Background: EP is a next-generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). Although a phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of overall survival (OS) (HR 0.087;P = 0.08), a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86];P< 0.01) (Perez Lancet Oncol 2015). The current phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP or TPC in an open-label phase 3 study. Eligibility includes: ECOG PS 0 or 1; adequate organ function; prior ATC therapy (neo/adjuvant or locally advanced/MBC setting);≥1 prior cytotoxic regimen for pts with triple negative MBC;≥2 prior cytotoxic regimens for pts with HR+ or HER2+ BC (pts with HR+/HER2+ BC must have received prior hormone therapy/HER2 targeted therapy); prior definitive local therapy of BM (whole brain radiation [RT], stereotactic RT or surgical resection as single-agent or combination); and stable signs/symptoms of BM with steroids (ie, unchanged or decreasing ≥7 days prior to randomization). Primary endpoint is OS. Key secondary endpoints are ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 cytotoxic IV agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain the number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR = 0.67); 1 interim analysis is planned at 50% of deaths (130 events). PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment began early 2017. Clinical trial information: NCT02915744