PS5-09-10: A randomized phase II study comparing monthly versus 3-monthly GnRH agonist for ovarian function suppression in premenopausal patients with HR-positive breast cancer: study design and rationale

Abstract Background: The SOFT and TEXT trials have shown substantial survival benefit from adding ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa) to aromatase inhibitors (AI), compared with tamoxifen alone in premenopausal patients with hormone receptor (HR)-positive breast cancer. This benefit was particularly pronounced among women with a higher risk of recurrence, such as younger patients and those who received adjuvant chemotherapy, with an absolute improvement of 15% in disease-free survival. Although most pivotal trials used monthly GnRHa, many clinicians prescribe 3-monthly depot injections for convenience, despite limited prospective data supporting their efficacy. Retrospective data from a Brazilian cohort presented at the 2023 ASCO Annual Meeting [JCO 41, no. 16_suppl (June 1, 2023) 527-527] suggested fewer estradiol (E2) increases with 3-monthly compared to monthly GnRHa, prompting the need for a prospective randomized trial. Methods: This single-institution, randomized, investigator-initiated phase II trial will enroll 50 premenopausal breast cancer patients (age ≤40) who are candidates for adjuvant OFS plus AI at Memorial Sloan Kettering. Eligible participants are women diagnosed with stage I, II, or III HER2-negative or HER2-positive, HR-positive breast cancer (ER >1% and/or PR >1%, according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines). Patients will be stratified by prior chemotherapy (yes vs. no) and randomly assigned in a 1:1 ratio to receive either leuprolide at a dose of 22.5 mg every 12 weeks (Cohort A) or leuprolide at a dose of 7.5 mg every 4 weeks (Cohort B), both administered as a single intramuscular injection, in combination with an AI. Leuprolide was selected due to its widespread use in the United States. E2 levels will be measured using high-sensitivity gas chromatography-tandem mass spectrometry (GC/MS/MS) at baseline and at 3, 6, 9, and 12 months. Patients with at least one E2 level above the pre-established threshold of 2.72 pg/mL during the 12-month follow-up will be considered to have suboptimal OFS. Patients in the 3-monthly group will undergo testing at the same frequency as those in the monthly group. The primary endpoint is the difference in the proportion of patients in each treatment arm who experience at least one E2 level > 2.72 pg/mL during the 12-month follow-up. Additionally, E2 levels will be described at each time point, and associations between baseline characteristics and E2 increases will be explored. Conclusions: OFS management remains a major challenge for oncologists worldwide, with limited evidence to guide optimal GnRHa dosing schedules. This study will generate prospective data comparing OFS using monthly versus 3-monthly GnRHa in combination with adjuvant endocrine therapy, addressing an important gap in clinical practice. The findings may contribute to future clinical guidelines for OFS, while also improving convenience, supporting treatment adherence, and enhancing quality of life for premenopausal breast cancer patients globally. Current Status: This investigator-initiated study is supported by the Long-term International Fellowship (LIFe) Award from Conquer Cancer, the ASCO Foundation. IRB approval was obtained in July 2025, and the study is currently in the activation phase. Patient enrollment is expected to begin shortly thereafter. Citation Format: D. Audi Blotta, Y. Chen, A. Buzaid, M. Robson. A randomized phase II study comparing monthly versus 3-monthly GnRH agonist for ovarian function suppression in premenopausal patients with HR-positive breast cancer: study design and rationale [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-10.