At the 2026 Society of Gynecologic Oncology Annual Meeting, Amanda Fader, MD, presented results of NRG-GY019 (NCT04095364), a randomized, phase 3 non-inferiority trial of letrozole monotherapy versus paclitaxel/carboplatin followed by letrozole as frontline treatment of stage II-IV low grade serous ovarian cancer (LGSOC) after cytoreductive surgery.
LGSOC is biologically distinct from and relatively chemoresistance to standard platinum/taxane therapy compared with high-grade SOC, although historically treated similarly. LGSOC usually presents as advanced disease with a high risk of recurrence and mortality.
LGSOC strongly expresses estrogen receptors in about 85–90% of cases and progesterone receptors in about 50% of cases. Adding aromatase inhibitors, especially letrozole, to frontline treatment has improved outcomes, although there have been no randomized data on optimal frontline therapy for advanced LGSOC nor whether chemotherapy can be safely omitted.
NRG-GY019 enrolled 450 patients. With a median follow-up of 27.3 months, a second interim analysis showed a hazard ratio (HR) for the primary objective, PFS, was 1.30, which was not significantly different between treatment arms (77.9% vs 71.9%) for the combination vs letrozole monotherapy. Therefore letrozole alone is not inferior to chemotherapy followed by letrozole. Median PFS has not reached. Overall survival (OS) was not significantly different between arms (95% vs 92%).
Adverse events (AE) were markedly different, nearly 4 times higher in the combination vs monotherapy arm (P<.001 for ≥1 grade ≥3 AE). AE for the combination were as expected for paclitaxel/carboplatin.
A prespecified subgroup analysis of PFS in patients with no gross residual disease (NGR) after cytoreductive therapy showed no significant difference in PFS between treatment arms. The non-inferiority hazard ratio for letrozole was 1.15, more favorable than in the overall intent-to-treat (ITT) population.
Dr. Fader said, “It merits consideration that in the letrozole monotherapy arm, recurrence was markedly higher with any residual disease, approximately double that in those NGR disease after cytoreductive surgery,” 41.5% vs 20.5%. This disparity likely contributed to the inability to establish non-inferiority of letrozole monotherapy versus the combination in the ITT population.
She observed, “This is a practice-defining trial and establishes for the first time a definitive standard of care, carboplatin/paclitaxel and letrozole, for patients being treated in the frontline setting with advanced stage LGSOC.”
Ongoing clinical follow-up and planned correlative tumor molecular profiling may clarify which patients derive the greatest benefit from chemotherapy/letrozole, and whether letrozole alone may be a reasonable alternative for select patients.
NRG-GY019 is the first phase 3 frontline trial in LGSOC, and the first phase 3 rare epithelial ovarian cancer study to complete enrollment. Dr. Fader said the trial design was shaped by input from patient advocates, ensuring alignment with the priorities and lived experiences of the patients it was intended to serve.
Results of two other phase 3 trials were published simultaneously at presentation: final OS results from ROSELLA, a trial of nab-paclitaxel +/-relacorilant, a glucocorticoid receptor antagonist in platinum resistant ovarian cancer (PROC) NCT05257408; and final results of ENGOT-ov65/KEYNOTE-B96, pembrolizumab vs placebo plus weekly paclitaxel +/- bevacizumab in PROC (NCT05116189.)
Dr. Lederman reports no conflicts of interest.
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