TPS1117 Background: The use of cyclin dependent kinase 4 and 6 (CDK4 & 6) inhibitors plus endocrine therapy (ET) has transformed the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, most patients will experience disease progression. Identification of treatment options following progression is an unmet medical need. Additionally, as CDK4 & 6 inhibitors are now being deployed in the adjuvant setting, determination of optimal therapy following metastatic relapse is an important question. In patients with disease progression following a CDK4 & 6 inhibitor-based regimen, continuing CDK4 & 6 inhibition with abemaciclib while switching the ET backbone may provide benefit and delay the need for cytotoxic chemotherapy. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered continuously and approved as monotherapy or with ET for treatment of HR+, HER2- ABC. Abemaciclib has also been approved with ET for the adjuvant treatment of HR+, HER2-, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20%. Fulvestrant is a selective ER degrader (SERD) approved for treatment of HR+, HER2- ABC. The postMONARCH study investigates whether abemaciclib plus fulvestrant will improve outcomes in patients with HR+, HER2- ABC after disease relapse or progression after adjuvant or first-line treatment with a CDK4 & 6 inhibitor plus ET. Methods: postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study in patients with HR+, HER2- ABC and with disease progression on treatment with a prior CDK4 & 6 inhibitor plus an aromatase inhibitor as initial therapy for ABC or recurrence on/after treatment with a CDK4 & 6 inhibitor plus ET in the adjuvant setting. Eligible patients are randomized 1:1 to receive abemaciclib 150 mg twice daily or placebo, plus fulvestrant. Stratification factors include geography, presence of visceral metastasis, and duration of prior CDK4 & 6 inhibitor-based regimen. The study is powered at 80% with a cumulative Type I error of 0.025 to detect the superiority of abemaciclib plus fulvestrant versus placebo plus fulvestrant in terms of investigator-assessed progression free survival. Key secondary endpoints include overall survival, PFS by blinded independent central review, objective response rate, safety, patient-reported outcomes, and pharmacokinetics. This study opened in Jan 2022, plans for approximately 122 centers in 18 countries, and anticipates enrolling ̃350 patients. Clinical trial information: NCT05169567.