Gene Signatures to Guide HR+MBC Therapy in a Diverse Cohort (INSIGHT)

Inclusion Criteria: Signed and dated written informed consent. Subjects ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence of invasive mammary carcinoma that is: ER/PR-positive (> 1% cells) by IHC and HER2 negative (by IHC or FISH) Previously progressed on: an aromatase inhibitor (AI)+ CDK4/6 inhibitor, OR a selective estrogenreceptor modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor Evaluable disease (measurable or non-measurable) Measurable disease, ie, at least 1 measurable lesion as per RECIST 1.1 (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation) Patients with bone only disease allowed if possible to evaluate on radiological exams (eg.bone scan, PET/CT, CT, MRI) even if lesions are non-measurable according to RECIST1.1. Adequate organ function including: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L Platelets ≥ 100 × 10^9/L Hemoglobin ≥ 9/g/dL (may have been transfused) Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present) Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50mL/min as calculated using the Cockcroft-Gault (CG) equation For randomized patients only: tumors must be diagnosed as non-Luminal A using the Blueprint® and Mammaprint® tests Exclusion Criteria: PIK3CA mutation Prior chemotherapy in the metastatic setting More than 1 line of prior endocrine therapy in the metastatic setting Radiation therapy ≤ 2 weeks prior to study entry. Patients who have received prior radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment (except for alopecia) Previous malignant disease other than breast cancer within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment). Symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment and off steroids) Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0]; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable. Pregnant or breastfeeding females.