A Study to Evaluate Efficacy and Safety of Giredestrant Compared With Fulvestrant (Plus a CDK4/6 Inhibitor), in Participants With ER-Positive, HER2-Negative Advanced Breast Cancer Resistant to Adjuvant Endocrine Therapy (pionERA Breast Cancer)

Inclusion Criteria:

• Locally advanced or metastatic adenocarcinoma of the breast, not amenable totreatment with curative intent

• Documented estrogen receptor-positive (ER+), HER2-negative (HER2-) tumor assessedlocally on the most recent tumor biopsy (or an archived tumor sample if a recenttumor sample is not available for testing)

• Confirmed ESR1 mutation status (ESR1m versus ESR1nmd) in baseline circulating tumorDNA (ctDNA) through central laboratory testing

• Resistance to prior adjuvant endocrine therapy (ET), which is defined as havingrelapsed with prior standard adjuvant ET, on-treatment after >/=12 months oroff-treatment within 12 months of completion. Prior use of adjuvant CDK4/6i isallowed (if relapse occurred >/=12 months since completion).

• No prior systemic anti-cancer therapy for advanced disease

• Measurable disease as defined per RECIST v.1.1 or non-measurable (includingbone-only) disease

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1

• For pre/perimenopausal women and for men: willing to undergo and maintain treatmentwith approved LHRH agonist therapy (as per local guidelines) for the duration ofstudy treatment

Exclusion Criteria:

• Prior systemic therapy (e.g., prior chemotherapy, immunotherapy, or biologictherapy) for locally advanced unresectable or metastatic breast cancer

• Prior treatment with another SERD (e.g., fulvestrant, oral SERDs) or novelER-targeting agents

• Advanced, symptomatic, visceral spread that is at risk of life-threateningcomplications in the short term

• Active cardiac disease or history of cardiac dysfunction

• Clinically significant history of liver disease