Letrozole Monotherapy Doesn’t Demonstrate PFS Noninferiority in LGSOC

Compared with carboplatin/paclitaxel followed by letrozole, letrozole monotherapy failed to demonstrate noninferiority for progression-free survival (PFS) as initial treatment for stage II to IV low-grade serous ovarian, fallopian tube, or primary peritoneal carcinoma (LGSOC). These data from the phase 3 NRG-GY019 trial (NCT04095364) were presented at the 2026 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).¹

Data from the protocol-specified second interim analysis showed that, at a median follow-up of 27.3 months, the HR for PFS in the intention-to-treat (ITT) population was 1.30 (95% CI, 0.90-1.89). This crossed the prespecified noninferiority margin of 1.18 and met futility stopping criteria, prompting early closure of the trial.

As of the January 5, 2026, data cutoff, 71.9% of patients treated with letrozole monotherapy (n = 224) remained alive and progression-free compared with 77.9% of patients treated with letrozole in combination with chemotherapy (n = 226). Twelve-month landmark PFS rates were approximately 91% and 80% in these respective arms. Overall survival (OS) data remained immature at the time of this analysis, with a limited number of events in both arms. The 12-month OS rate was 95% in the letrozole arm and 92% in the combination arm (HR, 1.52; 95% CI, 0.73-3.13)

"The trial met its prespecified futility stopping criteria and did not demonstrate the noninferiority of letrozole monotherapy compared with chemotherapy and letrozole,” lead study investigator Amanda N. Fader, MD, stated in her presentation of the data. “This trial, though, is practice-defining and establishes for the first time a definitive standard of care [SOC] for patients being treated in the frontline setting with advanced low-grade serous ovarian carcinoma.”

Fader is a professor in the Johns Hopkins Hospital Department of Gynecology and Obstetrics and the Sidney Kimmel Cancer Center, vice chair of Gynecologic Surgical Operations, and director of the Center for Rare Gynecologic Cancers at Johns Hopkins Medicine in Baltimore, Maryland.

What unmet need in frontline low-grade serous ovarian carcinoma did this study seek to address?

LGSOC is a rare and biologically distinct subtype characterized by relative chemotherapy resistance and hormonal sensitivity. Prior to NRG-GY019, no phase 3 trial had been completed in the frontline setting for patients with advanced LGSOC, leaving a lack of definitive evidence to guide initial management. As a result, treatment recommendations have largely been extrapolated from more common histologies, including high-grade serous and grade 2/3 endometrioid disease.

Since 2017, National Comprehensive Cancer Network guidelines have included aromatase inhibitors such as letrozole as a category 2B recommendation in the recurrent LGSOC setting, but the question of whether endocrine therapy could supplant chemotherapy in the upfront setting has remained unanswered.^1,2 Additionally, retrospective and early-phase data have suggested clinical activity with hormonal agents in LGSOC.¹ However, the absence of prospective randomized data is a key knowledge gap that NRG-GY019 was designed to address.

How was NRG-GY019 designed?

NRG-GY019 enrolled patients across sites in the United States (US), Canada, South Korea, and Ireland between September 2019 and May 2025. Key eligibility criteria included a diagnosis of stage II to IV LGSOC confirmed by institutional p53 wild-type immunohistochemistry testing, an ECOG performance status of 0 to 2, an attempt at maximal cytoreductive surgery, and no prior chemotherapy. Stratification factors were residual disease status and country.

Eligible patients were randomly assigned 1:1 to 1 of 2 arms:

• Arm A: Intravenous (IV) paclitaxel at 175 mg/m² every 3 weeks plus IV carboplatin at an area under the curve of 5 every 3 weeks for 6 cycles, followed by oral letrozole at 2.5 mg once daily
• Arm 2: Letrozole at 2.5 mg orally once daily for 6 cycles.

Treatment in both arms continued until disease progression or intolerable toxicity. Of the 450 patients originally enrolled onto the study, 213 patients in the combination arm and 221 in the letrozole arm were treated.

The study’s primary end point was PFS by investigator assessment, with secondary end points including safety, OS, and overall response rate and duration of response per RECIST 1.1 criteria.

The statistical design specified a noninferiority margin HR of 1.18, a 1-sided alpha of 0.1, power of 0.8, and 222 required PFS events. Efficacy was analyzed in the ITT population; safety was analyzed in all treated patients. Two interim analyses were prespecified, with the second interim analysis also serving as the final analysis should futility criteria be met. Prespecified exploratory analyses evaluated PFS by residual disease status, country, race, and ECOG performance status (PS).

