A Study of Tucatinib or Placebo With Trastuzumab and Pertuzumab for Metastatic HER2+ Breast Cancer

Inclusion Criteria: * Centrally confirmed HER2+ breast carcinoma according to the 2018 American Society of Clinical Oncologists (ASCO) College of American Pathologists (CAP) guidelines prior to randomization (defined as a 3+ score on immunohistochemistry (IHC) and/or 2+ IHC and concurrent positive by ISH). * Have unresectable locally advanced or metastatic disease. * If recurrent (after \[neo\]adjuvant therapy), must be at least 6 month treatment free from any trastuzumab and pertuzumab received in the early breast cancer setting for advanced HER2+ disease. * Have received 4-8 cycles of pre-study induction therapy including only trastuzumab, pertuzumab, and taxane as first-line of therapy for the treatment of advanced breast cancer prior to study enrollment. Participants are eligible provided they are without evidence of disease progression following completion of induction therapy. * Known hormone receptor status (per local guidelines; may be hormone receptor positive \[HR+\] or negative \[HR-\]) * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * CNS Inclusion - Based on screening contrast-enhanced brain magnetic resonance imaging (MRI), participants may have any of the following: * No evidence of brain metastases * Untreated brain metastases which are asymptomatic not needing immediate local treatment and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane * Previously treated brain metastases which are asymptomatic * Brain metastases previously treated with local therapy must not have progressed since treatment Exclusion Criteria: * Prior treatment with any tyrosine kinase inhibitor targeting HER2 and/or epidermal growth factor receptor (EGFR) including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and ≥ 12 months have elapsed since last neratinib dose prior to start of study drug) * Unable to undergo contrast-enhanced MRI of the brain * CNS Exclusion - Based on screening brain MRI and clinical assessment * Symptomatic brain metastasis after CNS-directed local therapy * Progression of brain metastases since starting first line trastuzumab, pertuzumab, and taxane * Ongoing use of systemic corticosteroids at a total daily dose of \>2 mg of dexamethasone (or equivalent) * Any untreated brain lesion in an anatomic site which may pose risk to participant * Known or suspected leptomeningeal disease (LMD) * Poorly controlled (\>1/week) seizures, or other persistent neurologic symptoms