SAN ANTONIO – Among patients with hormone receptor-positive breast cancer treated with an aromatase inhibitor plus palbociclib (Ibrance), those who displayed a rising ESR1 mutation detected in their blood before disease progression doubled their median progression-free survival following a switch to fulvestrant (Faslodex) plus palbociclib, according to results from the phase III PADA-1 clinical trial presented at the San Antonio Breast Cancer Symposium, held December 7-10, 2021.
“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 presenter François-Clément Bidard, MD, PhD, a professor of medical oncology at Institut Curie and Paris-Saclay University in France. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”
Patients with breast tumors that express estrogen receptor alpha (ERα) are often treated with aromatase inhibitors—drugs that block the body’s production of estradiol, the molecule that activates ERα and drives tumor growth. In recent years, studies have shown that these patients may derive more benefit from concurrent treatment with cell cycle inhibitors such as palbociclib, leading to the FDA approval of the combination as a first-line therapy in 2017.
Tumors can become resistant to aromatase inhibitors, however, by mutating ESR1, the gene that encodes ERα, so that it no longer requires estradiol to function. In this case, PADA-1 shows that some patients can benefit from the switch to another drug, such as fulvestrant, which degrades the estrogen receptor, while maintaining palbociclib.
“Fulvestrant remains effective against receptors with these mutations, but it provides a limited progression-free survival benefit when used as a second-line therapy,” Bidard said. “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.”
Blood-based detection of cancer-associated mutations provides a noninvasive means of monitoring patients for disease progression and may predict resistance to an ongoing therapy before it is visible by other detection methods. One method of detecting specific mutations in cell-free DNA harvested from blood is droplet digital PCR (ddPCR), a sensitive assay which can identify relatively small amounts of mutant DNA. Bidard and colleagues previously developed a ddPCR assay for the identification of ESR1 mutations, which they used in this study.
The PADA-1 trial recruited 1,017 patients with ERα-positive breast cancer that had no overexpression of the growth factor receptor HER2, who were being treated in a first-line setting with an aromatase inhibitor plus palbociclib. The patients provided blood samples for ESR1 mutation screening every two months.
Of the recruited patients, 407 experienced disease progression in the absence of an ESR1 mutation, and a mutation was detected in 279 patients prior to (219 patients) or concurrent with (60 patients) disease progression. Only those with an identified mutation who did not experience concurrent disease progression were randomly assigned either to continuing an aromatase inhibitor plus palbociclib (84 patients) or switched to fulvestrant plus palbociclib (88 patients).
After a median follow-up of 26 months, the median progression-free survival of patients who switched to fulvestrant was over twice as long as those who remained on an aromatase inhibitor—11.9 months, compared with 5.7 months.
Patients who progressed after continuing aromatase inhibitor treatment were given the option to cross over to the fulvestrant arm of the study. Among patients in the crossover cohort, the median progression- free survival was 3.5 months. This supported previous studies showing a relatively short benefit of fulvestrant when used as a second-line therapy, Bidard said, and emphasized the importance of early detection.
“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,” he 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.”
According to Bidard, future directions include learning more about the clinical features of ESR1-mutated tumors and trying to predict which patients will develop mutations. He mentioned that two other clinical trials investigating the efficacy of switching therapy after detection of an ESR1 mutation—the phase II INTERACT trial and the phase III SERENA-6 trial—are also ongoing.
Limitations of this study include the fact that the investigators who determined progression-free survival were not blinded to which treatment arm a patient was randomized to, and the fact that the ddPCR assay used to detect ESR1 mutations is not certified for clinical use in the United States.
This study was funded by Pfizer. Bidard holds a patent for the ESR1 ddPCR assay used in this study; receives consulting fees from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, Radius Health, Roche Pharmaceuticals, and Sanofi; receives fees for other services from Pfizer and Seagen; and performs contracted research for Pfizer, ProLynx Inc., and Seagen.
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
Background: ESR1 mutations are known drivers of resistance to first line aromatase inhibitors (AI)-based therapy in hormone receptor-positive (HR+) HER2- metastatic breast cancer (mBC) patients (pts), but their clinical actionability remains unknown. The randomized phase 3 PADA-1 trial aimed at evaluating the clinical benefit associated with a switch to fulvestrant-palbociclib upon the detection of a rising ESR1 mutation in blood (bESR1mut) in HR+ HER2- mBC pts treated by first line AI-palbociclib.Methods: PADA-1 (NCT03079011), a multicenter, randomized, open-label, phase 3 trial, enrolled HR+ HER2- mBC pts with no prior therapy for mBC in the absence of AI-resistance. In the first step, pts were treated with AI-palbociclib as first line therapy and underwent centralized bESR1mut screening every two months. Rising bESR1mut+ pts with no clinical/imaging concomitant disease progression were included in the second step, in which they were randomized between continuing the same therapy (standard arm) or switching to fulvestrant-palbociclib (experimental arm). The third step consisted in an optional crossover to fulvestrant-palbociclib following tumor progression for patients randomized in the standard arm. PADA-1 co-primary endpoints were PFS in the second step, and global safety. Results: Between 03/2017 and 01/2019, 1,017 pts have been included in the first step. After a median time of 15.6 months in the first step, 172 pts with rising bESR1mut and no synchronous disease progression were randomized to continuing AI-palbociclib (N=84 pts) or to fulvestrant-palbociclib (N=88 pts). Among the 172 randomized pts, N=136 PFS events have been observed in the second step after a median follow-up of 26 months. The median PFS was 5.7 months (95%CI[3.9;7.5]) in the AI-palbociclib arm and 11.9 months (95%CI[9.1;13.6]) in the fulvestrant-palbociclib arm (HR=0.63; 95%CI|0.45-0.88], p=0.007). Among the 70 patients who subsequently developed a disease progression in the AI-palbociclib arm, 47 were included in the optional crossover cohort. With a median follow-up of 14.7 months and 37 events, the median second-PFS observed in the cross-over cohort was 3.5 months (95%CI [2.7-5.1]). Treatment safety and validation of the ESR1mut assay are reported separately (poster session #1) Conclusion: PADA-1 reached its primary objective. This first-of-its-kind liquid biopsy-based trial demonstrates that targeting bESR1mut-associated resistance through a change in the endocrine partner of palbociclib is feasible and allows a doubling in the subsequent median progression free survival. Funding: Pfizer
Bidard holds a patent for the ESR1 ddPCR assay used in this study; receives consulting fees from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, Radius Health, Roche Pharmaceuticals, and Sanofi; receives fees for other services from Pfizer and Seagen; and performs contracted research for Pfizer, ProLynx Inc., and Seagen.