A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer

Inclusion Criteria:

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
Previous progression to standard of care anti-HER2 therapies, of which one was a trastuzumab-and-taxane-based systemic therapy (including in the early setting if recurrence occurred within 6 months of finishing adjuvant therapy) and one was a HER2-targeting ADC (e.g., ado-trastuzumab emtansine or trastuzumab-deruxtecan) or a HER2-targeting TKI (e.g., tucatinib, lapatinib, pyrotinib, or neratinib)
Postmenopausal status for women
Life expectancy ≥3 months
Availability of a representative tumor specimen that is suitable for biomarker evaluation via central testing
Up to one line of 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

Exclusion Criteria:

General Exclusion Criteria for all Treatment Arms in Stage 1, Cohorts 1 and 2 (unless only

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
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
Congenital long QT syndrome or screening QTcF >480 milliseconds
History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion
Treatment with strong CYP3A4 inducers and inhibitors within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

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 any of the following substances within 7 days before randomization: concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
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):

Currently receiving any of the following substances within 7 days before randomization: Concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
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