Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1m Before Progression (SERENA-6)

INCLUSION CRITERIA: INFORMATION FOR TRIAL PARTICIPANTS - Participants can join the trial if they: * Have advanced breast cancer that is not able to be treated with surgery or radiation; * Have an ESR1 mutation in their cancer; * Have breast cancer that is HR-positive and HER2-negative; * Are currently being treated with a CDK4/6 inhibitor and an AI and have been taking these drugs for at least 6 months; * Have not had their cancer get worse after taking an AI and CDK4/6 inhibitor; * Are able to do their daily activities; * Are at least 18. Full list of inclusion criteria: * Proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent; * Documentation of histologically confirmed diagnosis of estrogen receptor positive (ER+) /HER2- breast cancer based on local laboratory results; * Currently on AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib, abemaciclib or ribociclib) ± LHRH as the initial endocrine based treatment for advanced disease; * Eastern Cooperative Oncology Group performance status of 0 or 1; * ESR1m detected by central testing of ctDNA with Guardant360® CDx; * Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures; * Adequate organ and marrow function. EXCLUSION CRITERIA: INFORMATION FOR TRIAL PARTICIPANTS - Participants cannot join the trial if they: * Had certain types of tumors in the past that may come back; * Are currently taking any other treatments for their cancer or other conditions including hormone replacements, medications, or supplements that could interfere with the trial treatment; * Have or have had any major health problem, infection, or recent surgery that could make it difficult or dangerous to participate in this trial. Full list of exclusion criteria: * Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term; * Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease; * Any evidence of severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol; * Patient with known or family history of severe heart disease; * Previous treatment with AZD9833, investigational SERDs or fulvestrant; * Currently pregnant (confirmed with positive pregnancy test) or breastfeeding; * Persistent non-haematological toxicities (CTCAE Grade \> 2) caused by CDK4/6 inhibitor and/or AI treatment.