The purpose of this study is to evaluate use of lovastatin, a drug that may lower CAV-1 levels, in order to increase HER2 expression on cells and enhance the uptake and efficacy of trastuzumab deruxtecan (T-DXd) in HER2-low and ultralow advanced metastatic breast cancer. Trastuzumab deruxtecan (T-DXd) is an FDA approved antibody drug conjugate for HER2-low and ultralow breast cancer and lovastatin is a cholesterol lowering agent.

Inclusion Criteria:

• Histologically or cytologically confirmed HER2 low (IHC 1+ or 2+ with negative in-situ hybridization) or ultralow (IHC 0 with incomplete/faint membrane staining in >0 but ≤10% of tumor cells) breast cancer. Patients may be advanced/unresectable or metastatic.

• Patients must have received no more than 1 prior line of chemotherapy (e.g. capecitabine). There is no limit on the prior number of endocrine-based therapies for patients with hormone-receptor positivity.

• Measurable disease per RECIST 1.1.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9.0 g/dL
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Creatinine clearance > 30 mL/min by Cockcroft-Gault

• The effects of T-DXd and lovastatin on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 7 months after the last dose of either study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.

• Patients must have left ventricular ejection fraction (LVEF) of ≥50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before C1D-1.

• Agreement to adhere to Lifestyle Considerations throughout study duration

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior treatment with T-DXd or other topoisomerase I ADC including sacituzumab govitecan, datopotamab deruxtecan, or investigational ADCs with topoisomerase I payloads.
• Prior statin use within 7 days prior to C1D-1.
• Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade ≤1 or baseline. Participants with chronic grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Study PI or designee (e.g., grade 2 chemotherapy-induced neuropathy).
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
• Currently receiving any other investigational agents, or receipt of any investigational agents within 3 weeks or 5 half-lives, whichever is shorter, prior to C1D-1.
• Receipt of chemotherapy, immunotherapy, endocrine therapy, or other systemic anticancer therapy within 3 weeks or 5 half-lives, whichever is shorter, prior to C1D-1.
• Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression, and patients are not taking steroids to control edema or other symptoms.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to T-DXd, lovastatin, or other agents used in the study.
• Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e. Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy.
• Patients with a history of non-infectious ILD/pneumonitis that required steroids or has current ILD/pneumonitis. Patients with a history of infectious ILD/pneumonitis should be discussed with the study PI.
• Prior intolerance to statin therapy, defined as intolerable muscle symptoms or significant transaminitis elevation (>3x ULN) or CK elevation (>5x ULN) attributed to statin therapy within the last 2 years prior to C1D-1.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or clinically significant cardiac arrhythmia.
• History or current significant cardiovascular disease, stroke, severe dyslipidemia, or vascular disorders that require continuous statin dosing. Uncertain cases should be discussed with the study PI for clarification of eligibility.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of C1D1.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
• Use of strong inhibitors of CYP3A4 within 5 half-lives of the medication prior to C1D-1.