Background: ARV-471 is a novel, potent, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets the ER. In xenograft models, ARV-471 demonstrated substantially greater ER degradation and antitumor activity compared with the selective ER degrader fulvestrant. In the phase 1 dose escalation portion (Part A) of the first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed antitumor activity in patients with ER+/HER2- locally advanced or metastatic breast cancer who had previously received endocrine therapy and a cyclin-dependent kinase (CDK)4/6 inhibitor; the clinical benefit rate (rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26%–56%) in 47 evaluable patients. The phase 2 VERITAC expansion cohort (Part B) is further evaluating ARV-471 monotherapy in this patient population. Palbociclib, a CDK4/6 inhibitor, plus fulvestrant is a standard treatment option for patients with ER+/HER2- breast cancer who have had disease progression on endocrine therapy. ARV-471 plus palbociclib resulted in substantially greater tumor growth inhibition in xenograft models compared with palbociclib plus fulvestrant, supporting further investigation of the ARV-471 plus palbociclib combination in patients with ER+ breast cancer. Here we describe Part C of the phase 1/2 study, which evaluates the safety and clinical activity of ARV-471 plus palbociclib in patients with breast cancer who previously received endocrine therapy. Methods: Eligible patients (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- advanced breast cancer and have received ≥1 prior endocrine therapy and ≤2 prior chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor therapy is permitted. Patients with known symptomatic brain metastases requiring steroids are excluded. ARV-471 and palbociclib will be administered orally once daily in 28-day cycles; ARV-471 will be given continuously and palbociclib for 21 days followed by 7 days off treatment. Primary objectives are to evaluate the safety and tolerability of ARV-471 plus palbociclib and select the recommended phase 2 dose and schedule of the combination (based on the incidence of dose-limiting toxicities during the first cycle and the frequency and severity of adverse events and laboratory abnormalities). Secondary objectives are to assess preliminary antitumor activity of ARV-471 plus palbociclib (based on overall response rate per Response Evaluation Criteria in Solid Tumors v1.1, clinical benefit rate, progression-free survival, and duration of response) and pharmacokinetic parameters. Clinical trial information: NCT04072952.