Background: ARV-471, an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in a phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. The CDK4/6 inhibitors abemaciclib and ribociclib are approved in combination with endocrine therapy as first- and second-line treatment for ER+/HER2- advanced or metastatic breast cancer; abemaciclib is also approved as monotherapy and in combination with other agents in additional breast cancer settings. ARV-471 combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Here we describe the first sub-studies of the open-label, phase 1b/2 TACTIVE-U umbrella study, which evaluate the safety and clinical activity of ARV-471 plus abemaciclib (sub-study A; NCT05548127) and ribociclib (sub-study B; NCT05573555) in patients with ER+/HER2- advanced or metastatic breast cancer. Future combination sub-studies will be included in TACTIVE-U. Methods: Patients eligible for sub-studies A and B are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ≥1 measurable lesion by RECIST 1.1, and have received ≤2 lines of prior therapy for advanced or metastatic disease and 1 line of any CDK4/6 inhibitor–based regimen in any setting. In sub-studies A and B, patients will receive ARV-471 orally once daily (QD) continuously in a dose escalation/de-escalation approach. In sub-study A, abemaciclib will be given orally twice daily continuously, and in sub-study B, ribociclib will be given orally QD for 21 days followed by 7 days off treatment. For both sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of ARV-471 in combination with abemaciclib or ribociclib. Secondary endpoints of phase 1b are antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), progression free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Clinical trial information: NCT05548127, NCT05573555.