Early treatment switch may benefit patients with estrogen receptor mutations
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A liquid biopsy-based approach to treatment selection improved outcomes among patients with hormone receptor-positive, HER2-negative metastatic breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
Patients treated with an aromatase inhibitor plus the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance, Pfizer) who displayed a rising ESR1 mutation in their blood prior to disease progression doubled their median PFS if they switched to fulvestrant plus palbociclib rather than remaining on the same regimen, results of the randomized phase 3 PADA-1 trial showed.
“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,” François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Paris-Saclay University in France, said in a press release. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”
Patients with ER-positive breast cancer often receive aromatase inhibitors. These agents block production of estradiol, which activates ER-alpha and drives tumor growth. Prior studies showed patients may benefit from concurrent therapy with cell cycle inhibitors, such as palbociclib.
However, tumors can become resistant to aromatase inhibitors by mutating ESR1, a gene that encodes ER-alpha, so it no longer requires estradiol to function. Researchers hypothesized switching to another drug — such as fulvestrant, which degrades the estrogen receptor — but maintaining palbociclib could be beneficial for some patients.
Bidard and colleagues conducted the multicenter, open-label PADA-1 trial to assess the clinical benefit of switching therapy — from a first-line aromatase inhibitor-palbociclib regimen to a fulvestrant-palbociclib combination — upon detection of a rising ESR1 mutation via circulating tumor DNA.
The study included patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had received no prior therapy for metastatic breast cancer in the absence of aromatase inhibitor-resistance.
In the study’s first step, patients received an aromatase inhibitor plus palbociclib as first-line therapy and underwent centralized ESR1 mutation screening every 2 months.
“Our goal was to track the emergence of ESR1 mutations in patients’ blood during first-line therapy and act on them as soon as they appeared, before they led to an actual clinical progression of the disease,” Bidard said.
Patients found to have rising ESR1 mutations with no concomitant disease progression per clinical assessment or imaging advanced to the study’s second step, in which researchers randomly assigned them to either continue their same therapy or switch to fulvestrant-palbociclib. Patients assigned to continue initial therapy could cross over to fulvestrant-palbociclib following tumor progression.
PFS in the study’s second step and safety served as the study’s co-primary endpoints.
Researchers enrolled 1,017 patients between March 2017 and January 2019.
After a median 15.6 months in the study’s first step, 172 patients found to have rising ESR1 mutations but no synchronous disease progression advanced to the randomization phase. Researchers randomly assigned 84 patients to the standard group and 88 patients to the experimental group.
After median follow-up of 26 months, 136 PFS events occurred in the study’s second step.
Researchers reported significantly longer median PFS among patients who switched to fulvestrant-palbociclib than those who remained on the aromatase inhibitor-palbociclib regimen (11.9 months vs. 5.7 months; HR = 0.63; 95% CI, 0.45-0.88).
Seventy patients randomly assigned to continue the aromatase inhibitor-palbociclib regimen developed disease progression, and 47 crossed over to fulvestrant-palbociclib.
After median follow-up 14.7 months, 37 events had occurred. Researchers reported median second PFS in the crossover cohort of 3.5 months (95% CI, 2.7-5.1). This finding supports prior studies that suggested limited benefit of fulvestrant as second-line therapy, Bidard said.
Additional studies are needed to yield insights about the clinical features of ESR1-mutated tumors, as well as to better predict which patients may develop these mutations, researchers wrote.
Researchers acknowledged two limitations to their study: The digital droplet polymerase chain reaction assay used to detect ESR1 mutations is not certified for clinical use in the United States, and the investigators who calculated PFS were not blinded to the treatment group patients were assigned to in the randomization stage.
“This targeted approach, after the start of the first-line endocrine therapy but before the second line, yields a statistically and clinically significant gain in progression-free survival,” Bidard said. “That benefit might not catch up when you wait, which might justify the adoption of the PADA-1 treatment strategy as a valid option in routine care.”
Perspective
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This is a tremendously exciting study, as it is the first in breast cancer to show that switching therapy based on genomic findings prior to clinical progression improves outcomes for patients with metastatic breast cancer. Patients with emerging acquired ESR1 mutations — which confer resistance to aromatase inhibitors — found on circulating tumor DNA who switched from an aromatase inhibitor plus a CDK 4/6 inhibitor to fulvestrant with continuation of the CDK 4/6 inhibitor achieved more than a doubling of PFS (from 5.7 to 11.9 months). However, patients who switched to fulvestrant based on standard clinical progression had only a PFS of 3.5 months. The implication is that early detection of resistant disease — and switching therapy based on this finding — actually makes a difference, and this had never been shown before. There are other ongoing trials investigating this finding, which hopefully will lend support to this approach.
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Bidard F-C, et al. Abstract GS3-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
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