Among patients with HR-positive/HER2-negative metastatic breast cancer, combining palbociclib with fulvestrant beyond progression on prior CDK4/6 inhibition did not significantly improve progression-free survival (PFS) compared with using fulvestrant alone, results from the PACE trial showed. However, a trend for longer PFS was observed when a PD-L1 inhibitor was added to fulvestrant/palbociclib.


Mechanisms for resistance to CDK4/6 inhibitors plus endocrine therapy, the standard-of-care for first-line treatment of patients with ER-positive/HER2-negative metastatic breast cancer, are under study. It is not clear if alterations at the time of progression provide resistance to CDK4/6 inhibitor, resistance to endocrine therapy, or both. Therefore, it is an open question whether a CDK4/6 inhibitor should be continued at time of disease progression. Preclinical data suggest that combination therapy with CDK4/6 inhibitor plus checkpoint inhibition beyond prior progression may provide synergistic efficacy.1 The phase 3 PACE trial was designed to explore the activity of continuation of CDK4/6 inhibitor beyond progression, with a change of endocrine therapy to fulvestrant, and to explore the addition of PD-L1 inhibition. Dr. Erica Mayer (Dana-Farber Cancer Institute) presented the results2 at the 2022 San Antonio Breast Cancer Symposium.

PACE enrolled 220 patients with ER-positive/HER2-negative metastatic breast cancer who progressed on CDK4/6 inhibition plus endocrine therapy. Participants were randomized 1:2:1 to receive fulvestrant alone, fulvestrant/palbociclib, or fulvestrant/palbociclib/avelumab (triple therapy). The primary objective was to study the superiority of fulvestrant/palbociclib over fulvestrant alone.

Fulvestrant with palbociclib beyond progression did not improve PFS compared with fulvestrant alone: median PFS was 4.8 months for fulvestrant alone versus 4.6 months for fulvestrant/palbociclib (HR, 1.11; P=0.62). However, triple therapy did increase the median PFS to 8.1 months (HR vs fulvestrant, 0.75; P=0.23). The PFS rates at 12 months were 17.5%, 13.1%, and 35.6% for fulvestrant alone, fulvestrant/palbociclib, and triple therapy, respectively. In addition, an exploratory analysis of baseline mutation showed favorable outcomes of fulvestrant/palbociclib versus fulvestrant alone in patients with a mutation in PIK3CA, ERR1, or Rb1.

“Among patients with HR-positive/HER2-negative metastatic breast cancer, combining palbociclib with fulvestrant beyond progression on prior CDK4/6 inhibition did not significantly improve PFS compared with using fulvestrant alone,
Dr. Mayer concluded. “However, the observed longer PFS when a PD-L1 inhibitor was added to fulvestrant/palbociclib is an intriguing signal in this population and deserves further study.”

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