This phase 3 clinical trial compares the safety and efficacy of palazestrant (OP-1250) to the standard-of-care options of fulvestrant or an aromatase inhibitor in women and men with breast cancer whose disease has advanced on one endocrine therapy in combination with a CDK4/6 inhibitor.

This is an international, multicenter, randomized, open-label, active-controlled, phase 3 clinical trial. The purpose of this trial is to compare the safety and efficacy of palazestrant (OP-1250) as a single agent to the standard of care endocrine therapy: either fulvestrant or an aromatase inhibitor (anastrozole, letrozole, or exemestane).

This trial is seeking adult participants with ER+, HER2- advanced or metastatic breast cancer whose disease has relapsed or progressed on 1 or 2 prior lines of standard-of-care endocrine therapy for metastatic breast cancer. Prior lines of therapy must include one line of endocrine therapy in combination with a CDK 4/6 inhibitor. In the dose-selection part of the trial, approximately 120 participants will be randomized to one of the two doses of palazestrant or to the standard-of-care endocrine therapy. Thereafter, approximately 390 participants will be randomized to palazestrant at the selected dose or to the standard-of-care endocrine therapy.

Key inclusion criteria:

• Adult female or male participants.
• ER+, HER2- locally advanced or metastatic breast cancer that is not amenable to curative therapy.
• Evaluable disease (measurable disease or bone-only disease).
• Previously received a CDK4/6 inhibitor in combination with an endocrine therapy in the advanced setting. One additional line of ET as a monotherapy is allowed. Duration of the most recent prior ET must be at least 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate hematologic, hepatic, and renal functions.
• Female participants can be pre-, peri- or postmenopausal.
• Male and pre- or peri-menopausal female participants must be willing to take a GnRH (or LHRH) agonist.

Key exclusion criteria:

• Symptomatic visceral disease, imminent organ failure, or any other reason that makes the participant ineligible for endocrine monotherapy.
• Previously received chemotherapy in the advanced/metastatic setting.
• Previously received treatment with elacestrant or an investigational estrogen receptor-directed therapy.
• History of allergic reactions to study treatment.
• Any contraindications to the selected standard-of-care endocrine therapy in the local prescribing information.
• Symptomatic central nervous system metastases, carcinomatous meningitis, leptomeningeal disease, or a spinal cord compression that require immediate treatment.
• Clinically significant comorbidities such as significant cardiac or cerebrovascular disease, gastrointestinal disorders that could affect absorption of study treatment.