ABSTRACT

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of
checkpoint inhibitor therapy has value in this setting.

METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor–positive/HER2– MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F 1 P), or fulvestrant plus palbociclib and avelumab (F 1 P 1 A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F 1 P.

RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F 1 P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P 5 .62). The median PFS on F 1 P 1 A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P 5 .23). The difference in PFS with F 1 P and F 1 P 1 A versus F was greater among patients with baseline ESR1 and PIK3CA alterations.

CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor–positive/HER2– MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.