The addition of palbociclib to endocrine therapy was not associated with preventing disease recurrence in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative early breast cancer, according to final results of the phase 3 PALLAS trial.
Final study results of the phase 3 PALLAS trial showed that adding palbociclib (Ibrance, Pfizer) to endocrine therapy in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative early breast cancer may not prevent disease recurrence.
Data from the global, prospective, open-label, randomized phase 3 PALLAS (PALbociclib CoLlaborative Adjuvant Study) trial — which were presented at the 2021 San Antonio Breast Cancer Symposium and simultaneously published in the Journal of Clinical Oncology — showed that even though the combination of CDK4/6 inhibitors with endocrine therapy has prolonged outcomes in the metastatic setting, those benefits were not observed in those with stage 2 to 3 disease.
The aim of the trial was to determine if adding Ibrance as an adjuvant treatment to endocrine therapy would suppress secondary tumor formation. Therefore, the main end point of the trial was invasive disease-free survival — defined as the time that a patient’s primary treatment ends, and the patient survives without any signs or symptoms of that cancer recurring. The researchers also evaluated invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival and overall survival (a survival rate or the length of time from the start of treatment that a patient is alive).
In the trial, Dr. Michael Gnant, a professor in the Department of Surgery at the Medical University of Vienna in Austria, and colleagues randomized patients to receive either two years of oral Ibrance at a dose of 125 milligrams once daily on days one through 21 of a 28-day cycle in combination with adjuvant endocrine therapy (2,884 patients) or adjuvant endocrine therapy alone for at least five years (2,877 patients).
In total, 5,796 patients were enrolled at 406 centers across 21 countries over three years, of which 5,761 patients were included in the intent to treat population.
At a median follow-up of 31 months, invasive disease-free survival events occurred in 252 patients (8.8%) in the Ibrance combination group and 263 patients (9.1%) of the endocrine therapy-only group. Similarly, four-year invasive disease-free survival rates were 84.2% vs 84.5%, respectively, with Ibrance only reducing the risk for invasive disease recurrence by 4%, which was not statistically significant.
In addition, there was no difference observed in the subgroup analysis or in the secondary endpoints of the trial.
No new safety signals were found among those treated with Ibrance. Any severity side effect occurred in 99.5% of the Ibrance group (grade 3, 67.5%; grade 4, 5.7%) and 89.7% of the endocrine therapy-only group (grade 3, 14.4%; grade 4, 0.8%). Serious side effects were observed in 13% of the Ibrance group, compared with 7.9% among those who received endocrine therapy alone. Of the 176 deaths recorded in the trial, Gnant noted that none were related to study treatment.
“The treatment was, in general, well tolerated in the early-disease setting,” he said during a presentation at the meeting. “Neutropenia, however, was an issue in the trial.”
Gnant added that because this was a pivotal trial in the curative setting, dose reduction and stoppages were “much stricter than we use nowadays in clinical practice. As a result, the rates of early discontinuation of palbociclib based on competing risk analysis were substantial.” For example, rates of early discontinuation of Ibrance at six, 12, 18 and 24 months were 17.9%, 30.2%, 38.3% and 44.9%, respectively.
“This relatively high proportion of patients who did not receive palbociclib the full two years was interpreted by some as a potential reason for the disappointing result. At the second interim analysis, we can today put this myth to rest.”
In the planned second interim analysis, at a median follow-up of 23.7 months, 170 patients in the Ibrance group and 181 patients in the endocrine therapy-only group experienced invasive disease-free survival events, with three-year rates of 88.2% and 88.5%, respectively.
“On the basis of these findings, this regimen cannot be recommended in the adjuvant setting,” the study authors concluded in the study, published in Lancet Oncology in January.
Gnant concluded, noting that long-term follow-up is essential to comprehensively examine outcomes in HR-positive luminal breast cancers, which is ongoing in the PALLAS trial. Moreover, there is an ongoing analysis in the Trans-PALLAS program, evaluating thousands of tumor blocks and blood samples, to improve the understanding of CDK4/6 inhibition and the contemporary management of HR-positive, HER2-negative breast cancer.