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:

• Histologically or cytologically confirmed and documented human epidermal growthfactor receptor 2 (HER2)-positive/estrogen receptor (ER)-positive adenocarcinoma ofthe breast with metastatic or locally-advanced disease not amenable to curativeresection

• At least one measurable lesion and/or non-measurable disease evaluable according toResponse Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• Disease-free interval from completion of adjuvant or neoadjuvant systemicnon-hormonal treatment to recurrence of ≥6 months

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

• Left ventricular ejection fraction (LVEF) of at least (≥)50% measured byechocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)

• Adequate hematologic and end-organ function

• For women of childbearing potential: Participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agree to refrainfrom donating eggs, during the treatment period and for 7 months after the finaldose of Phesgo

• For men: participants who agree to remain abstinent (refrain from heterosexualintercourse) or use a condom, and agree to refrain from donating sperm, during thetreatment period and for 7 months after the final dose of Phesgo to avoid exposingthe embryo

Maintenance Phase Inclusion Criteria

• Complete a minimum of four cycles to a maximum of eight cycles of induction therapy;the minimum cycles are defined as either: Phesgo injections + 4 docetaxel infusions,or Phesgo injections + 12 paclitaxel infusions

• 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 assessmentduring the induction therapy phase

• LVEF of ≥50% at the last assessment during the induction therapy phase

Exclusion Criteria:

• 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-agentendocrine therapy given in the metastatic or locally advanced setting will beallowed.

• Prior treatment with a selective estrogen receptor degrader (SERD)

• Previous treatment with approved or investigative anti-HER2 agents in any breastcancer treatment setting, except Phesgo (or trastuzumab SC with pertuzumab IV, orpertuzumab and trastuzumab IV), single-agent trastuzumab IV or SC, ado-trastuzumabemtansine, lapatinib, and neratinib in the neoadjuvant or adjuvant setting

• Disease progression within 6 months of receiving adjuvant anti-HER2 therapy (such astrastuzumab, with or without pertuzumab [IV, SC, or fixed-dose combination], orado-trastuzumab emtansine, or neratinib)

• Non-resolution of all acute toxic effects of prior anti-cancer therapy or surgicalprocedures to National Cancer Institute Common Terminology Criteria for AdverseEvents version 5.0 (NCI CTCAE v5.0) Grade 1 or better

• History of persistent Grade ≥2 (NCI-CTC, Version 5.0) hematological toxicityresulting from previous adjuvant or neo-adjuvant therapy

• 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.

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

• Dyspnea at rest due to complications of advanced malignancy, or other diseaserequiring continuous oxygen therapy

• Pregnant or breastfeeding, or intending to become pregnant during the study orwithin 7 months after the final dose of Phesgo (Women of childbearing potential musthave a negative serum pregnancy test result within 14 days prior to initiation ofinduction therapy).

• Treated with investigational therapy within 28 days prior to initiation of inductiontherapy

• Treated with localized palliative radiotherapy within 14 days prior to initiation ofinduction therapy

• Concurrent participation in any other therapeutic clinical trial

• Known hypersensitivity to any of the study medications or to excipients ofrecombinant human or humanized antibodies

• Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone or equivalent)

• Poorly controlled hypertension

• Known clinically significant history of liver disease consistent with Child-PughClass B or C, active liver disease including active viral or other hepatitis virus,autoimmune hepatic disorders, or sclerosing cholangitis, current alcohol abuse, orcirrhosis

• Active cardiac disease or history of cardiac dysfunction

• Major surgical procedure or significant traumatic injury within 14 days prior toenrollment or anticipation of need for major surgery during induction therapy

• Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or majorupper gastrointestinal surgery

• Concurrent, serious, uncontrolled infections, or known infection with HIV with thefollowing exception: Individuals who are HIV positive are eligible provided they arestable on anti-retroviral therapy for ≥4 weeks, have a CD4 count ≥350 cells/uL, andhave an undetectable viral load and no history of AIDS-defining opportunisticinfections within 12 months prior to enrollment.

• Serious COVID-19 infection within 14 days prior to enrollment; however, no screeningtesting for SARS-CoV-2 is required

• Serious infection requiring oral or IV antibiotics within 7 days prior to screening

• Any serious medical condition or abnormality in clinical laboratory tests thatprecludes an individual's safe participation in the study

• History of malignancy within 5 years prior to screening with the exception of thecancer under investigation in this study and malignancies with a negligible risk ofmetastasis or death

• For pre- and perimenopausal women, and men: Known hypersensitivity to luteinizinghormone-releasing hormone agonist (LHRHa); Not willing to undergo and maintaintreatment with approved LHRHa therapy for the duration of endocrine therapy thatrequires gonadal function suppression

• Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5drug-elimination half-lives, whichever is longer, prior to initiation ofgiredestrant treatment in Arm B

• A documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism,including deep vein thrombosis, unless the condition is adequately treated and undercontrol