Breast cancer patients with ER mutations may benefit from early switch to fulvestrant/palbociclib

Among patients with HR-positive breast cancer treated with an aromatase inhibitor plus palbociclib, those who displayed rising ESR1 mutations before disease progression doubled their median progression-free survival following a switch to fulvestrant plus palbociclib, according to results from the phase 3 PADA-1 trial.

Estrogen receptor gene ESR1 mutations are known drivers of resistance to first-line aromatase inhibitor-based therapy in HR-positive, HER2-negative, metastatic breast cancer patients. ESR1 mutations predict resistance to aromatase inhibitors, but not to fulvestrant [1]. The randomized, phase 3 PADA-1 trial (NCT03079011) aimed to evaluate the clinical benefit of a switch to fulvestrant/palbociclib upon the detection of a rising ESR1 mutation in blood (bESR1_mut) in HR-positive, HER2-negative, metastatic breast cancer patients treated by first-line aromatase inhibitor/palbociclib. The PADA-1 trial enrolled 1,017 patients who were being treated in a first-line setting with an aromatase inhibitor plus palbociclib. The patients provided blood samples for ESR1 mutation screening every 2 months. After a median time of 15.6 months, 172 patients demonstrated a rising of bESR1_mut during aromatase inhibitor/palbociclib (without clinical signs of progression). These patients were randomized to continuation of aromatase inhibitor/palbociclib (standard arm) or to treatment with fulvestrant/palbociclib (experimental arm). Co-primary endpoints of PADA-1 were progression-free survival (PFS) after randomization and global safety. Dr. Francois-Clément Bidard (Institut Curie, France) presented the results [2]. After a median follow-up of 26 months after randomization, the median PFS in the standard arm was 5.7 months versus 11.9 months in the experimental arm (HR 0.63; P=0.007), so an absolute difference in median PFS of 6.2 months. The benefit of fulvestrant/palbociclib over aromatase inhibitor/palbociclib was observed in all prespecified subgroups. Patients who progressed after continuing aromatase inhibitor/palbociclib treatment were given the option to cross over to fulvestrant/palbociclib. Among patients in the crossover cohort (n=47), the median second-PFS was 3.5 months, which is much shorter than the 6.2 months benefit of early switch to fulvestrant/palbociclib. No new safety signals were observed. Based on these results, Dr. Bidard concluded that “this first-of-its-kind liquid biopsy-based trial demonstrates that targeting bESR1_mut-associated resistance through a change in the endocrine partner of palbociclib is feasible and allows a doubling in the subsequent median PFS. The observed clinical benefit might justify the implementation of the PADA-1 treatment strategy as a valid option in clinical routine.”

1. Turner NC, et al. Clin Cancer Res. 2020;26:5172-5177.
2. Bidard F-C, et al. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial. SABCS 2021 Virtual Meeting, abstract GS3-05.

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