (95% CI, 27.9-41.4), respectively in the non–germline BRCA-mutant cohort (HR, 1.06; 95% CI, 0.81-1.37). Survival status was available for 97.6% (n = 540) of patients.³

“[Now that] we’ve rectified the missing data from [the initial report], it’s important for oncologists to follow the changed FDA label,” said Matulonis, who is chief of the Division of Gynecologic Oncology and Brock-Wilson Family Chair at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School in Boston, Massachusetts.

In an interview with OncLive^®, Matulonis highlighted previous data from the trial’s initial readout and subsequent preplanned OS analysis, discussed new findings from the final analysis, and emphasized how these data clarify some of the study’s limitations and reinforce the importance of adhering to the adjusted FDA label for niraparib in recurrent ovarian cancer.

OncLive^®: Please discuss the design and eligibility criteria in the NOVA trial.

Matulonis: The NOVA study would now be considered an older trial, with the original results being published in 2016 in the New England Journal of Medicine. This was a trial of patients with platinum-sensitive recurrent ovarian cancer, with the emphasis on high-grade serous ovarian cancer. Patients who responded to platinum [chemotherapy] were then randomly assigned 2:1 to either the oral PARP inhibitor niraparib or to placebo.

Patients were enrolled into a germline BRCA-mutated cohort or non–germline BRCA-mutated cohort. Within the non–germline BRCA-mutation cohort, patients [underwent] homologous recombination deficiency [HRD] testing. [Patients were either] HRD, homologous recombination proficient, or [had undetermined status because] the test just couldn’t be done, [which] happens occasionally. A total of 553 patients were enrolled [in the trial], and the primary end point [was] PFS via blinded independent central review.

Could you discuss any previous data from this trial that have been reported to date? How do updated OS data from the trial’s final analysis address any previous deficits with these results?

Primary data [from the NOVA study] showed that PFS was improved for patients receiving niraparib regardless of underlying BRCA mutation or HRD status.

I presented the OS data [from this trial] at the SGO Annual Meeting on Women’s Cancer in 2021. Those data eventually led to a change in the FDA label for niraparib. The label for the use of niraparib [was kept for] patients [with] germline BRCA-mutated [ovarian cancer] but removed for everybody else. [There were] some issues with the OS data in 2021, [as] 17% [of the] data on survival status [were missing]. Over the past couple of years, we’ve gone back to [participating] institutions to obtain that survival data and rectify [this issue]. We’ve [reduced the percentage of missing OS data] from 17% to 2%.

What survival data on the use of niraparib in high-grade serous ovarian cancer were presented at this year’s SGO Annual Meeting?

For patients [with] germline BRCA mutations, the hazard ratio for OS was 0.85. [Final median] OS was [40.9] months for patients with germline BRCA mutations receiving niraparib vs [38.1] months [with placebo]. That trend continues to [move] in the correct direction. For patients who are non-germline BRCA mutated, the hazard ratio is 1.06. [Median OS was 34.8] months [with] placebo vs 31 months [with niraparib]. Remarkably, that [result is] driven by the HRD population, where the hazard ratio is 1.29 in favor of placebo vs niraparib.

Other [secondary] end points, [such as] chemotherapy-free interval, time to first progression, [and] time to second progression all favored niraparib vs placebo. None of the OS data were statistically significant because [the study] wasn’t powered for [OS].

What is important to note about the incidence of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with niraparib use in this patient population?

Another secondary end point looked at the [incidence of] MDS and AML. [Overall], the risk of [developing] AML in patients who received niraparib is 3.8% vs 1.7% [with] placebo. That risk was highest in patients with an underlying germline BRCA mutation receiving niraparib. That is consistent with [data from] other phase 3 trials, so this is a [common] issue that comes up. No other safety signals came about.

Based on this research, what challenges or questions regarding the investigation of PARP inhibitors in ovarian cancer remain unaddressed?

In summary, it’s important to [conduct] trials where we understand [how to gather] missing data. One issue is that patients go on different [regimens] when [they] come off the PARP inhibitor or placebo, and that’s hard to control for [in clinical trials]. [However], there was a difference in PARP inhibitor usage [in the NOVA study]. [Lastly, we need to] make sure that OS data and status is monitored during the study.

[We need to] understand the results of the NOVA study and how the FDA label has changed. It’ll be important for us to understand treatment resistance mechanisms post PARP inhibitor use. There also continues to be a risk of AML/MDS [in this tumor type]. That’s especially an issue in patients with underlying germline BRCAmutations treated in the recurrent setting, where we see [that the] risk is 7.4% [in this trial], and higher in others.

What other findings were you excited to see presented at this year’s meeting?

We saw intriguing results [from] the [phase 2 GOG 3026 trial (NCT03673124)] of the CDK4/6 inhibitor [ribociclib (Kisqali)] plus letrozole in low-grade serous ovarian cancer. [Data on the] addition of immunotherapy to chemotherapy for advanced endometrial cancer [were also a] high point [of the meeting].

Disclosures: Dr Matulonis reports consulting fees from Agenus, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, GSK, Merck, NextCure, Novartis, and Trillium; and data and safety monitoring board participation for Advaxis, Alkermes, and Symphogen. This study was sponsored by GSK.

References

1. FDA approves maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers. News release. FDA. March 27, 2017. Accessed April 3, 2023. https://www.fda.gov/news-events/press-announcements
2. GSK provides an update on Zejula (niraparib) US prescribing information. News release. GlaxoSmithKline plc. November 11, 2022. Accessed April 3, 2023. https://otp.tools.investis.com/generic/regulatory-story
3. Matulonis UA, Herrstedt J, Oza A, et al. Final overall survival and long-term safety in the ENGOT-OV16/NOVA phase 3 trial of niraparib in patients with recurrent ovarian cancer. Presented at: 2023 Annual Meeting on Women’s Cancer; March 25-28; Tampa, Florida.