Approximately 70% of advanced breast cancer cases are estrogen receptor (ER)-positive and HER2-negative. The current 1L standard of care (SOC) for ER-positive/HER2-negative advanced breast cancer is a combination of aromatase inhibitors (AIs) with CDK4/6 inhibitors. Ribociclib is the only CDK4/6 inhibitor to show significant improvements in both progression-free survival (PFS) and overall survival (OS) when combined with AIs in this setting. However, despite these advancements, most patients eventually develop resistance to this therapy. A potentially effective therapeutic approach would be the ability to suppress both wild-type and mutant ER activity in the 1L setting, and, therefore, maintain endocrine responsiveness, and improve outcomes for patients with ER-positive/HER2-negative advanced breast cancer. Palazestrant (OP-1250) is a novel oral complete ER antagonist and selective SERD that inhibits both transcriptional activation function domains, AF1 and AF2. Furthermore, palazestrant has shown efficacy in patients previously treated with CDK4/6 inhibitors, regardless of ESR1 mutation status. Safety data from the combination of palazestrant and ribociclib were consistent with the known safety profiles of each drug. This article describes the ongoing OPERA-02 trial.

OPERA-02 is a global, multicenter, randomized, double-blind, active, controlled phase 3 trial designed to evaluate the efficacy and safety of palazestrant in combination with ribociclib compared with letrozole plus ribociclib in patients with ER-positive/HER2-negative advanced breast cancer who have not received previous systemic treatment for advanced disease. Eligible participants include adult female patients of any menopausal status or male patients with de novo or recurrent ER-positive/HER2-negative advanced breast cancer (recurrence occurring ≥12 months after completion of adjuvant endocrine therapy). Patients must have measurable disease per RECIST v1.1 or evaluable bone disease, an ECOG Performance Score of 0 to 1, and adequate hematologic, hepatic, and renal function. Pre- or perimenopausal female patients and male patients must also agree to receive gonadotropin-releasing hormone agonists for gonadal suppression. Patients with contraindications to ribociclib are excluded.

Approximately 1000 participants will be randomized 1:1 to receive either 90 mg oral palazestrant once daily (QD) plus ribociclib 600 mg QD (21 days on, 7 days off) along with a letrozole-matching placebo, or letrozole 2.5 mg QD plus ribociclib with a palazestrant-matching placebo. Randomization will be stratified by menopausal status, presence of visceral metastases, de novo metastatic disease versus recurrent disease, and geographic region.

The primary endpoint of the trial is PFS as assessed by local investigators. Secondary endpoints include PFS as assessed by a blinded independent review committee, OS, overall response rate, clinical benefit rate, duration of response, safety, pharmacokinetics, and health-related patient-reported outcomes.

This study aims to determine whether palazestrant in combination with ribociclib can provide superior clinical outcomes compared with the current SOC for 1L treatment of ER-positive/HER2-negative advanced breast cancer. The OPERA-02 trial is ongoing and being conducted across multiple international sites.

Source: Tolaney SM, Bianchini P, Borges VF, et al. 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. Presented at: San Antonio Breast Cancer Symposium 2025. December 12, 2025; San Antonio, TX. Presentation PS5-12-18.