Testing the Drug Atezolizumab or Placebo With Usual Therapy in First-Line HER2-Positive Metastatic Breast Cancer

This randomized phase III trial studies how well paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab works in treating patients with breast cancer that has spread to other parts of the body (metastatic). Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab is a form of "targeted therapy" because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Monoclonal antibodies, such as pertuzumab, may interfere with the ability of cancer cells to grow and spread. Immunotherapy with monoclonal antibodies, such as atezolizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab may kill more tumor cells.

\*NOTE: This study has a central confirmation step. The purpose of this step is to confirm by central testing that the patient's tumor has specific receptors. If the patient meets all the study requirements, the patient will join the study and begin therapy for breast cancer while the tumor is being tested.

PRIMARY OBJECTIVE:

I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the progression-free survival (PFS), assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, relative to the addition of a placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) in patients with newly documented HER2-positive measurable metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall survival (OS) relative to the addition of placebo to a regimen of pertuzumab and trastuzumab, combined with a taxane (paclitaxel or docetaxel).

II. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall objective response (OR) in the cohort of patients randomized 6 months or more prior to study accrual closure assessed by investigator using RECIST 1.1 criteria, relative to the addition of placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

III. To determine the immune-related toxicity profile of the two treatment regimens.

IV. To determine the cardiac safety profile of the two treatment regimens.

EXPLORATORY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will decrease the incidence of subsequent brain metastases in patients without known brain metastases at study entry relative to the addition of a placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

II. To determine the utility of PD-L1 immunohistochemistry (IHC) staining as a predictive and prognostic biomarker associated with clinical response, as assessed by investigator using RECIST 1.1 criteria, to atezolizumab in combination with trastuzumab and pertuzumab combined with a taxane (paclitaxel or docetaxel).

III. To identify potential biomarkers that can predict benefit from the addition of atezolizumab in patients with newly documented HER2-positive measurable metastatic breast cancer treated with a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

IV. To explore the toxicity profile of the two treatment regimens using patient-reported symptomatic adverse events in addition to standard adverse event reports.

V. To determine the feasibility and added value of frequent assessment of toxicity using Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) with electronic(e)PRO reporting.

VI. To explore whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will contribute to increased patient-reported fatigue in comparison to the addition of placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

OUTLINE:

STEP 1: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on days 1 and 22, trastuzumab IV over 30-90 minutes on days 1 and 22, and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 or docetaxel IV over 60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients may undergo a biopsy at baseline. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or bone scan at baseline.

STEP 2: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive pertuzumab IV over 30-60 minutes on days 1 and 22 of each cycle, trastuzumab IV over 30-90 minutes on days 1 and 22 of each cycle, and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 of each cycle or docetaxel IV over 60 minutes on days 1 and 22 of each cycle. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on day 22 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, prior to weeks 10, 19, 28 and then at 9, 12, 15, 18, 21, and 24 months from study entry, every 3 months through year 3, every 6 months for years 4 and 5, and then every 6 months for years 6 through 10 from study entry. Patients undergo a bone scan at baseline, every 6 months from study entry, every 6 months through year 3, and every 12 months for years 4 and 5.

ARM II: Patients receive pertuzumab, trastuzumab, and paclitaxel or docetaxel as in Arm I. Patients also receive placebo IV 30-60 minutes on day 22 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, prior to weeks 10, 19, 28 and then at 9, 12, 15, 18, 21, and 24 months from study entry, every 3 months through year 3, every 6 months for years 4 and 5, and then every 6 months for years 6 through 10 from study entry. Patients undergo a bone scan at baseline, every 6 months from study entry, every 6 months through year 3, and every 12 months for years 4 and 5.

After completion of study treatment, patients are followed up at 30 days and every 3 months for 3 years and then every 6 months for 5 years.

Eligibility Criteria:
Inclusion Criteria:

* The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
* The trial is open to female and male patients
* Patients must be \>= 18 years old
* Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Histologically confirmed adenocarcinoma of the breast with locally recurrent, unresectable disease or metastatic disease outside the central nervous system (CNS) confirmed as described below; eligible patients include those with either:

  * De novo metastatic disease presenting without prior history of HER2-positive breast cancer:

    * Diagnosis should have been made from a biopsy of a metastatic disease site, but biopsy from the breast primary or involved regional lymph nodes is acceptable if biopsy of the metastatic sites was thought to carry excessive risk for the patient
  * Locally recurrent or metastatic disease following prior therapy for early breast cancer:

