This study has three parts:

• 1) Screening (to determine if you are eligible for the study) - amongst other procedures, we will test your blood for mutations in ESR1, the gene for the estrogen receptor
• 2) Study drug period
• 3) Follow-up (to check on you after the study drug regimen is finished)

You will be assigned to one of the following study groups, with your assigned regimen given in drug cycles that last 4 weeks:

• Group 1 will receive giredestrant (as a pill taken every day) and the study doctor's choice of a CDK4/6 inhibitor between palbociclib or ribociclib (for both, tablets taken once a day for 3 weeks followed by 1 week off treatment), or abemaciclib (tablets taken twice a day continuously)
• Group 2 will receive fulvestrant, given as an injection twice in the first cycle and once at the start of every 4-week cycle after that, and the study doctor's choice of a CDK4/6 inhibitor between palbociclib or ribociclib (for both, tablets taken once a day for 3 weeks followed by 1 week off treatment), or abemaciclib (tablets taken twice a day continuously)

Women who have not completed menopause and men will also receive a hormonal suppression medicine known as an LHRH agonist as part of their study treatment. The group to which you are assigned will be determined by random chance (like tossing a coin). You will have an equal chance of being placed in either group. Your study doctor will discuss with you and decide which CDK4/6 inhibitor you will take for the duration of the study treatment.