Switching from an aromatase inhibitor to fulvestrant upon early identification of the ESR1 mutation in plasma—before disease progression—doubled progression-free survival in the phase III PADA-1 trial, presented at the 2021 San Antonio Breast Cancer Symposium.¹

“PADA-1 is the first trial to demonstrate that, in most patients, resistance-associated mutations in the estrogen receptor gene can be detected and targeted before tumor progression,” said François-Clément Bidard, MD, PhD, Professor of Medical Oncology at Institut Curie and Paris-Saclay University, France. “ESR1 mutation monitoring in blood allows us to optimize the endocrine therapy partner of CDK4/6 [cyclin-dependent kinase 4 and 6] inhibitor.”

“Upon ESR1 mutation detection, we observed a doubling in median progression-free survival by switching from an aromatase inhibitor plus palbociclib to fulvestrant and palbociclib….”

— François-Clément Bidard, MD, PhD

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“Upon ESR1 mutation detection, we observed a doubling in median progression-free survival by switching from an aromatase inhibitor plus palbociclib to fulvestrant and palbociclib…. The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity,” he said.

Background and Study Rationale

Tumors can become resistant to aromatase inhibitors by mutating ESR1, the gene that encodes estrogen receptor alpha. ESR1 mutations are known drivers of resistance to first-line aromatase inhibitors in hormone receptor–positive, HER2-positive metastatic breast cancer, but their clinical actionability has not been clear. “ESR1 mutations are frequent at the time of disease progression on aromatase-based first-line therapy,” he added.

“PADA-1 evaluated a completely new strategy,” according to Dr. Bidard. “First, detect an ESR1 mutation in patients receiving first-line aromatase/palbociclib therapy and target it with a switch of the endocrine therapy arm while maintaining CDK4/6 inhibition. Overall, the aim is to delay disease progression.”

Investigators detected the mutations in cell-free DNA in the blood using droplet digital polymerase chain reaction (PCR). This is a sensitive assay that can identify relatively small amounts of mutant DNA. The assay targets exome 5 and 8 mutations of the ESR1 gene.

Dr. Bidard explained: “Our assay basically allows for a fast and inexpensive analysis compared with next-generation sequencing, the most common test in the United States. You can get the same result with next-generation sequencing.”

About PADA-1

PADA-1 recruited 1,017 patients with estrogen receptor–positive, HER2-negative advanced breast cancer being treated in the first-line setting with an aromatase inhibitor plus palbociclib. The study was conducted in three steps:

Step 1: Patients underwent centralized ESR1 mutation screening every 2 months. The median time before the onset of ESR1 mutation in the study was 18 months.

Step 2: Patients found to have a mutation in the absence of clinical disease progression were randomly assigned between continuing the same therapy (standard therapy) or switching to fulvestrant/palbociclib (experimental therapy).

Step 3: Patients randomly assigned to the standard arm could cross over to receive fulvestrant/palbocicilb after tumor progression.

Step 3 was important for showing that switching to fulvestrant/palbociclib after disease progression usually results in a minor benefit, thus establishing the wisdom of detecting it subclinically, Dr. Bidard said. “Fulvestrant remains effective against receptors with these mutations, but it provides limited progression-free survival when used as a second-line therapy,” he said. “Our goal was to track the emergence of ESR1 mutations during first-line therapy and act on them as soon as they appeared, before they led to clinical progression.”

Of the 1,017 patients included in the first step, 407 (40%) experienced disease progression in the absence of an ESR1 mutation, whereas 279 (27%) had a rising ESR1 mutation detected before disease progression or concurrently with disease progression. In step 2, 172 patients were randomly assigned: 84 to the standard arm and 88 to the experimental arm.

Switching Therapy Doubled Progression-Free Survival

PADA-1 met its primary endpoint. After a median follow-up of 26 months, median progression-free survival of patients who switched before disease progression was more than twice that of those who remained on an aromatase inhibitor: 11.9 months vs 5.7 months (stratified hazard ratio = 0.61; P = .005). The study found no significant interaction with patient characteristics and no new safety signal, he added.

As expected, the benefit of switching was far greater among patients with early identification of an ESR1 mutation. The 47 patients who switched over after disease progression on standard therapy had a median progression-free survival of 3.5 months, he reported.

According to Dr. Bidard, these data demonstrate the relatively short benefit of fulvestrant when used as a second-line therapy. “This suggests that the progression-free survival gain observed with early switching might not be caught up later when tumors develop an ESR1 mutation,” he said.

According to Dr. Bidard, the results “justify the implementation of the PADA-1 treatment strategy as a valid option in routine care.” Moreover, monitoring the rise in resistance-associated mutations may create new opportunities related to new agents and in other clinical settings, he added. 

DISCLOSURE: The study was funded by Pfizer. Dr. Bidard holds a patent for the ESR1 digital droplet polymerase chain reaction assay used in this study. He also has financial relationships with AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, ProLynx, Radius Health, Roche Pharmaceuticals, Sanofi, and Seagen.

REFERENCE

1. Bidard FC, Hardy-Bessard AC, Bachelot T, et al: Fulvestrant-palbociclib vs continuing AI-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. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-05. Presented December 9, 2021.