A Study to Evaluate the Efficacy and Safety of Giredestrant in Combination With Phesgo (Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf) Versus Phesgo in Participants With Locally Advanced or Metastatic Breast Cancer (heredERA Breast Cancer)

Inclusion Criteria:

1. Histologically or cytologically confirmed and documented human epidermal growth factor receptor 2 (HER2)-positive/estrogen receptor (ER)-positive adenocarcinoma of the breast with metastatic or locally-advanced disease not amenable to curative resection
2. At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
3. Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence of ≥6 months
4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
5. Left ventricular ejection fraction (LVEF) of at least (≥)50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
6. Adequate hematologic and end-organ function
7. For women of childbearing potential: Participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agree to refrain from donating eggs, during the treatment period and for 7 months after the final dose of Phesgo
8. For men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, during the treatment period and for 7 months after the final dose of Phesgo to avoid exposing the embryo

Maintenance Phase Inclusion Criteria

1. Complete a minimum of four cycles of induction therapy
2. Achieve a minimum of stable disease (SD) (or Non-complete response [CR]/Non-progressive disease [PD] for participants with non-measurable disease) (i.e., did not experience PD) according to RECIST v1.1 at the last tumor assessment during the induction therapy phase
3. LVEF of ≥50% at the last assessment during the induction therapy phase

Exclusion Criteria:

1. Previous systemic non-hormonal anti-cancer therapy in the metastatic breast cancer (MBC) or advanced breast cancer (ABC) setting. Note: Up to one line of single-agent endocrine therapy given in the metastatic or locally advanced setting will be allowed.
2. Prior treatment with a selective estrogen receptor degrader (SERD)
3. Previous treatment with approved or investigative anti-HER2 agents in any breast cancer treatment setting, except Phesgo (or trastuzumab SC with pertuzumab IV, or pertuzumab and trastuzumab IV), single-agent trastuzumab IV or SC, ado-trastuzumab emtansine, lapatinib, and neratinib in the neoadjuvant or adjuvant setting
4. Disease progression within 6 months of receiving adjuvant anti-HER2 therapy (such as trastuzumab, with or without pertuzumab [IV, SC, or fixed-dose combination], or ado-trastuzumab emtansine, or neratinib)
5. Non-resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade 1 or better
6. History of persistent Grade ≥2 (NCI-CTC, Version 5.0) hematological toxicity resulting from previous adjuvant or neo-adjuvant therapy
7. History of exposure to the following cumulative doses of anthracyclines; Doxorubicin >360 mg/m2; Liposomal doxorubicin >500 mg/m2; Epirubucin >720 mg/m2; Mitoxantrone >120 mg/m2; Idarubicin >90 mg/m2.
8. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
9. Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy
10. Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the final dose of Phesgo (Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of induction therapy).
11. Treated with investigational therapy within 28 days prior to initiation of induction therapy
12. Treated with localized palliative radiotherapy within 14 days prior to initiation of induction therapy
13. Concurrent participation in any other therapeutic clinical trial
14. Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies
15. Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone or equivalent)
16. Poorly controlled hypertension
17. Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, active liver disease including active viral or other hepatitis virus, autoimmune hepatic disorders, or sclerosing cholangitis, current alcohol abuse, or cirrhosis
18. Active cardiac disease or history of cardiac dysfunction
19. Major surgical procedure or significant traumatic injury within 14 days prior to enrollment or anticipation of need for major surgery during induction therapy
20. Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery
21. Concurrent, serious, uncontrolled infections, or known infection with HIV with the following exception: Individuals who are HIV positive are eligible provided they are stable on anti-retroviral therapy for ≥4 weeks, have a CD4 count ≥350 cells/uL, and have an undetectable viral load and no history of AIDS-defining opportunistic infections within 12 months prior to enrollment.
22. Serious COVID-19 infection within 14 days prior to enrollment; however, no screening testing for SARS-CoV-2 is required
23. Serious infection requiring oral or IV antibiotics within 7 days prior to screening
24. Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in the study
25. History of malignancy within 5 years prior to screening with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death
26. For pre- and perimenopausal women, and men: Known hypersensitivity to luteinizing hormone-releasing hormone agonist (LHRHa); Not willing to undergo and maintain treatment with approved LHRHa therapy for the duration of endocrine therapy that requires gonadal function suppression
27. Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of giredestrant treatment in Arm B
28. A documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism, including deep vein thrombosis, unless the condition is adequately treated and under control