Switching treatment from a first-line aromatase inhibitor (AI) to fulvestrant upon detection of a rising ESR1 mutation in the blood improves progression-free survival (PFS) in patients with HER2-negative advanced breast cancer, according to results of the phase 3 PADA-1 trial published in The Lancet Oncology.

The study authors noted that acquired ESR1-mutated subclones are frequently responsible for resistance to AIs, but these subclones may be sensitive to treatment with fulvestrant. 

The aim of the PADA-1 trial (ClinicalTrials.gov Identifier: NCT03079011) was to determine if switching treatment from an AI plus palbociclib to fulvestrant plus palbociclib, based on early detection of a rising ESR1 mutation in the blood, could improve outcomes.

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The trial included 1017 patients with HER2-negative advanced breast cancer who were receiving an AI plus palbociclib as first-line treatment. AI treatment consisted of letrozole (2.5 mg), anastrozole (1 mg), or exemestane (25 mg) once per day, taken continuously. Palbociclib was given at 125 mg once per day on days 1-21 of a 28-day cycle.

At study entry, 74.9% of patients were postmenopausal, 38.8% had newly metastatic disease, and 54.1% had visceral metastases. The median age at random assignment was 61 years. 

Patients who had newly present or increased levels of ESR1 mutations in circulating tumor DNA (without synchronous disease progression) were randomly assigned to continue their current therapy or switch from an AI to fulvestrant. Crossover was allowed. 

Of the 279 patients (27%) with a rising ESR1 mutation, 172 (17%) were randomly assigned to treatment. There were 88 patients assigned to fulvestrant-palbociclib, 84 assigned to remain on AI-palbociclib, and 47 who eventually crossed over from the AI group to the fulvestrant group.

The median follow-up from the inclusion of randomized patients was 35.3 months. The co-primary endpoints were PFS and grade 3 or higher hematologic adverse events (AEs). 

Among the randomized patients, the median PFS was significantly longer in the fulvestrant group than in the AI group — 11.9 months and 5.7 months, respectively (hazard ratio, 0.61; 95% CI, 0.43-0.86; P =.004). 

In the entire cohort, the most common grade 3 or higher hematologic AEs were neutropenia (70.3%), lymphopenia (6.5%), and thrombocytopenia (2.0%).

Among the randomized patients, the most common grade 3 or higher AEs were neutropenia (41.7% in the AI group and 44.3% in the fulvestrant group) and lymphopenia (3.6% and 4.5%, respectively). The most common grade 3 or higher AE in the crossover cohort was neutropenia (34%).

“[P]ADA-1 is the first randomized 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,” the study authors wrote. “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.”

Disclosures: This study was supported by Pfizer through a grant to Unicancer. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Bidard F-C, Hardy-Bessard A-C, 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 online September 29, 2022. doi:10.1016/S1470-2045(22)00555-1

This article originally appeared on Cancer Therapy Advisor