1197 – OPERA-02: a phase 3, randomized, doubleblind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2– advanced breast cancer

Abstract

Estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) disease accounts for 70%
of advanced breast cancer (ABC). The standard first-line treatment is an aromatase inhibitor (AI) plus a cyclin–dependent
kinase 4/6 inhibitor (CDK4/6i). Ribociclib is the only CDK4/6i that, when combined with Ais, improved both progression-free
survival (PFS) and overall survival (OS) in ER+, HER2- ABC. Despite this, endocrine resistance develops in many patients,
often due to AI-induced activating mutations in the ESR1 gene. Early sustained suppression of both wild-type and mutated
ERs during first-line treatment of ER+, HER2- ABC may enhance endocrine sensitivity, delay resistance to endocrine therapy, and improve clinical outcomes. Palazestrant (OP-1250) is a novel oral, complete estrogen receptor antagonist and
selective estrogen receptor degrader (SERD). Early palazestrant studies showed favorable safety and encouraging antitumor activity both as monotherapy and in combination with ribociclib, regardless of ESR1 mutation status. Palazestrant
showed no clinically meaningful drug interactions with ribociclib, and the combination safety profile was consistent with
the known profiles of each drug. OPERA-02 (NCT07085767) is a phase 3, international, multicenter, randomized, doubleblind study evaluating the efficacy and safety of palazestrant plus ribociclib versus letrozole plus ribociclib as first-line
treatment for ER+, HER2- ABC. Approximately 1,000 patients will be randomized 1:1 to palazestrant plus ribociclib or
letrozole plus ribociclib, with matching placebos. The primary endpoint is investigator-assessed PFS; secondary endpoints
are OS, PFS by blinded independent review committee, overall response rate, duration of response, clinical benefit rate,
safety, pharmacokinetics, patient-reported outcomes, and PFS2. Adults with de novo or recurrent endocrine therapysensitive disease and no prior systemic therapy for ABC are eligible. Patients must have measurable disease or evaluable
bone disease, ECOG 0–1, and adequate organ function. Those with contraindication to ribociclib were excluded. Pre- or
perimenopausal women and men must receive gonadotropin-releasing hormone agonists. The study is recruiting globally.