The main purpose of this study is to measure how well imlunestrant works compared to standard hormone therapy in participants with early breast cancer that is estrogen receptor positive (ER+) and human epidermal receptor 2 negative (HER2-). Participants must have already taken endocrine therapy for two to five years and must have a higher-than-average risk for their cancer to return. Study participation could last up to 10 years.

Inclusion Criteria:

• Have a diagnosis of ER+, HER2- early-stage, resected, invasive breast cancer without evidence of distant metastasis.
• Participants must have received at least 24 months but not more than 60 months of any adjuvant ET, from time of adjuvant ET initiation.
• Participants may have received (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor.
• Must have an increased risk of disease recurrence based on clinical-pathological risk features.
• Have a Performance Status of 0 or 1 on the Eastern Cooperative Oncology Group scale.
• Have adequate organ function.

Exclusion Criteria:

• Have any evidence of metastatic disease (including contralateral ALN) or inflammatory breast cancer at primary breast cancer diagnosis.
• Participants with more than a 6-month consecutive gap in therapy during the course of prior adjuvant ET.
• Participants who have completed or discontinued prior adjuvant ET >6 months prior to screening.
• Participants with a history of previous breast cancer are excluded, with the exception of ipsilateral DCIS treated by locoregional therapy alone ≥5 years ago.
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study intervention.
• Participant has previously received ET of any duration for breast cancer prevention (tamoxifen or AIs) or raloxifene.
• Participants with a history of any other cancer.
• Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study.

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later. Data will be indefinitely available for requesting.

A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.