Early switch to fulvestrant plus palbociclib beneficial for patients with ESR1 mutation

Among patients with hormone receptor (HR)-positive/HER2-negative breast cancer treated with an aromatase inhibitor plus palbociclib, those who displayed a rising oestrogen receptor (ESR1) mutation, detected in their blood before disease progression, doubled their median progression-free survival (PFS) following a switch to fulvestrant plus palbociclib.

ESR1 mutations are known drivers of resistance to first-line aromatase inhibitors-based therapy in HR-positive/HER2-negative metastatic breast cancer patients. ESR1 mutations predict resistance to aromatase inhibitors, but not to fulvestrant [1]. The randomised, multicentre, open-label, phase 3 PADA-1 trial (NCT03079011) aimed to evaluate the clinical benefit of a switch to fulvestrant plus palbociclib upon the detection of a rising ESR1 mutation in blood (bESR1_mut). The PADA-1 trial enrolled 1,017 patients, who were 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 rising of bESR1_mut during aromatase inhibitor plus palbociclib treatment (without clinical signs of progression). These patients were randomised to continuation of aromatase inhibitor plus palbociclib (standard arm, n=84) or to treatment with fulvestrant plus palbociclib (experimental arm, n=88). Prof. François-Clément Bidard (Institut Curie, France) presented the results [2].

After a median follow-up of 26 months after randomisation, 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), representing an absolute difference in median PFS of 6.2 months. The benefit of fulvestrant plus palbociclib over aromatase inhibitor plus palbociclib was observed across all prespecified subgroups.

Patients who progressed after continuing aromatase inhibitor plus palbociclib treatment were given the option to cross over to fulvestrant plus palbociclib. Among patients in the crossover cohort (n=47), the median second-PFS was 3.5 months, which is numerically shorter than the 6.2 months benefit of early switch to fulvestrant plus palbociclib.

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. GS3-05, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January 2022