Switch of Endocrine Therapy Backbone Yields PFS Benefit in ER+ HER2– Breast Cancer After ESR1 Mutation Onset, Before Progression

Switch treatment with palbociclib and fulvestrant from aromatase inhibitors plus palbociclib upon onset of ESR1 blood mutations and before progression yielded better progression-free survival among those with estrogen receptor–positive, HER2-negative advanced breast cancer.

Results from the randomized phase 3 PADA-1 trial (NCT03079011) indicated that switch treatment from aromatase inhibitors plus palbociclib (Ibrance) to palbociclib and fulvestrant (Faslodex) produced significantly improved progression-free survival (PFS) benefit in patients with estrogen receptor–positive HER2-negative metastatic breast cancer following onset of ESR1 blood mutations and prior to disease progression.

The median progression-free survival was 11.9 months (95% CI, 9.1-13.6) in the fulvestrant and palbociclib cohort vs 5.7 months (95% CI, 3.9-7.5) in the aromatase inhibitor and palbociclib group (HR, 0.60; 95% CI, 0.42-0.85; P = .0040). The most common grade 3 or worse hematological adverse effects (AEs) observed in the fulvestrant and palbociclib versus the aromatase inhibitor and palbociclib cohorts, respectively, were neutropenia ( 44.3% vs 41.7%) and lymphopenia (4.5% vs 3.6%).

A total of 1017 patients were included, of whom 279 developed a rising ESR1 blood mutation; of these patients, 172 were randomly assigned 1:1 to receive fulvestrant and palbociclib (n = 88) or aromatase inhibitor and palbociclib (n = 84). The study included patients 18 years and older with locally advanced disease who had not been treated with a previous systemic therapy for advanced disease and did not receive an adjuvant aromatase inhibitor or ended treatment after over 12 months. Moreover, patients needed to demonstrate an increasing ESR1 mutation during aromatase/palbociclib treatment but no synchronous disease progression by RECIST criteria.

In the first portion of the study, patients were treated with a first-line aromatase inhibitor such as letrozole (Femara) at 2.5 mg, anastrozole (Arimidex) at 1 mg, or exemestane (Aromasin) at 25 mg taken orally once a day along with a 125 mg of oral palbociclib taken once a day in a 3 weeks on, 1 week off schedule. Patients in step 2 whose screenings showed increased ESR1 blood mutations were randomly assigned to the aforementioned regimen or switch to 500 mg of fulvestrant taken intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1 along with the same palbociclib backbone.

The co-primary end points of the trial were investigator-assessed PFS in the intent-to-treat (ITT) population and grade 3 or worse hematological AEs in all patients. Secondary end points included second-line PFS among patients who crossed over to the fulvestrant and palbociclib cohort, time to strategy failure from the time of randomization to the time of therapy discontinuation or death, and chemotherapy-free survival.

In the second step, the median patient age was 61 years (range, 50-70) in the aromatase inhibitor/palbociclib arm vs 62 years (range, 52-70) in the fulvestrant/palbociclib arm. A total of 72.6% of those in the control arm vs 71.6% of those in the experimental arm were postmenopausal at study entry. Moreover, most patients in both respective arms (59.3% vs 56.3%) had a disease-free interval of more than 5 years. Moreover, 63.1% of patients in the control group and 65.9% of those in the experimental group had not received a previous aromatase inhibitor in the adjuvant setting.

The median time to strategy failure was 11.9 months in the fulvestrant group compared with 10.6 months in the aromatase inhibitor group (HR, 1.02; 95% CI, 0.71-.145; log-rank test P = .90). The median chemotherapy-free interval in each respective group was 14.6 months (95% CI, 11.8-17.0) and 13.1 months (95% CI, 10.8-17.6; HR, 0.91; 95% CI, 0.62-1.33; log-rank test P = .60)

A total of 1.7% of patients experienced SAEs during step 2, including grade 4 neutropenia (1.2%) and grade 3 fatigue (1.2%) in the aromatase inhibitor and palbociclib cohort, and grade 4 neutropenia (1.1%) in the fulvestrant and palbociclib group. In the first step, 1 event of death from pulmonary embolism occurred that was determined to be related to treatment.


Bidard F, Hardy-Bessard A, Dalenc F, et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. Published onlineSeptember 29, 2022. doi:10.1016/S1470-2045(22)00555-1

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