OPERA-02: A phase 3 study of palazestrant plus ribociclib as first-line treatment of ER+, HER2- advanced breast cancer.

Abstract

TPS1152 Background: Estrogen receptor-positive, human epidermal growth factor 2-negative advanced breast cancer (ER+, HER2- ABC) accounts for nearly 70% of all ABC. The standard first-line treatment for ER+, HER2- ABC is the combination of an aromatase inhibitor (AI) with cyclin–dependent kinase 4/6 inhibitor (CDK4/6i). When combined with AI, the CDK4/6i ribociclib has demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) in this setting. Despite these advances, resistance to AI + CDK4/6i develops in a substantial proportion of patients (pts), most commonly driven by acquired mutations in the ligand-binding domain of ERα, resulting in constitutive ligand-independent ER activation. Early and sustained suppression of both wild-type and mutated ERs in the first line treatment of ER+, HER2- ABC may enhance endocrine sensitivity, delay resistance to endocrine therapy and improve clinical outcomes. Palazestrant (OP-1250) is an investigational oral, complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD). In early phase studies, palazestrant has shown favorable safety and encouraging antitumor activity as monotherapy (Hamilton et al, 2025) and in combination with ribociclib (Lin et al, 2025), regardless of ESR1 mutation status, including in those previously treated with CDK4/6i. Palazestrant showed no clinically meaningful drug-drug interactions with ribociclib, and the combination safety profile was consistent with the known profiles of each drug. Methods: OPERA-02 (NCT07085767) is a phase 3, international, multicenter, randomized, double-blind, study designed to evaluate the efficacy and safety of palazestrant plus ribociclib versus letrozole plus ribociclib in the first line treatment of pts with ER+, HER2- ABC. Approximately 1,000 pts will be randomized 1:1 to either palazestrant plus ribociclib or letrozole plus ribociclib, with matching placebos. The primary endpoint is investigator-assessed PFS; secondary endpoints are OS, PFS by a blinded-independent review committee, overall response rate, duration of response, clinical benefit rate, safety, pharmacokinetics, pt-reported outcomes and PFS2. Eligible pts are adult women, regardless of menopausal status, and men, with de novo or recurrent disease (≥ 12 months after completion of adjuvant endocrine therapy) who have not received prior systemic therapy for ER+, HER2- ABC. Pts must have measurable disease per RECIST 1.1 or evaluable bone disease, ECOG performance score of 0-1, and adequate organ function. Pts with a contraindication to ribociclib are excluded. Pre- or perimenopausal women and men must receive gonadotropin-releasing hormone (GnRH) agonists for gonadal function suppression. The study has been recruiting globally since November 2025. Clinical trial information: NCT07085767 .