Camizestrant plus ribociclib in hormone receptor–positive/HER2-negative advanced breast cancer: The phase II CADILLAC trial.

TPS1150 Background: CDK4/6 inhibitors combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor–positive (HR+)/HER2–negative (HER2–) advanced breast cancer (ABC). Secondary endocrine resistance includes patients (pts) relapsing after ≥2 years of adjuvant ET during treatment or within 12 months of discontinuation but does not distinguish according to adjuvant ET duration; thus, whether HR+ tumors progressing after prolonged adjuvant ET (≥5 years) constitute a biologically and prognostically distinct entity remains unclear. Next-generation oral selective estrogen receptor degraders (SERDs) provide more potent estrogen receptor (ER) degradation and have demonstrated superiority over standard ET in pts with previously treated endocrine-resistant ABC. We hypothesized that camizestrant plus ribociclib as first-line therapy may improve outcomes versus historical ribociclib plus aromatase inhibitor (AI) or fulvestrant in HR+/HER2– ABC relapsing after long-term adjuvant ET. Methods: CADILLAC (NCT07195227) is an international, multicenter, open-label, single-arm, external historical-controlled phase II trial. A total of 150 pts with HR+/HER2– ABC who have not received systemic treatment for advanced disease will be enrolled from Spain, Germany, and China. Key eligibility criteria include: (a) ≥18 years; (b) histologically confirmed unresectable locally recurrent or metastatic breast cancer; (c) evaluable disease as per RECIST v.1.1; (d) prior adjuvant ET duration ≥5 years, including ≥2 of AI (with a cap of 30% pts with an ET-free interval ≥12 months); and (e) ECOG performance status 0-1. Pts will receive camizestrant 75 mg orally once daily continuously in 28-day cycles, combined with ribociclib 600 mg orally once daily on days 1-21 of each 28-day cycle, until unacceptable toxicity, disease progression, death, or discontinuation for other reasons, whichever occurs first. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), quality of life assessed by EORTC QLQ-C30 and QLQ-BR42 questionnaires, and safety according to NCI-CTCAE v5.0. PFS, ORR, and CBR will be locally assessed by investigators per RECIST v1.1. and compared with outcomes from a historical control cohort of at least 150 pts treated with ribociclib plus AI or fulvestrant. The null hypothesis is defined as a median PFS ≤20.3 months, whereas the alternative hypothesis corresponds to a median PFS ≥28.7 (target hazard ratio 0.707). The primary hypothesis will be tested using a stratified log-rank test at one-sided 5% significance level with 70% power. An effective total of 157 PFS events across arms is required. Interim efficacy and safety analyses are planned once the first 50 pts have completed ≥6 months of treatment. Enrollment will not be paused during this interim analysis. Clinical trial information: NCT07195227 .