    * Diagnosis must have been made from the biopsy of the locally recurrent or metastatic disease
    * There must be an interval of \>= 6 months between completion of neoadjuvant/adjuvant HER2-targeted therapy and documentation of locally recurrent or metastatic HER2-positive disease by biopsy
* Patients must have measurable disease based on RECIST 1.1, as determined by the site, which has not been irradiated to be eligible
* Patients with brain metastases are eligible if they meet ALL the following criteria:

  * Four or fewer metastatic sites to CNS
  * Largest unexcised tumor does not exceed 3 cm
  * No metastases to brain stem, midbrain, pons, medulla or the optic nerves and chiasm
  * Must have measurable disease outside the CNS, based on RECIST 1.1, as determined by the site, which has not been irradiated
  * If patient presented with symptoms from CNS metastases, the symptoms must have resolved with initiation of steroids and initial local therapy (surgery, radiation therapy, or both)
  * Must have been evaluated by Medical Oncologist and plan is to administer trastuzumab, pertuzumab, and a taxane as first-line systemic therapy
  * May have received administration of trastuzumab OR lapatinib concurrently with radiation therapy for brain metastases. Toxicities related to lapatinib if administered, should be =\< grade 1 per the CTCAE v5.0, and the lapatinib must have been completed at least 2 weeks prior to study entry
  * No history of intracranial hemorrhage or spinal cord hemorrhage
  * No neurosurgical resection or brain biopsy within 10 days prior to study entry
* After study entry and before randomization, send tissue for central HER2 confirmation; a tumor specimen obtained at the time of diagnosis of locally recurrent or metastatic disease must have been determined to be HER2-positive based on local testing according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (Wolff 2018); HER2 status should initially be assessed using an Food and Drug Administration (FDA)-cleared IHC assay; positive is defined as IHC 3+ staining intensity; if HER2 IHC results are equivocal (2+), then HER2 status will be determined using a FDA-cleared HER2 in situ hybridization (ISH) test according to ASCO/CAP guidelines; Note: Once HER2-positive is confirmed on central testing, patients will be randomized to atezolizumab/placebo; randomization within 14 days from study entry will ensure that the Pharmaceutical Management Branch (PMB)-supplied agents will be received at the site for treatment on day 22 of cycle 1
* The tumor specimen obtained at the time of diagnosis used for HER2 testing must also have central testing for PD-L1 status; patients will be eligible irrespective of PD-L1 testing result including PD-L1 indeterminant
* The tumor specimen obtained at the time of diagnosis used for HER2 and PD-L1 testing should also have central testing for estrogen receptor (ER) and progesterone receptor (PgR) according to current ASCO/CAP guideline recommendations for hormone receptor testing; patients with \< 1% ER and PgR staining by IHC will be classified as negative; if enough material for central confirmation of ER and PgR is unavailable, local testing results for ER and PgR may be used for eligibility
* Localized palliative radiation therapy to sites of non-measurable disease is allowed for symptom management and may begin prior to study entry and continue following study entry while receiving study therapy
* Patients must have imaging of the chest/abdomen/pelvis, preferably with a CT scan, and a bone scan within 5 weeks prior to study entry; (NOTE: if a patient is unable to receive CT contrast, a MRI of the abdomen/pelvis and non-contrast chest CT should be performed; positron emission tomography/computed tomography \[PET/CT\] is not an acceptable alternative)
* MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo MRI) must be obtained in patients with symptoms suggesting possible central nervous system (CNS) metastatic disease; neuroimaging is recommended but not required in asymptomatic patients
* Absolute neutrophil count (ANC) must be \>= 1200/mm\^3 (within 14 days prior to study entry)
* Platelet count must be \>= 100,000/mm\^3 (within 14 days prior to study entry)
* Hemoglobin must be \>= 8 g/dL (within 14 days prior to study entry)
* Total bilirubin must be =\< 1.5 x upper limit of normal (ULN) for the lab or direct bilirubin =\< ULN for patients with bilirubin levels \> 1.5 x ULN (within 14 days prior to study entry)
* Aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) must be =\< 2.5 x ULN for the lab or =\< 5 x ULN for patients with liver metastases (within 14 days prior to study entry)
* Serum creatinine =\< 1.5 x ULN or measured or calculated creatinine clearance \>= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine levels \> 1.5 x ULN for the lab (within 14 days prior to study entry)
* Patients not receiving anti-coagulant therapy must have prothrombin time (PT) and international normalized ratio (INR) =\< 1.5 x ULN within 14 days prior to study entry; for laboratories that do not report an ULN for the INR assay, use =\< 1.5 as the value for the ULN; patients receiving anti-coagulants should have a baseline INR assessed, but the value does not affect eligibility
* A serum thyroid-stimulating hormone (TSH) and AM (preferably in morning) cortisol must be obtained within 14 days prior to study entry to obtain a baseline value; patients with abnormal TSH or AM cortisol baseline levels should be further evaluated and managed per institutional standards; asymptomatic patients who require initiation or adjustment of medication or are followed without initiating treatment based on endocrinologist's recommendations are eligible
* Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks prior to study entry; (LVEF assessment performed by echocardiogram is preferred; however, multigated acquisition scan (MUGA) scan may be substituted based on institutional preferences); the LVEF must be \>= 50% regardless of the cardiac imaging facility's lower limit of normal
* Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of child-bearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of atezolizumab/placebo and 7 months after the last dose of trastuzumab and pertuzumab; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of study entry are eligible for this trial

