Monitoring ESR1 Mutations May Optimize Treatment in Metastatic Breast Cancer

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Monitoring circulating mutated ESR1 among patients with hormone receptor (HR)-positive/HER2-negative, metastatic breast cancer enabled optimization of the endocrine therapy used with a CDK4/6 inhibitor, resulting in prolonged progression-free survival (PFS), according to the results of the PADA-1 trial presented at the 2021 San Antonio Breast Cancer Symposium (SABCS).

“This is the first clinical trial to demonstrate the clinical utility of bESR1mutmonitoring,” François-Clément Bidard, MD, PhD, of Institut Curie in France, and lead author of the study, said.

The PADA-1 trial (ClinicalTrials.gov Identifier: NCT03079011) treated 1017 patients with HR-positive/HER2-negative metastatic breast cancer with an aromatase inhibitor plus palbociclib. Blood monitoring of circulating tumor DNA (ctDNA) for ESR1 mutations was conducted at baseline, 1 month, and then every 2 months. If bESR1mut was rising and there was no synchronous progressive disease, patients entered step 2 of the trial and were randomly assigned to continue on an aromatase inhibitor or to switch to fulvestrant.


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The coprimary endpoints were the occurrence of grade 3 or greater hematologic adverse events (AEs) and investigator-assessed PFS for patients who entered stage 2 of the trial. Secondary endpoints included overall survival, PFS in step 1, and patient-reported outcomes.

There were 172 patients who were randomly assigned in stage 2 of the trial. At study inclusion, the median age was 61 and the majority of patients had no prior history of aromatase inhibitor therapy. The most common site of metastasis was visceral.

In the primary analysis, using rising bESR1mut levels to initiate the switch from an aromatase inhibitor to fulvestrant significantly prolonged PFS. The median PFS from inclusion of the study was 5.7 months in the patients who remained on an aromatase inhibitor in addition to palbociclib compared with 11.9 months for patient who were switched to fulvestrant (stratified hazard ratio [HR], 0.61; 95% CI, 0.43-0.86; P =.005).

“Of note, the absolute difference in median PFS is 6.2 months, which is very relevant from a clinical perspective,” Dr Bidard said.

The most common grade 3 to 4 adverse event was neutropenia, which occurred among 36.9% of patients in the aromatase inhibitor arm and 36.4% of patients in the fulvestrant arm. Dose reductions of palbociclib were required for approximately 7.1% and 7.9% of patients in the aromatase inhibitor or fulvestrant arms, respectively. One patient withdrew from the study due to a fulvestrant-associated adverse event.

Dr Bidard concluded that, “Monitoring the rise of resistance-associated mutations opens up new opportunities for cancer therapy.”

Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Read more of Cancer Therapy Advisor’s coverage of SABCS 2021 by visiting the conference page.

Reference

Bidard FC, Hardy-Bessard AC, Bachelot T, 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. Presented at SABCS 2021; December 7-10, 2021; San Antonio, TX. GS3-05.



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