Palazestrant and Ribociclib versus Letrozole and Ribociclib for First-line Treatment of ER+/HER2- Advanced Breast Cancer

The primary objective is to compare progression-free survival (PFS), as determined by local investigator assessment, between the investigational arm receiving palazestrant with ribociclib and the control arm receiving letrozole with ribociclib in patients with ER+, HER2- advanced breast cancer. 5

Secondary objectives include:

• Comparison of overall survival (OS) between the two study arms.
• Evaluation of PFS, objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR) using assessments from a Blinded Independent Review Committee (BIRC).
• Evaluation of ORR, DOR, and CBR via local investigator assessment.
• Assessment of safety and tolerability. 4
• Evaluation of the pharmacokinetics (PK) of palazestrant and ribociclib. 6
• Analysis of changes from baseline in patient-reported outcomes (PRO) related to health.
• Evaluation of PFS2.

This study involves 644 participants diagnosed with ER+, HER2- advanced breast cancer. The study population consists of adults, including both males and females, regardless of menopausal status. Eligible participants must present with locally advanced or metastatic breast cancer that is not amenable to curative therapy. The population includes individuals with de novo disease or recurrence following at least 12 months of adjuvant endocrine therapy. Inclusion requires measurable disease according to RECIST 1.1 or bone-only disease. Participants must demonstrate an ECOG performance status of 0 or 1 and possess adequate hematologic, hepatic, and renal functions. Male participants and pre- or peri-menopausal females are required to undergo treatment with a GnRH agonist.

This phase 3, randomized, double-blind, active-controlled study is designed to evaluate the efficacy and safety of palazestrant combined with ribociclib compared to letrozole combined with ribociclib for the first-line treatment of ER+, HER2- advanced breast cancer. The investigational arm consists of palazestrant and ribociclib plus a letrozole-matching placebo, while the control arm consists of letrozole and ribociclib plus a palazestrant-matching placebo. Participants receiving endocrine therapy must also receive a gonadotropin-releasing hormone analogue. The primary endpoint is progression-free survival as assessed by a local investigator. Secondary endpoints include overall survival, objective response rate, duration of response, clinical benefit rate, safety, tolerability, and pharmacokinetics. The study is estimated to occur between February 2026 and September 2032.

Ribociclib is administered as an oral medication at a dosage of 600 mg.

Palazestrant, also referred to as OP-1250, is provided in the pharmaceutical form of a film-coated tablet and administered at an oral dose of 90 mg.

Letrozole is utilized as a comparator treatment and is administered at an oral dose of 2.5 mg.

Background therapy consists of gonadotropin-releasing hormone analogues administered via implantation at a dosage of 3.6 mg.

Placebo is utilized in the form of Palazestrant matching placebo tablets and Letrozole matching placebo capsules.

The primary efficacy endpoint is progression-free survival, which is evaluated via local investigator assessment. Secondary endpoints include overall survival, objective response rate, duration of response, and clinical benefit rate. These parameters are assessed through both local investigator and blinded independent central review methods.

Additional efficacy evaluations include:

• The time from randomization to disease progression on the first subsequent systemic anti-cancer therapy or death.
• Patient-reported outcomes, measured using the EORTC QLQ-C30, EORTC QLQ-BR42, and EQ-5D-5L questionnaires.
• Pharmacokinetic parameters, determined by measuring plasma levels of palazestrant and ribociclib in the investigational arm, and ribociclib in the control arm, at predefined intervals.