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)

Progression-Free Survival (PFS) in the ESR1 mutation (ESR1m) Subgroup

Timeframe: From randomization to first occurrence of progressive disease (PD) or death (up to 5 years)

PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), or death from any cause during the study.

PFS in the Full Analysis Set (FAS) Population

Timeframe: From randomization to first occurrence of PD or death (up to 5 years)

PFS in the ESR1 no-mutation-detected (ESR1nmd) Subgroup

Timeframe: From randomization to first occurrence of PD or death (up to 5 years)

Overall Survival (OS)

Timeframe: From randomization until death from any cause (up to 5 years)

OS is defined as the time from randomization to death from any cause. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

Confirmed Objective Response Rate (cORR)

Timeframe: From randomization until treatment discontinuation (up to 5 years)

The cORR is defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart, as determined by the investigator according to RECIST v1.1. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

Duration of Response (DOR)

Timeframe: From the first occurrence of a documented objective response to PD or death (up to 5 years)

DOR is defined as the time from the first occurrence of a documented objective response to PD, as determined by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

Clinical Benefit Rate (CBR)

Timeframe: From randomization until treatment discontinuation (up to 5 years)

The CBR is defined as the percentage of participants with stable disease for at least (≥)24 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

Time to Chemotherapy

Timeframe: From randomization until the start of chemotherapy or death (up to 5 years)

Time to chemotherapy is defined as the time from randomization until the start date of the first chemotherapy or death from any cause (whichever occurs first). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

Time to Confirmed Deterioration (TTCD) in Pain Severity

Timeframe: From randomization until end of follow-up (up to 5 years)

TTCD in pain severity is defined as the time from randomization to the first documentation of ≥2-point increase from baseline on the "worst pain" item score of the Brief Pain Inventory-Short Form (BPI-SF). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

TTCD in Pain Presence and Interference

Timeframe: From randomization until end of follow-up (up to 5 years)

TTCD in pain presence and interference is defined as the time from randomization to the first documentation of ≥10-point increase in pain score, as determined using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

TTCD in Physical Functioning

Timeframe: From randomization until end of follow-up (up to 5 years)

TTCD in physical functioning (PF) is defined as the time from randomization to the first documentation of ≥10-point decrease in PF score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

TTCD in Role Functioning

Timeframe: From randomization until end of follow-up (up to 5 years)

TTCD in role functioning (RF) is defined as the time from randomization to the first documentation of ≥10-point decrease in RF score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

TTCD in Global Health Status/Quality of Life

Timeframe: From randomization until end of follow-up (up to 5 years)

TTCD in in Global Health Status/Quality of Life (GHS/QoL) is defined as the time from randomization to the first documentation of ≥10-point decrease in GHS/QoL score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.

Incidence and Severity of Adverse Events

Timeframe: From Baseline until 28 days after the final dose of study treatment (up to 5 years)

Incidence will be reported as the number of participants with at least one adverse event, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0).

Number of Participants with Vital Sign Abnormalities Over the Course of the Study

Timeframe: From Baseline until 28 days after the final dose of study treatment (up to 5 years)

Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.

Number of Participants with Clinical Laboratory Test Abnormalities for Hematology and Biochemistry Parameters Over the Course of the Study

Timeframe: From Baseline until 28 days after the final dose of study treatment (up to 5 years)