Exclusion Criteria:

* Patients with brain metastases are excluded if they meet ANY of the following criteria:

  * Symptoms from brain metastases have not resolved prior to study entry
  * Five or more clearly identified foci of metastases to the brain
  * Largest unexcised tumor exceeds 3 cm
  * Spinal cord metastases
  * Medical Oncologist plans to employ HER2-directed tyrosine kinase inhibitor as component of systemic therapy
  * Metastatic disease limited to CNS
* Leptomeningeal carcinomatosis
* History of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for metastatic breast cancer (MBC) except as described in inclusion criteria
* History of exposure to cumulative doses of doxorubicin greater than 360 mg per square meter of body-surface area or its equivalent
* Prior treatment with mTOR inhibitors or CDK 4/6 inhibitors in combination with endocrine therapy for treatment of metastatic disease
* Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
* History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry
* Uncontrolled hypertension defined as sustained systolic blood pressure (BP) \> 150 mmHg or diastolic BP \> 90 mmHg; (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)
* History of asymptomatic LVEF decline to \< 40% during or after prior HER2-targeted therapy even if the current LVEF is \>= 50%
* Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens; this includes but is not confined to:

  * Active cardiac disease

    * Angina pectoris that requires the current use of anti-anginal medication;
    * Ventricular arrhythmias except for benign premature ventricular contractions;
    * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
    * Conduction abnormality requiring a pacemaker;
    * Valvular disease with documented compromise in cardiac function; or
    * Symptomatic pericarditis
  * History of cardiac disease

    * Prior myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular (LV) function;
    * History of documented congestive heart failure (CHF) defined as symptomatic heart failure with an LVEF \< 40%; or
    * Documented cardiomyopathy
* Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) \>= grade 2, per the CTCAE v 5.0
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to pertuzumab or trastuzumab or to any of its excipients, as well as any chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or other recombinant antibodies
* Known allergy or hypersensitivity to the components of the atezolizumab formulation or to any of the study drugs or excipients, (e.g., Cremophor EL, polysorbate 80)
* History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis

  * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
  * Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
  * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

    * Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
    * Rash must cover less than 10% of body surface area (BSA)
    * Disease is well controlled at baseline and only requiring low-potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
    * No acute exacerbations of underlying conditions within the last 12 months (not requiring psoralen plus ultraviolet A radiation \[PUVA\], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
* Treatment with systemic immunomodulatory medications (including but not limited to interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to study entry
* Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis \[anti-TNF\] factor agents) within 14 days prior to study entry or anticipation of need for systemic immunosuppressive medications during the study; Note: Intranasal and inhaled corticosteroids or systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or an equivalent corticosteroid are allowed
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to study entry
* Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening; patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV deoxyribonucleic acid (DNA) viral load per local guidelines
* Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV ribonucleic acid (RNA)
* Patients with clinically active tuberculosis
* Severe infection within 4 weeks prior to study entry, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
* Prior allogeneic stem cell or solid organ transplantation
* Symptomatic peripheral ischemia
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis or \>= grade 1 pulmonary fibrosis, per the CTCAE v5.0, on screening chest CT scan
* Administration of a live, attenuated vaccine within 4 weeks prior to study entry or anticipation that such vaccine will be required during the study

  * Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to study entry, during treatment or within 5 months following the last dose of atezolizumab/placebo
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
* Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results
* Pregnancy or lactation at the time of study entry or intention to become pregnant during the study; (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 3 days prior to study entry)
* Use of any investigational product within 4 weeks prior to study entry