Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.