Following changes were made: •Added details on information for demography and added follicle stimulating hormone (FSH) test. •Added one blood sample for SAR439859 treatment arms to investigate allelic variants of drug metabolising enzymes and/or drug transporters. •Revised core-cut biopsy from surgery specimen. •For clinical sites reporting Ki67 expression by range rather than single value, local re-evaluation might be requested to confirm Ki67 expression >=15%.” was added. •Revised safety data language according to new approved version of investigator's brochure. •Modified inclusion criteria (IC) to add Stage I subjects and subjects intended for upfront mastectomy. •Modified IC to remove premenopausal women on gonadotropin releasing hormone analog and perimenopausal women (cessation of menses of duration less than or equal to [<=] 12 months). •Modified a breast tumor size of at least 10 millimetres (mm) in greatest dimension measured by ultrasound. •Modified exclusion criteria(EC) to recent use of hormone replacement therapy (last dose <=30 days prior to randomisation). •New EC added and drugs that were potential inhibitors of UDP-glucuronosyltransferases (UGTs) were moved to prohibited list. •The duration of sun protection for subjects taking SAR439859 was extended to during study treatment and for at least 5 days after discontinuation of SAR439859. •Dose modification criteria for SAR439859 and letrozole was modified to not allow any dose modification or reintroduction of study drug for NCI CTCAE Grade >=3 AEs. •Modified asymptomatic overdose had to be reported as a standard AE. •Diagnostic biopsy baseline sample timelines changed to within 4 weeks prior to randomisation. •The fixing time for the tumor biopsy sample was revised to 24-72 hours prior to processing and embedding at local pathology centres. •Genome-wide sequencing of DNA isolated to mutation analysis of DNA isolated from tumor biopsy. •Estradiol was removed from screening tests.

Following changes were made: •Updated protocol to reflect serial FSH measurements were required to confirm postmenopausal status for subjects who had received hormonal replacement therapy but had discontinued treatment and in absence of amenorrhea >12 months. •Added Cyclin D1 in exploratory protein biomarker panel-tested by IHC in tumor tissues. •Added Complete Cell Cycle Arrest (CCCA) as exploratory endpoint to further assess impact on proliferation; and added digital assessment of protein biomarkers. •Removed PK sampling on Day 1, Day 7, and added sampling on Day 15. •Added “or country's legal age of majority if legal adult age was >18 years old”. •Added hepatitis A/B/C viral serologies at screening. Updated to exclude subjects with known active hepatitis A/B/C, or hepatic cirrhosis. •Updated EC to remove treatment with moderate Cytochrome P450, family 3, subfamily A (CYP3A) inducers; updated list of CYP3A inducer. •Removed EC-'Treatment with strong or moderate Cytochrome P4502C8 (CYP2C8) inducers within 2 weeks before first study drug administration or 5 elimination half-lives whichever was longest and could not be replaced’. Removed prohibited concomitant therapies with regards to CYP2C8 inducers. •Added BCRP substrate in prohibited concomitant medication. •Added recommendation of using broad spectrum sunscreens filtering both UVA and UVB light exposure. •Prolonged duration of prior treatment to be recorded in eCRF to “from 30days prior to randomisation”. •Added phototoxicity reaction in AESI. •Added guidance on increase in alanine transaminase >=Grade 2 management. •Added new section describing contingency measures for regional or national emergency that was declared by government agency. •Changed statistical model from t-test to analysis of covariance model. •Updated formula of eGFR calculation and provided linkage. •Added INN name amcenestrant.