For certain patients with hormone receptor–positive breast cancer, switching from an aromatase inhibitor plus palbociclib to fulvestrant plus palbociclib after an estrogen receptor 1 (ESR1) mutation was detected significantly increased progression-free survival (PFS), a new study found.

Specifically, among patients whose ESR1 mutation was detected before disease progression, the median PFS doubled for those who switched to fulvestrant compared with those who remained on an aromatase inhibitor, the results from the 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,” said lead study author Francois-Clement Bidard, MD, PhD, a professor of medical oncology at Institut Curie and the University of Paris-Saclay, in France, who spoke at a press conference during the San Antonio Breast Cancer Symposium (abstract GS3-05).

Patients with breast tumors that express estrogen receptor alpha (ERalpha) often are treated with aromatase inhibitors to block production of estradiol, which activates ERalpha and drives tumor growth. Tumors can become resistant to aromatase inhibitors, however, by mutating ESR1, the gene that encodes ERalpha, so it no longer requires estradiol to function.

The PADA-1 trial recruited 1,017 patients with ERalpha-positive breast cancer that had no overexpression of HER2, who were being treated in a first-line setting with an aromatase inhibitor plus palbociclib (Ibrance, Pfizer). 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, while a mutation was detected in 279 patients before (n=219) or concurrent with (n=60) disease progression. Only those with an identified mutation who did not experience concurrent disease progression were randomly assigned to continue receiving an aromatase inhibitor plus palbociclib (n=84) or switch to fulvestrant plus palbociclib (n=88).

After a median follow-up of 26 months, the median PFS was 11.9 months among the patients who switched to fulvestrant and 5.7 months in those who remained on an aromatase inhibitor (hazard ratio [HR], 0.63; 95% CI, 0.45-0.88; P<0.007). Patients whose disease progressed after continuing aromatase inhibitor treatment were given the option to cross over to the fulvestrant and palbociclib arm of the study. In the crossover group, the median PFS was 3.5 months.

The targeted approach—after the start of the first-line endocrine therapy but before the second line—yields a statistically and clinically significant gain in PFS, Dr. Bidard said. However, that benefit might not catch up when patients wait, which might justify the adoption of the PADA-1 treatment strategy as a valid option in routine care, he said.

“This is an excellent trial that validates the discovery in the laboratory, a few years ago, that estrogen receptor mutations do not depend on the estrogen hormone,” Carlos Arteaga, MD, the director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, in Dallas, said at the press conference. “The aromatase inhibitor arm of the study was clearly inferior to the fulvestrant-containing arm.”

—Kate O’Rourke

Dr. Bidard reported that he holds a patent for the ESR1 ddPCR assay used in this study and has financial relationships with AstraZeneca, Lilly, Novartis, Pfizer (which funded the study), ProLynx, Radius Health, Roche, Sanofi and Seagen. Dr. Arteaga reported financial relationships with Arvinas, AstraZeneca, Athenex, Daiichi Sankyo, Immunomedics, Lilly, Merck, Novartis, Pfizer, Provista, Taiho Oncology and Takeda.