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)

Open to people ages 18 years and up

• Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
• Documented estrogen receptor-positive (ER+), HER2-negative (HER2-) tumor assessed locally on the most recent tumor biopsy (or an archived tumor sample if a recent tumor sample is not available for testing)
• Confirmed ESR1 mutation status (ESR1m versus ESR1nmd) in baseline circulating tumor DNA (ctDNA) through central laboratory testing
• Resistance to prior adjuvant endocrine therapy (ET). Prior use of neo/adjuvant CDK4/6i is allowed.
• No prior systemic anti-cancer therapy for advanced disease
• Measurable disease as defined per RECIST v.1.1 or non-measurable (including bone-only) disease
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
• For pre/perimenopausal women and for men: willing to undergo and maintain treatment with approved LHRH agonist therapy (as per local guidelines) for the duration of study treatment

• Prior systemic therapy (e.g., prior chemotherapy, immunotherapy, or biologic therapy) for locally advanced unresectable or metastatic breast cancer
• Prior treatment with another SERD (e.g., fulvestrant, oral SERDs) or novel ER-targeting agents
• Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
• Active cardiac disease or history of cardiac dysfunction
• Clinically significant history of liver disease