CAPELA: A phase II multicenter open-label randomized study of capecitabine in combination with elacestrant versus capecitabine alone in advanced estrogen receptor (ER)–positive breast cancer (TBCRC 070).

TPS1156 Background: Endocrine therapy (ET) in combination with targeted treatments can effectively treat metastatic ER-positive (ER+) breast cancer (BC); however, nearly all patients ultimately progress on these therapies, eventually requiring treatment with chemotherapy. Current standard of care, based on older data, is to discontinue ET when starting chemotherapy. Many of these studies used tamoxifen, which has partial agonist activity, in combination with chemotherapy. Newer estrogen-targeting agents, e.g. oral selective ER degraders (SERDs), function as ER antagonists. Preclinical work investigating the combination of SERD and chemotherapy has demonstrated an additive effect of the agents in ER wildtype tumors and a synergistic effect in tumors with ESR1 mutation ( ESR1m ); this synergy was attenuated with P53 silencing. Methods: CAPELA, an investigator-initiated, multicenter, open-label randomized phase II study, is designed to assess the safety and efficacy of capecitabine monotherapy vs. capecitabine + elacestrant in patients with advanced/unresectable ER+ HER2- BC. Eligible patients will have progressed on a CDK4/6 inhibitor and had no prior treatment with chemotherapy for metastatic disease. At least 50% of enrolled patients are required to have ESR1m tumors. Patients will be randomized 1:1 to receive capecitabine 1000mg/m 2 PO BID days 1-14 of a 21-day cycle +/- the oral SERD elacestrant 345 mg PO daily. Randomization will be stratified by prior lines of ET in the metastatic setting (1 vs. >1), visceral disease (yes/no), TP53 mutation status, and ESR1m status. Patients with tumors with an ESR1m who are randomized to the monotherapy arm will have the option to crossover to elacestrant monotherapy at the time of progression to evaluate benefit of concurrent vs. sequential use of these agents. The primary endpoint is hierarchical assessment of median progression free survival (mPFS) in 1) the ESR1m population and if positive 2) the intention to treat (ITT) population. Secondary endpoints include safety/tolerability, median overall survival (OS), objective response rate, median time to second progression, clinical benefit rate, and patient reported outcomes in the ESR1m and ITT populations. PFS and OS in the ESR1m not detected population will also be evaluated. Exploratory correlative studies on collected plasma, serum, and archival tissue will also be conducted. The study will enroll 297 patients over an estimated 3 years. The trial will open at 10 sites through the Translational Breast Cancer Research Consortium (TBCRC). Clinical trial information: NCT07222215 .