A study to compare Giredestrant + Abemaciclib, Giredestrant + Ipatasertib, Giredestrant + Inavolisib, Giredestrant + Ribociclib, and Giredestrant + Everolimus with Giredestrant Monotherapy in people with inoperable, locally advanced or metastatic, estrogen receptor (ER)-positive breast cancer who had disease progression during or following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in the first- or second-line setting.

Inclusion Criteria for Cohort 1 (Stage 1 [and Stage 2, only where indicated]):

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Documented estrogen receptor-positive (ER+) tumor
• Patients for whom endocrine therapy is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatment guidelines
• Radiologic/objective evidence of recurrence or progression after the most recent systemic therapy for breast cancer
• Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease (note: at least one line of therapy must have contained a CDK4/6i administered for a minimum of 8 weeks prior to disease progression.)
• Postmenopausal status for women
• Life expectancy ≥3 months
• Availability of a representative tumor specimen that is suitable for biomarker evaluation via central testing
• Prior fulvestrant therapy is allowed
• Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1
• Stages 1 and 2: Adequate hematologic and end-organ function
• Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation

Inclusion Criteria for Cohort 2 (Stage 1 [and Stage 2, only where indicated]):

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection
• ER-positive, HER2-positive breast cancer
• Postmenopausal status for women
• Life expectancy ≥3 months
• Willingness to have a representative tumor specimen that is suitable for biomarker evaluation via central testing submitted, if available
• Prior endocrine therapy in the advanced setting allowed, including fulvestrant if given more than 28 days prior to randomization, but excluding other selective estrogen receptor degraders (SERDs)
• Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1
• Stages 1 and 2: Baseline left ventricular ejection fraction (LVEF) ≥50% as measured by ECHO or MUGA scans
• Stages 1 and 2: Adequate hematologic and end-organ function
• Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation

Inclusion Criteria for Cohorts 1 and 2 (Stage 2):

• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator, provided that a Stage 2 slot is available and patient meets eligibility criteria for Stage 2
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 because of unacceptable toxicity to drugs, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator

General Exclusion Criteria for all Treatment Arms in Stage 1, Cohorts 1 and 2 (unless only applicable to one cohort, as indicated):

• Prior treatment with any of the protocol-specified study treatments
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Systemic treatment for breast cancer within 2 weeks of Cycle 1, Day 1 or 5 half-lives of the drug prior to Cycle 1, Day 1
• Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to randomization
• Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤1 or better, with the exception of alopecia of any grade and Grade ≤2 peripheral neuropathy
• Eligible only for the control arm
• Prior allogeneic stem cell or solid organ transplantation
• Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
• History of malignancy other than breast cancer within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled tumor-related pain
• Uncontrolled or symptomatic hypercalcemia
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• History of leptomeningeal disease
• Active tuberculosis
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
• Active cardiac disease or history of cardiac dysfunction
• Positive HIV test at screening or at any time prior to screening
• Active Hepatitis B or Hepatitis C virus infection
• Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery, including gastric resection, potentially affecting enteral absorption
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients applicable to one cohort, as indicated):
• Cohort 1 only: Known HER2-positive breast cancer
• Cohort 1 only: Concurrent hormone replacement therapy
• Cohort 1 only: Prior treatment with cytotoxic chemotherapy for metastatic breast cancer (with the exception of single agent capecitabine, which will count as a single line of therapy)
• Cohort 2 only: Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy
• Cohort 2 only: Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone equivalent), excluding inhaled steroids

Additional Exclusion Criteria for Giredestrant + Abemaciclib Arm and Giredestrant + Abemaciclib + Atezolizumab Arm (Cohort 1, Stage 1):

• Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
• History of major surgical resection involving the stomach or small bowel, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea
• History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest

Additional Exclusion Criteria for Giredestrant + Ipatasertib Arm (Cohort 1, Stage 1):

• Prior treatment with an Akt inhibitor
• Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
• Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceremia
• History of Type 1 or Type 2 diabetes mellitus requiring insulin
• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion

Additional Exclusion Criteria for Giredestrant + Inavolisib Arm (Cohort 1, Stage 1):

• Prior treatment with any PI3K, Akt, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway
• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes
• Fasting glucose ≥126 mg/dL or ≥7.0 mmol/L and HbA1c ≥5.7%
• Any concurrent ocular or intraocular condition that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition
• Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye
• Symptomatic active lung disease, including pneumonitis
• Inability to confirm biomarker eligibility based on valid results from either central testing of blood or local testing of blood or tumor tissue that documents one of the protocol-defined PIK3CA mutations

Additional Exclusion Criteria for Giredestrant + Ribociclib Arm (Cohort 1, Stage 1):

• Currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting trial treatment
• Impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments

Additional Exclusion Criteria for Giredestrant + Samuraciclib Arm (Cohort 1, Stage 1):

• Prior treatment with mTOR inhibitor
• Receipt of systemic corticosteroids (at a dose >10 mg prednisone/day or equivalent) within 14 days before the first dose of samuraciclib
• Active bleeding diatheses
• History of hemolytic anemia or marrow aplasia
• Receipt of a live-virus vaccination within 28 days or less of planned treatment start

Additional Exclusion Criteria for Giredestrant + Atezolizumab-Containing Arms (Cohort 1, Stage 1):

• Active or history of autoimmune disease or immune deficiency
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Pregnant or breastfeeding, or intending to become pregnant during study treatment or within 5 months for atezolizumab

Additional Exclusion Criteria for Giredestrant + PH FDC SC + Abemaciclib Arm (Cohort 2, Stage 1):

• Interstitial lung disease or severe dyspnea
• History of major surgical resection involving the stomach or small bowel, preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or a condition that may significantly alter the absorption of the oral trial treatments
• History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest

Additional Exclusion Criteria for Giredestrant + PH FDC SC + Palbociclib Arm (Cohort 2, Stage 1):

• History of major surgical resection involving the stomach or small bowel, preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or a condition that may significantly alter the absorption of the oral trial treatments
• Interstitial lung disease or severe dyspnea