A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With Exemestane Plus Everolimus in Participants With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (evERA Breast Cancer)

Inclusion Criteria:

Locally advanced unresectable or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
Documented estrogen receptor-positive (ER+) tumor and HER2-negative tumor, assessed locally
Availability of blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) Estrogen Receptor 1 (ESR1) mutation status determination by central testing

Prior endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors in either setting as follows:

Metastatic setting: Disease progression ≥6 months after initiating ET plus CDK4/6 inhibitor in the locally advanced or metastatic setting. If ET plus CDK4/6 inhibitor is not the most recent therapy, then patient must also have had disease progression after ≥4 months on most recent ET
Adjuvant Setting: Relapse either while taking or within 12 months of exposure to combination adjuvant ET and CDK4/6 inhibitor. Patients must have taken at least 12 months of adjuvant ET, 6 months of which was in combination with a CDK4/6 inhibitor.
Measurable disease as defined per RECIST v.1.1 or evaluable bone metastases. Patients with evaluable bone disease in the absence of measurable disease outside of the bone must have at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) which can be followed
Eastern Cooperative Oncology Group Performance Status 0-1
For women who are premenopausal or perimenopausal and for men: treatment with approved luteinizing hormone-releasing hormone (LHRH) agonist therapy for the duration of the study treatment

Exclusion Criteria:

Prior treatment with another oral selective estrogen receptor degrader (SERD), proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), or novel oral selective estrogen receptor modulator (SERM) in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization
Progression on no more than 2 prior lines of systemic endocrine therapy in the locally advanced unresectable or metastatic breast cancer setting
Prior chemotherapy for locally advanced unresectable or metastatic disease
Treatment with the multidrug efflux pump P-glycoprotein (P-gp) and strong Cytochrome P450 3A4 (CYP3A4) inhibitors within 14 days or 5 drug elimination half-lives prior to randomization
Treatment with any investigational therapy within 28 days prior to initiation of study treatment
Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days prior to randomization
History of any other malignancy other than breast cancer within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, papillary thyroid cancer treated with surgery, Stage I endometrial cancer, or other non-breast cancers at very low risk of recurrence
Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
Active cardiac disease or history of cardiac dysfunction
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C including active viral or other hepatitis virus, current alcohol abuse, or cirrhosis
Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization
Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
Known allergy or hypersensitivity to any of the study drugs or any of their excipients
For premenopausal or perimenopausal women and for men: known hypersensitivity to LHRH agonists
Pregnant or breastfeeding