Clinical benefits of an early therapeutic targeting of ESR1 mutation

The PADA-1 trial, recently published on The Lancet Oncology, shows for the first time that the early therapeutic targeting of ESR1 mutation with a switch to fulvestrant and palbociclib can lead to significant clinical benefits compared to continuing an aromatase inhibitor and palbociclib.

In advanced ER-positive, HER2-negative breast cancer, acquired ESR1 mutations are a known mechanism of resistance to aromatase inhibitors but no study has yet targeted ESR1-mutant subclones as soon as they become detectable in blood of patients administered aromatase inhibitor-based first-line treatment for advanced ER+ breast cancer. Thus, the PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood, while assessing the global safety of combination fulvestrant and palbociclib. The study, a randomised, open-label, phase 3 trial, involved 1017 of whom 297 developed a ESR1 mutation and were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. After a median follow-up of 35.3 months from inclusion and 26 months from random assignment, the median progression-free survival from random assignment was 11.9 months in the fulvestrant and palbociclib group versus 5.7 months in the aromatase inhibitor and palbociclib group. «PADA-1 is the first trial to show the feasibility of large-scale, real-time serial monitoring and targeting of resistance-associated mutations by circulating tumor DNA analysis», researchers explain. «Additionally, PADA-1 is the first randomised study to show that, in the setting of an ESR1 mutation rising in the blood, a switch of endocrine therapy improved progression-free survival, with no increased toxicity. These results show the clinical utility of circulating tumor DNA monitoring to target resistance-associated mutations when the burden of resistant tumor cells is still low, a finding which might be relevant beyond ESR1 mutations».