Abstract PS5-12-18: OPERA-02: a phase 3 randomized, double-blind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2- advanced breast cancer

Abstract Background: Approximately 70% of advanced breast cancers (ABC) are estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) tumors. The standard-of-care first-line treatment for ER+, HER2- ABC is an aromatase inhibitor (AI) plus cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). As the first line treatment, ribociclib is the only CDK4/6i that in combination with AIs improved both progression-free survival (PFS) and overall survival (OS) in ER+, HER2- ABC. Despite the improved survival outcomes with AI + CDK4/6i, resistance develops eventually in most patients. The most common mechanism of endocrine resistance involves mutations in the ESR1 gene that encodes the estrogen receptor alpha (ERα). Treatment with AIs induces these mutations in the ligand-binding domain of ERα, thereby determining an estrogen-independent constitutive activation of ER. The ability to suppress the activity of both wild-type and mutated ERs in the first line setting is a potentially effective therapeutic approach. By preventing the appearance of ESR1 mutations, this approach has the potential of maintaining endocrine responsiveness and improving clinical outcomes in patients with ER+, HER2− ABC. Palazestrant (OP-1250) is a novel oral, complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that acts by blocking both transcriptional activation function domains, AF1 and AF2. Early phase studies investigating palazestrant as monotherapy (Lin et al. ESMO 2023) and in combination with ribociclib (Borges et al. SABCS 2024) demonstrated a tolerable safety profile, favorable pharmacokinetics with no drug-drug interactions with ribociclib, and encouraging antitumor efficacy in both ESR1-mut and ESR1-wt ER+, HER2- ABC. In addition, palazestrant showed promising anti-tumor efficacy in patients who received prior treatment with CDK4/6i in both ESR1-mut and ESR1-wt ER+, HER2- ABC. When combined, palazestrant and ribociclib safety was consistent with known safety profiles of each drug. Methods: OPERA-02 is an international, multicenter, randomized, double-blind, active-controlled phase 3 clinical trial comparing the efficacy and safety of palazestrant in combination with ribociclib versus letrozole plus ribociclib in patients with ER+, HER2- ABC who have not previously received systemic treatment for ABC. Eligible patients are adult women of any menopausal status or men with de novo or recurrent (after 12 months of completion of adjuvant endocrine therapy) ER+, HER2- ABC who have not received any prior systemic therapy for advanced disease. Additional inclusion criteria include measurable disease per RECIST 1.1 or evaluable bone disease, ECOG performance score of 0-1, adequate hematologic, hepatic, and renal functions. Pre- or perimenopausal women and men must be willing to receive GnRH agonists for gonadal suppression. Patients with a contraindication to ribociclib are excluded. Overall, approximately 1000 participants will be randomized 1:1 to receive 90 mg qd palazestrant plus ribociclib 600 mg qd for 21 consecutive days followed by 7 days off plus letrozole-matching placebo or letrozole 2.5 mg qd plus ribociclib plus palazestrant-matching placebo. Randomization will be stratified by menopausal status, visceral metastasis, and de novo metastatic disease versus recurrent disease. The primary endpoint is PFS assessed by local investigator. Secondary endpoints include PFS by a blinded-independent review committee, OS, overall response rate, clinical benefit rate, duration of response, safety, pharmacokinetics and health-related patient-reported outcomes. The study is conducted globally. Citation Format: S. M. Tolaney, P. Bianchini, V. F. Borges, E. Ciruelos, W. Janni, K. Jhaveri, P. Schmid, J. Tsang, G. Werutsky, D. Vecchio, Y. Luan, N. Di Santo, B. Pistilli. OPERA-02: a phase 3 randomized, double-blind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2- advanced breast cancer [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 PS5-12-18.