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

Inclusion Criteria:

1. Locally advanced unresectable or metastatic adenocarcinoma of the breast, notamenable to treatment with curative intent

2. Documented estrogen receptor-positive (ER+) tumor and HER2-negative tumor, assessedlocally

3. Ability to provide a blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) Estrogen Receptor 1 (ESR1) mutation status determination by central testing

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

• Metastatic setting: Disease progression after ≥6 months on ET plus CDK4/6inhibitor in the locally advanced or metastatic setting. If ET plus CDK4/6inhibitor is not the most recent therapy, then patient must also have haddisease progression after ≥4 months on most recent ET

• Adjuvant Setting: Relapse either while taking or within 12 months of exposureto combination adjuvant ET and CDK4/6 inhibitor. Patients must have taken atleast 12 months of adjuvant ET, 6 months of which was in combination with aCDK4/6 inhibitor.

5. 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 ofthe bone must have at least one predominantly lytic bone lesion confirmed bycomputed tomography (CT) or magnetic resonance imaging (MRI) which can be followed

6. Eastern Cooperative Oncology Group Performance Status 0-1

7. For women who are premenopausal or perimenopausal and for men: treatment withapproved luteinizing hormone-releasing hormone (LHRH) agonist therapy for theduration of study treatment

Exclusion Criteria:

1. Prior treatment with another oral selective estrogen receptor degrader (SERD),proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), novel oral selective estrogen receptor modulator (SERM), or everolimus inany setting. Prior fulvestrant is allowed if treatment was terminated at least 28days prior to randomization. Prior treatment with tamoxifen is allowed.

2. Progression on more than 2 prior lines of systemic endocrine therapy in the locallyadvanced unresectable or metastatic breast cancer setting

3. Prior chemotherapy for locally advanced unresectable or metastatic disease

4. Treatment with strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 14days or 5 drug elimination half-lives (whichever is longer) prior to randomization

5. Treatment with any investigational therapy within 28 days prior to initiation ofstudy treatment

6. Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14days prior to randomization

7. History of any other malignancy other than breast cancer within 5 years prior toscreening, except for appropriately treated carcinoma in situ of the cervix,nonmelanoma skin carcinoma, papillary thyroid cancer treated with surgery, Stage Iendometrial cancer, or other non-breast cancers at very low risk of recurrence

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

9. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,carcinomatous meningitis, or leptomeningeal disease

10. Active cardiac disease or history of cardiac dysfunction

11. Known clinically significant history of liver disease consistent with Child-PughClass B or C including active viral or other hepatitis virus, current alcohol abuse,or cirrhosis

12. Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or majorupper gastrointestinal (GI) surgery including gastric resection

13. Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy

14. Serious infection requiring oral or intravenous (IV) antibiotics, or otherclinically significant infection, within 14 days prior to randomization

15. Any serious medical condition or abnormality in clinical laboratory tests that, inthe investigator's judgment, precludes the patient's safe participation in andcompletion of the study

16. Known allergy or hypersensitivity to any of the study drugs or any of theirexcipients

17. For premenopausal or perimenopausal women and for men: known hypersensitivity toLHRH agonists

18. Pregnant or breastfeeding