Abstract BACKGROUND Endocrine therapy (ET) modulates estrogen synthesis and/or estrogen receptor (ER) activity and is the mainstay of ER+ breast cancer (BC) treatment. ET + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in patients (pts) with ER+, HER2– metastatic BC (mBC) in the first-line setting. Fulvestrant ± a CDK4/6i, and everolimus + exemestane, are the current regimens approved for use in the second-line setting. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1 mutation status. While phase I SERD combination data in the post CDK4/6 setting is encouraging, there is no randomized combination data. Combining giredestrant and everolimus may potentially improve outcomes after CDK4/6is and in pts with ESR1-mutated tumors; evERA BC is investigating this combination to address the unmet need in the post-CDK4/6i setting. TRIAL DESIGN This phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs exemestane + everolimus in pts with ER+/HER2– locally advanced (LA)/mBC who had previous treatment with a CDK4/6i and ET in the LABC/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD) on Days 1–28 of each 28-day cycle, or exemestane (25 mg) + everolimus (10 mg) PO QD on Days 1–28 of each 28-day cycle. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse four times QD for 8 weeks, started concurrently with study treatment. ELIGIBILITY Female/male pts ≥18 years with ER+/HER2– LA/mBC, an Eastern Cooperative Oncology Group Performance Status of 0–1, measurable disease defined per RECIST v.1.1 (or evaluable bone metastases with at least one predominantly lytic bone lesion confirmed by computed tomography or magnetic resonance imaging), disease progression ≥6 months after initiating ET + CDK4/6i in the LABC/mBC setting (and ≥4 months on most recent ET, if ET + a CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 months of exposure to combination adjuvant ET (≥12 months) and a CDK4/6i (≥6 months). Availability of a baseline blood sample to determine ESR1 mutation status by circulating tumor DNA assay for testing at a central laboratory. Men and pre-/perimenopausal women will receive a luteinizing hormone-releasing hormone agonist on Day 1 of each 28-day cycle. AIMS Primary endpoint: investigator-assessed progression-free survival (PFS; per RECIST v1.1). Secondary endpoints: investigator-assessed PFS in pts with detectable ESR1-mutated tumors in circulating tumor DNA at baseline; overall survival; objective response rate; duration of response; clinical benefit rate; patient-reported outcomes; safety; pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An independent data monitoring committee will be in place for safety. ACCRUAL Target enrollment is 224 pts globally, and this study is currently recruiting. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05306340. Citation Format: Erica L. Mayer, Sara Tolaney, Adam M. Brufsky, William Gradishar, Komal Jhaveri, Miguel Martín, Luca Moscetti, Gregory Vidal, Patricia Cortazar, Merilin Feldman, Bann-mo Day, Hope Rugo. evERA Breast Cancer: A phase III study of giredestrant (GDC-9545) + everolimus vs exemestane + everolimus in patients with estrogen receptor+, HER2– locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-07.