ERADICATE: A Phase Ib/II Study of Elacestrant Plus Trastuzumab Deruxtecan in Patients With CDK4/6 Inhibitor and Endocrine-resistant HR+/HER2-low or HER2-ultralow Metastatic Breast Cancer

Inclusion Criteria: * Participants must have a histologically or cytologically confirmed diagnosis of HR+/HER2-low metastatic or unresectable locally advanced breast cancer, defined as ER ≥ 10%, any PR in the most recent sample and HER2-low (IHC 1+ or IHC 2+ and ISH non-amplified) or HER2-ultralow (IHC 0 and any membranous staining on any prior primary or metastatic sample). Cutoff values for positive/negative HER2 staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.76 * Participants must have had prior CDK4/6 inhibitor and may have any number of prior endocrine based therapies in the metastatic setting. * Participants may have progressed on up to 1 prior line of prior chemotherapy or ADC in the metastatic setting. * Participants must have measurable disease per RECIST 1.1 criteria. See Section 11 for the definition of measurable disease. Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease. * Participants must have known ESR1 mutation status in tumor or ctDNA within 6 months of enrollment to the trial. Participants must have Guardant360 CDx testing for ESR1-mutation status if status has not been validated within 60 days of registration. * Women or men age ≥18 years are eligible. * ECOG performance status ≤ 2. * Participants must have adequate organ and marrow function as defined below: * Absolute neutrophil count ≥ 1,500/µL * Platelets ≥ 100,000/µL * Hemoglobin ≥ 9.0 g/dL * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (or ≤ 2 x ULN in patients with documented Gilbert's syndrome) * AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional ULN (or \< 5 x ULN in patients with liver metastases) * Creatinine ≤ 1.5 x institutional ULN OR * Calculated creatinine clearance ≥ 45 mL/min via the Cockcroft-Gault formula for participants with creatinine levels above institutional ULN * Baseline LVEF ≥ 50% prior to registration, as measured by echocardiogram (or multiple-gated acquisition \[MUGA\] scan if an echocardiogram cannot be performed or is inconclusive). * Participants with a history of central nervous system (CNS) metastases are eligible if: Stable or untreated, asymptomatic brain metastases not needing immediate local therapy. For patients with untreated CNS lesions \> 2.0 cm on screening contrast brain MRI, discussion with and approval from the Sponsor Investigator is required prior to enrollment. 1. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator 2. Patients treated with CNS local therapy for newly identified lesions may be eligible to enroll if all of the following criteria are met: Time since WBRT is ≥ 14 days prior to first dose of treatment, time since SRS is ≥ 7 days prior to first dose of treatment, and time since surgical resection is ≥ 14 days * Postmenopausal women must be postmenopausal, which is defined as any of the following: * Age ≥ 60 years * Age \< 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH, and estradiol in the postmenopausal range per local normal range * Premenopausal women made postmenopausal through the use GnRH agonist prior to study entry are eligible and MUST remain on the GnRH agonist for the duration of protocol treatment. * Status-post bilateral oophorectomy - After adequate healing post-surgery * Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female participants who are postmenopausal according to the definition in 3.1.10. * Women of child-bearing potential and men must agree to use adequate contraception at time of enrollment and for 4 months after the last dose of elacestrant or 7 months after the last dose of trastuzumab deruxtecan, whichever is later. * Participants must be able to swallow and retain oral medication. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Prior treatment with aatopoisomerase inhibitor antibody drug conjugate in any setting. * Prior treatment with an oral novel estrogen receptor degrader or modulator in the metastatic setting (SERD, SERM, PROTAC, or CERAN). Prior fulvestrant is allowed. A washout period of 7 days is required for any endocrine or targeted therapy. A washout period of 14 days is required for any chemotherapy. * Patients with known brain metastases that are symptomatic or that require therapy for symptom control are not eligible. Patients with stable or asymptomatic brain metastases are allowed. Participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 4 weeks before day 1 of study therapy will be excluded. * Receipt of any other investigational compound or device within 2 weeks of the first dose of treatment in this study. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to elacestrant or T-DXd. * History of (non-infectious) pneumonitis that required steroids or current ILD by imaging at screening. * Patients who are pregnant or breastfeeding, or who expect to become pregnant within the projected duration of the study. * Patients with active tuberculosis. * Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring systemic therapy, clinically significant cardiovascular disease including: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, uncontrolled diabetes mellitus, gastrointestinal disorders potentially affecting the absorption of elacestrant, inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or total gastric resection, or psychiatric illness/social situations that would limit compliance with study requirements. Moderate or severe hepatic impairment (Child-Pugh B or C). Active hepatitis B or active hepatitis C infection. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation. History of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last six months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV. * Patients with a history of different malignancy are ineligible, except for those who have been disease-free for at least three years and are deemed by the investigator to be at low risk for recurrence of the prior malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.