Background: Despite best management with standard ETs, ≤ 20% of pts with ER+, HER2– eBC develop resistance (due to ESR1 mutations that can drive estrogen-independent transcription and proliferation) and have high recurrence rates. New treatments are needed to reduce recurrence risk and improve survival, tolerability, quality of life, and adherence. Giredestrant, a highly potent, nonsteroidal oral selective ER antagonist and degrader, achieves robust ER occupancy and is active against ER-sensitive or ESR1-mutated tumors. It is more potent in vitro and achieves higher ER occupancy in vivo than fulvestrant. Early-phase studies showed that 30 mg daily as a single agent has promising clinical and pharmacodynamic activity and is well tolerated for ER+, HER2– BC. Methods: lidERA BC (NCT04961996) is a Phase III, global, randomized, open-label, multicenter study evaluating adjuvant giredestrant vs. PCET in ER+, HER2– eBC. Pts are randomized 1:1 to oral 30 mg daily giredestrant or PCET (tamoxifen, anastrozole, letrozole, or exemestane; per prescribing information). Stratification factors: Risk (medium vs. high, based on anatomic [tumor size, nodal status] and biologic features [grade, Ki67, gene signatures if available]); geographic region (US/Canada/Western Europe vs. Asia-Pacific vs. rest of the world); prior chemotherapy (no vs. yes); menopausal status (pre-/peri- vs. postmenopausal). Pts will be treated for ≥ 5 years. Continuing PCET > 5 years is per investigator discretion and local standard of care. Eligibility: Female/male; medium-/high-risk stage I–III ER+, HER2– eBC; prior curative surgery; completion of (neo)adjuvant chemotherapy (if given) and/or surgery < 12 months before enrollment; no prior ET (≤ 12 weeks of [neo]adjuvant ET allowed). For men and pre-/perimenopausal women, an LHRH agonist will be given per local prescribing information (mandatory for the giredestrant arm). Primary endpoint: Invasive disease-free survival (IDFS, excluding second non-primary BC). Secondary endpoints: Overall survival; IDFS (STEEP definition, including second non-primary BC); disease-free survival; distant recurrence-free survival; locoregional recurrence-free interval; safety; pharmacokinetics; pt-reported outcomes. This study also aims to improve health equity in research and expand clinical trial access. It will use/develop digital healthcare solutions, enabling better understanding of pts’ needs and adherence to ET. The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). Interim and futility analyses are planned; an independent data monitoring committee will be in place. 2950/4100 pts have been recruited globally. Clinical trial information: NCT04961996.