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 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 without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiographic evaluation. * Participants must have had prior CDK4/6 inhibitor and either: * Disease progression on or within 12 months of endocrine therapy plus a CDK4/6 inhibitor in the adjuvant setting * One previous line of endocrine therapy in metastatic setting if disease progression within 6 months of first-line CDK4/6 plus endocrine treatment for metastatic disease or disease recurrence within 24 months after initiation of adjuvant endocrine therapy * Two previous lines of endocrine therapy in the metastatic with or without a targeted therapy (such as but not limited to CDK4/6, mTOR, or PI3K inhibitors) administered for the treatment of metastatic disease. * Of note with regards to the 2 lines of previous endocrine therapy requirement:- Disease recurrence while on the first 24 months of adjuvant endocrine therapy will be considered a line of therapy; these patients will only require 1 line of endocrine therapy in the metastatic setting. * Single-agent PARP inhibitor therapy is not considered a line of endocrine therapy but is allowed. * Changes in dosing schedules, or discontinuations/restarting of the same drugs of the addition of a targeted therapy to an endocrine therapy without progression (e.g., adding a CDK4/6 inhibitor to a current aromatase inhibitor regimen) will not be considered separate lines of therapy. * Participants may have not received 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. * Women or men age ≥18 years are eligible. * ECOG performance status ≤ 2. * Participants must meet the following 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 * 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 medical monitor is required prior to enrollment. * Previously treated brain metastases * a. 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 * b. Patients treated with CNS local therapy for newly identified lesions may be eligible to enroll if all of the following criteria are met: i. Time since WBRT is ≥ 14 days prior to first dose of treatment, time since SRS is ≥ 7 days prior to first dose of treatment, or time since surgical resection is ≥ 14 days * 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 must be on GnRH agonist prior to study entry are eligible. Women in this group 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: * Age \> 60 years; or * Age \< 60 with intact uterus and amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; or * Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation * The effects of elacestrant and T-DXd on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. 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. Women treated or enrolled on this protocol must use an effective method of birth control for 4 months after the last dose of elacestrant or 7 months after the last dose of trastuzumab deruxtecan, whichever is later. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of elacestrant and T-DXd administration. * Adequate contraception is defined as one highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the participant and/or partner. * Highly Effective Non-Hormonal Contraception Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are considered highly effective forms of contraception. * The following non-hormonal methods of contraception are acceptable: * True abstinence when this is in line with the preferred and usual lifestyle of the participant. \[Periodic abstinence (e.g., calendar, ovulation, symptothermal post- ovulation methods) and withdrawal are not acceptable methods of contraception\]. * Male sterilization (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female participants, the vasectomized male partner should be the sole partner. * Participants must be able to swallow and retain oral medication. * Participants must be willing to undergo two mandatory research biopsies (one at baseline, one during treatment) if tumor is safely accessible. * Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged) Exclusion Criteria: * Prior treatment with an 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. * 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 (starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for those who have not). * Patients with a known history of 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. 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. * 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. * Significant cardiovascular disease, such as: 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