Analysis of PADA-1 Trial Highlights Kinetics and Determinants of ESR1 Mutations in HR+/HER2– Metastatic Breast Cancer

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An analysis from the phase 3 PADA-1 trial (NCT03079011) examining the kinetics and determinants of ESR1 mutations detected in the blood of patients with hormone receptor–positive, HER2-negative metastatic breast cancer showed that the incidence of these emerging alterations was uneven over time.1

Findings presented at the 2025 ESMO Breast Congress demonstrated that the incidence of ESR1 mutations mirrored a bell-shaped curve, with fewer mutations detected before 6 months and after 30 months compared with patients who experienced disease progression without the emergence of an ESR1 mutation.

A multivariate analysis examining factors modulating the relative incidence of ESR1 mutations showed that estrogen recepotr expression per immunohistochemistry (odds ratio [OR], 1.12; 95% CI, 1.01-1.26), the presence of bone and another site of metastasis (OR, 2.08; 95% CI, 1.30-3.38), the presence of bone-only metastases (OR, 2.67; 95% CI, 1.52-4.76), and elevated lactate dehydrogenase levels (OR, 1.58; 95% CI, 1.10-2.27) were associated with an increased incidence of emerging ESR1 mutations compared with progressive disease without ESR1 mutations.

“Interception of ESR1 mutations before progressive disease was easier in [patients with] bone metastases and low proliferation,” presenting study author François-Clément Bidard, MD, PhD, said in a presentation of the data. “These results may inform how to customize ESR1 mutation monitoring in the first line.

Bidard is a professor of medicine in the Department of Medical Oncology at Institut Curie and UVSQ/Université Paris-Saclay; co-coordinator of breast cancer research at Institut Curie; and the vice chair of the French breast cancer research group, UCBG.

Prior Findings From PADA-1

PADA-1 was a proof-of-concept trial that evaluated a switch in therapies for patients with hormone receptor–positive/HER2-negative breast cancer who were receiving their first aromatase inhibitor (AI) in combination with palbociclib (Ibrance). Patients who had a newly detected or increased level of ESR1 mutations in the blood in the absence of synchronous disease progression were then randomly assigned to stay on the same therapy or switch to fulvestrant (Faslodex) in combination with palbociclib.

Findings showed that at a median follow-up of 35.3 months (interquartile range [IQR], 29.2-41.4) from enrollment and 26.0 months (IQR, 13.8-34.3) from randomization, patients who switched to fulvestrant plus palbociclib (n = 88) experienced a median progression-free survival (PFS) from randomization of 11.9 months (95% CI, 9.1-13.6) compared with 5.7 months (95% CI, 3.9-7.5) for those who continued to receive an AI plus palbociclib (n = 84; stratified HR, 0.61; 95% CI, 0.43-0.86; P = .0040).

“This was the first evidence to support ESR1 mutation monitoring during the first line,” Bidard said during the presentation.

During step 1 of the study prior to randomization, 1017 patients were enrolled to receive palbociclib in combination with an AI.1 During this stage, ESR1 mutations were detected in 283 patients prior to disease progression, and 395 patients experienced disease progression without the detection of an ESR1 mutation. Once the target number of patients was reached for randomization, ESR1 mutation testing was discontinued for step 1; at this point, 339 patients were still received palbociclib plus an AI or had dropped out of the study.

When accounting for patients who had ESR1 mutations detected and those who had disease progression in the absence of an ESR1 mutation, the ESR1 mutation detection rate was 41.9% (n = 283/678).

The populations of patients with ESR1 mutations detected and those with progressive disease without ESR1 mutations were included in the analysis of the cumulative and instantaneous incidences of ESR1 mutations.

Further ESR1 Analysis From Step 2

Among the 283 patients who had an ESR1 mutation detected, 71 ultimately had synchronous progressive disease and exited the trial; the remaining 212 patients without synchronous progressive disease were eligible for random assignment.

Investigators used another multivariate analysis to evaluate factors that could contribute to a higher incidence of synchronous progressive disease with an ESR1 mutation vs the absence of progressive disease in the presence of an ESR1 mutation. Findings showed that tumor grade of 3 vs 1 (OR, 2.56; 95% CI, 0.90-8.4) and a metastasis-free interval of more than 3 years (OR, 6.61; 95% CI, 2.3-20.8). However, age (OR, 0.77; 95% CI, 0.60-0.90), bone plus another site of metastasis (OR, 0.34; 95% CI, 0.16-0.75), and bone-only metastasis (OR, 0.21; 95% CI, 0.08-0.55) were not associated with an increased incidence of ESR1 mutations without progressive disease.

Future Directions

After PADA-1, the phase 3 SERNEA-6 trial (NCT04964934) evaluated a similar strategy, where patients with hormone receptor–positive/HER2-negative advanced breast cancer who had a detected ESR1 mutation prior to clinical disease progression either switched from an AI plus a CDK4/6 inhibitor to the oral selective estrogen receptor degrade camizestrant in combination with the same CDK4/6 inhibitor, or stayed on the same AI plus CDK4/6 inhibitor regimen.

Notably, SERENA-6 met its primary end point, with camizestrant plus a CDK4/6 inhibitor generating a statistically significant and clinically meaningful improvement in PFS compared with an AI plus a CDK4/6 inhibitor.3

“PADA-1 was a proof-of-concept trial. [At the 2025 ASCO Annual Meeting], we will have the results of SERENA-6,” Bidard concluded.1

References

1. Cabel L, Bachelot T, Hardy-Bessard A-C, et al. Kinetics and determinants of bESR1 under AI and palbociclib in patients with HR+/HER2- mBC in the PADA-1 trial. Presented at: 2025 ESMO Breast Cancer Congress. May 14-17, 2025; Munich, Germany. Abstract 1O.
2. Bidard FC, Hardy-Bessard AC, 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. 2022;23(11):1367-1377. doi:10.1016/S1470-2045(22)00555-1
3. Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 Phase III trial. News release. AstraZeneca. February 26, 2025. Accessed May 15, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.html