Neu Direction: Testing the Efficacy of Adding HER Inhibition to Standard of Care in Metastatic MLH1-low Endocrine-resistant ER+/HER2- Breast Cancer

The goal of this clinical trial is to learn if neratinib, an FDA-approved oral pan-HER2/3/4 inhibitor, improves disease control for participants with metastatic endocrine-resistant ER+/HER2-negative breast cancer. Neratinib is already approved for the treatment of HER2-postive breast cancers. The study will also learn about the safety of adding this drug to standard of care treatments. The main questions it aims to answer are:

1. Does adding neratinib to standard of care systemic therapy improve disease control for patients with metastatic hormone-driven breast cancer that is resistant to endocrine therapy?
2. What side effects do participants have when adding neratinib to standard of care therapy? Researchers will compare standard of care endocrine therapy regimens with and without neratinib to see if neratinib improves control of treatment-resistant metastatic breast cancer that has continued to progress while eon first line endocrine therapy.

Participants will:

1. Take standard of care endocrine therapy for metastatic endocrine-resistant breast cancer as determined by their medical oncologist or standard of care therapy with neratinib daily
2. Visit the clinic every 3 months for checkups, tests and imaging studies

This is a prospective 2-arm Phase II study testing the efficacy of adding neratinib to standard of care therapy in patients with MLH1-low ER+/HER2- endocrine-resistant breast cancer . Patients with endocrine-resistant ER+/HER2- breast cancer who have lesions visible on CT scan will be recruited as they are seen in breast medical oncology and radiation oncology clinics at UC San Diego Health. Patients will be eligible if they have measurable persistent, recurrent, progressive or metastatic disease on imaging (including FDG PET scan) while on endocrine therapy. At least one lesion must be biopsied and confirmed ER+ by immunohistochemistry and HER2- within 6 months of study screening. Genomic mutation profile will be analyzed along with trial results to identify other potential mutations associated with MLH1 expression and/or neratinib response. Participants will be stratified by nuclear MLH1 expression on their biopsy tissue using immunohistochemistry. MLH1negative (nuclear MLH1 detectable in <5% of tumor cells) and MLH1-low patients (<50% tumor cells positive) hereafter grouped as "MLH1-low" will be randomized to standard of care without (75 participants) or with (75 participants) the addition of neratinib in Arm 1 and Arm 2 respectively . Standard of care therapy can include any endocrine therapy with or without CDK4/6 inhibitors. Prior exposure to CDK4/6 inhibitors is acceptable but not prior HER2-targeted therapy. Neratinib will be administered with a standard ramp up to therapeutic dose to minimize side effects with 120mg daily for 1 week, 160mg daily for 1 week and then 240mg daily thereafter. Treatment response will be monitored via imaging every 3 months while on study and measured using RECIST v. 1.1 criteria and/or mPERCIST criteria as appropriate using FDG-PET. Participants will remain on study until cessation due to side effects or disease progression. Biopsy at disease progression will be encouraged but not required.