A Single-arm Phase II Trial of SAcituzumab Govitecan and Trastuzumab for HER2+ Metastatic Breast Cancer After Trastuzumab dEruxtEcaN (SATEEN)

Inclusion Criteria: * Participants must have histologically or cytologically confirmed invasive breast cancer, with unresectable locally advanced or metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation. * At least one measurable lesion that can be accurately assessed at baseline by CT (MRI where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.149 (see Section 11). NOTE: If the only site of measurable of disease has been previously irradiated, there must be evidence of post-radiation progression. * Either the primary tumor or the metastasis (or both) must be HER2+ per ASCO/CAP 2018 guidelines.1 Central confirmation of HER2 status is not required. * Any ER and PR expression are permitted but must be known. * Participants must have received prior treatment with a taxane, trastuzumab, and T-DXd. These agents may have been administered in the curative or the advanced setting. Prior progression on these agents is not required. T-DXd does not need to be the most recent prior therapy. * Participants must have discontinued all chemotherapy, biologic treatment or investigational agent at least 14 days prior to study treatment initiation (any prior endocrine therapy does not require washout). * All toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade 1 or lower, except alopecia can be any grade and neuropathy can be grade 2 or lower. * Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment and also may initiate therapy with these agents on study if clinically indicated. * Prior radiation therapy must be completed at least 7 days prior to study treatment initiation, and all toxicities related to prior radiation therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified in 3.1.14. * Previously treated brain metastases are permitted, with the following provisions: (1) Prior SRS should be completed ≥ 7 days before study treatment initiation; (2) Prior WBRT should be completed ≥ 7 days before study treatment initiation. (3) Any corticosteroid use for brain metastases must have been discontinued for ≥ 7 days prior to study treatment initiation. * Pre- and postmenopausal women or male patients ≥ 18 years old. * ECOG performance status of 0 - 2 (Karnofsky \> 50%). * Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan. * Participants must have normal organ and bone marrow function as defined below: * Absolute neutrophil count ≥1,000/mcL * Platelets ≥100,000/mcL * Hemoglobin ≥ 9.0 g/dl * INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is in therapeutic range of anticoagulant * Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤2.0 x ULN in patients with documented Gilbert's Syndrome) * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤5 × institutional ULN for participants with documented liver metastases * Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/ 1.73m2 for participants with creatinine levels above institutional ULN. * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation. Childbearing potential is defined as participants who have not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus). * WOCBP must agree to use an adequate method of contraception. Contraception is required starting with the first dose of study medication through 7 months after the last dose of study medication. Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception (Appendix C). * Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment 7 months after the last dose of study treatment. * Participants must be willing to undergo a research biopsy at baseline. If disease is not safely accessible according to the treating investigator, permission to waive the mandatory baseline biopsy must be received from the sponsor-investigator. Patients must be willing to provide archival tissue for research purposes. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Prior therapy with any Trop-2 directed ADC, including sacituzumab govitecan. * Prior hypersensitivity to trastuzumab, sacituzumab govitecan, or the excipients of trastuzumab or sacituzumab govitecan. * Known history of UDP-glucuronosyltransferase 1A1 (UGT1A1) \*28 allele homozygosity, which is associated with increased risk for neutropenia and diarrhea related to irinotecan.50 UGT1A1 genotyping is not required for eligibility. Note: Concurrent administration of strong UGT1A1 inhibitors or inducers is not allowed during the study (See Section 5.5). * Known brain metastases that are untreated, symptomatic, or require corticosteroid therapy to control symptoms. * Known leptomeningeal disease. * Major surgery within 2 weeks prior to study treatment initiation. Patients must have recovered from any effects of any recent major surgery. * Individuals with a history of a second malignancy are ineligible except for the following circumstances: * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy. * Individuals with the following cancers that have been diagnosed and treated within the past 3 years are eligible: cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer of the skin. * Patients with other cancers diagnosed within the past 3 years and felt to be at low * risk of recurrence should be discussed with the study principal investigator to determine eligibility. * Uncontrolled, significant intercurrent or recent illness including, but not limited to, ongoing or active infection, uncontrolled non-malignant systemic disease, uncontrolled seizures, or psychiatric illness/social situation that would limit compliance with study requirements in the opinion of the treating investigator. * Participants who are pregnant or breast-feeding are not eligible for enrollment.