What should be known about the baseline characteristics of patients in this study?

The median age in this patient population was 51.9 years (range, 19.3-81.7). The majority of patients were White (85.8%), not Hispanic or Latino (88.0%), and enrolled from the US or Canada (96%). Regarding disease stage, 78.2% of patients had stage III disease, 13.8% had stage IV disease, and 7.1% had stage II disease. At the time of enrollment, 63.6% of patients had no gross residual (NGR) disease following cytoreductive surgery, 27.3% had residual disease of no more than 1 cm, and 9.1% had residual disease greater than 1 cm. Most patients had an ECOG PS of 0 (71.3%), with 26.7% and 1.4% having an ECOG PS of 1 and 2, respectively.

What did exploratory analyses reveal about PFS outcomes according to prespecified subgroups?

In the prespecified subgroup analysis, PFS benefit was consistent across most subgroups, with no statistically significant heterogeneity. HRs according to residual disease status (homogeneity P = .499), country (P = .980), ECOG status (P = .224), and race (P = .811) were as follows:

• NGR disease: HR, 1.15 (95% CI, 0.68-1.94); Any residual disease: HR, 1.48 (95% CI, 0.87-2.53)
• US/Canada: HR, 1.26 (95% CI, 0.86-1.83); Rest of the world: not applicable
• Fully active patients: HR, 1.55 (95% CI, 0.97-2.46); Restricted or ambulatory status: HR, 0.95 (95% CI, 0.51-1.78)
• White patients: HR, 1.20 (95% CI, 0.80-1.79); Patients of other races: HR, 2.30 (95% CI, 0.84-6.27)

An exploratory analysis of patients who achieved NGR disease following cytoreductive surgery (n = 286) revealed a more modest difference in PFS outcomes between treatment arms (HR, 1.15; 95% CI, 0.68-1.94; NI P = .4560). Among patients in the letrozole-alone arm with any residual disease, recurrence was observed in 34 of 82 patients (41.5%), compared with 39 of 142 patients (20.5%) in those with NGR disease.

“These findings suggest that a clinically relevant subset of patients may be appropriate candidates for letrozole monotherapy,” Fader explained. “However, ongoing clinical follow-up and planned correlatives to molecular analyses are essential to better contextualize these observations and clarify which patients drive the greatest benefit from chemotherapy followed by letrozole…”

How did toxicity profiles differ between treatment arms?

Regarding safety, the toxicity profiles differed substantially between treatment arms, particularly during cycles 1 through 6. Any-grade adverse effects (AEs) occurred in 100% of CP/L-treated patients (n = 213) and 96.8% of letrozole-treated patients (n = 221) during cycles 1 through 6. Grade 3 to 5 AEs were observed in 46.9% of patients receiving the combination vs 17.6% of those receiving letrozole alone during the same period. No deaths attributed to AEs occurred in the combination arm during cycles 1 through 6, though 1 patient (0.5%) in the letrozole arm experienced a treatment-related death.

During cycle 7 and beyond, any-grade AEs continued to occur in all patients in the combination (n = 191) and letrozole (n = 189) arms. Grade 3 to 5 AEs were observed in 41.4% and 34.9% of patients, respectively, with 1 additional AE-related death (0.5%) in the letrozole arm. The odds of experiencing at least 1 grade 3 or 4 AE during cycles 1 through 6 were 3.99-fold higher (95% CI, 2.57-6.18; P < .001) in the combination arm compared with the letrozole arm. System-organ class analyses showed substantially higher rates of hematologic, gastrointestinal, metabolic, nervous system, injury, and infection-related AEs in the combination arm, with vascular events appearing numerically higher in the letrozole arm.

Disclosures: Fader disclosed a financial relationship with an ACCME-defined ineligible company, GSK, over the past 24 months and received institutional grants from NRG Oncology Operations and NRG Oncology SDMC in support of the current study.

References

1. Fader AN, Miller A, Gien L, et al. Results of a randomized phase III trial of letrozole alone versus paclitaxel and carboplatin followed by letrozole as initial treatment for patients with stage II–IV ovarian, fallopian tube, or primary peritoneal low-grade serous carcinoma (NRG-GY019, NCT04095364). Presented at: 2026 SGO Annual Meeting on Women's Cancer; April 10–13, 2026; San Juan, PR.
2. NCCN. Clinical Practice Guidelines in Oncology. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer, Version 3.2025. Accessed April 11, 2026. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf