Background: CDK4/6 inhibition (CDK4/6i) has a well-established role in the management of hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC). The addition of a CDK4/6i to endocrine therapy (ET) in HR+/HER2- MBC leads to prolongation of progression-free survival in the first-line and pre-treated settings. Mechanisms of resistance to CDK4/6i are not well described, and it is not known if continuation of CDK4/6i with subsequent lines of ET improves outcomes over ET alone. Further, preclinical data suggest combination therapy with ET, CDK4/6i, and anti-PDL1 may provide synergistic efficacy. The PACE trial was designed to determine optimal subsequent line of therapy in patients (pts) with HR+ /HER2- MBC that has progressed despite prior CDK4/6 inhibition and endocrine therapy. Methods: PACE is a multicenter phase II trial randomizing pts 1:2:1 to Arm A: fulvestrant alone (with option for palbociclib monotherapy crossover at time of progression); Arm B: fulvestrant and palbociclib; or Arm C: fulvestrant, palbociclib, and avelumab. The primary objective is to evaluate progression-free survival (PFS) with the combination of fulvestrant and palbociclib vs. fulvestrant alone; secondary objectives include overall response (OR) and PFS comparisons for other arms; assessment of outcomes in predefined molecular subgroups including ESR mutation, PI3K mutation, loss of Rb; safety and tolerability; and comparing OR by RECIST vs irRECIST. Extensive analysis of tissue, ctDNA, and CTC for markers of response and resistance to therapy is planned. Eligible pts have HR+/HER2- MBC, with prior response to and subsequent progression on CDK4/6i and ET, defined as at least 6 months of prior treatment, with confirmed subsequent progression, and no more than one prior P dose reduction for toxicity. Pts may have had 1-2 prior ET, and 0-1 prior lines of chemotherapy. A sample size of 220 patients is planned. NCT03147287.