The addition of palbociclib to a 2-year course of adjuvant endocrine therapy did not meaningfully improve invasive disease-free survival (DFS) over endocrine therapy alone in patients with early-stage breast cancer, according to an interim analysis of a phase 3 trial published in The Lancet Oncology.
These findings suggest the combination should not be considered an effective regimen for adjuvant therapy, according to the researchers.
Palbociclib, a CDK4/6 inhibitor, previously exhibited efficacy in improving progression-free survival when added to adjuvant endocrine therapy in patients with hormone receptor (HR)–positive, HER2–negative metastatic breast cancer.
Erica L. Mayer, MD, MPH, senior physician at Dana-Farber Cancer Institute, and colleagues initiated the randomized, open-label PALLAS trial to determine whether the combination was effective in preventing invasive DFS among early-stage patients with HR–positive, HER2–negative disease.
Mayer and colleagues randomly assigned an international cohort of 5760 patients (median age, 52 years; interquartile range [IQR], 45-61) to a 2-year course of adjuvant palbociclib plus endocrine therapy (n = 2883) or endocrine therapy alone (n = 2877).
Patients assigned palbociclib received the agent orally (125 mg) on days 1-21 of a 28-day cycle. Endocrine therapy consisted of tamoxifen or an aromatase inhibitor, based on provider or patient choice, with or without a concurrent luteinising hormone-releasing hormone agonist.
In total, 58.7% of the cohort (n = 3382) had high-clinical-risk disease, which the researchers defined as involvement of four or more nodes; or one to three nodes with T3 or T4, grade 3 disease, or both.
Median follow-up at the planned interim analysis was 23.7 months (IQR, 16.9-29.2). At the time of reporting, invasive DFS events had occurred in 170 patients assigned palbociclib plus endocrine therapy, and in 183 patients assigned endocrine therapy alone.
The 3-year rates of invasive DFS did not significantly differ between patients assigned palbociclib and those assigned endocrine therapy alone (88.2% vs. 88.5%; hazard ratio [HR], 0.93; 95% CI, 0.76-1.15). Similarly, the researchers did not observe a significant difference in 3-year rates of distant recurrence-free survival (89.3% vs. 90.7%; HR, 1; 95% CI, 0.79-1.27).
“[T]he test statistic comparing invasive DFS between groups crossed the prespecified futility boundary, leading the independent data monitoring committee to recommend the discontinuation of palbociclib in patients receiving palbociclib plus endocrine therapy and moving all patients to the follow-up phase of the study — a recommendation approved by the PALLAS steering committee,” Mayer and colleagues wrote.
A post-hoc analysis found that no prespecified subgroup benefited from the addition of palbociclib to adjuvant endocrine therapy.
A total of 99.4% of patients assigned palbociclib plus endocrine therapy and 88.6% of patients assigned endocrine therapy alone experienced a treatment-emergent adverse event of any grade. The most frequent grade 3-4 adverse events included neutropenia (palbociclib plus endocrine therapy vs. endocrine therapy alone, 61.3% vs. 0.3%), leukopenia (30.2% vs. 0.1%) and fatigue (2.1% vs. 0.3%). Serious adverse events were observed in 12.7% of patients assigned palbociclib plus endocrine therapy and in 7.6% of patients assigned endocrine therapy alone — the most common being tissue infection (1.7% vs. 1%) and upper respiratory tract infection (0.8% vs. 0.1%).
The researchers observed no new safety signals or treatment-related deaths.
“The PALLAS trial represents an important global collaboration between academia, community practice and industry, rapidly achieving its desired target accrual to answer an important question about the management of breast cancer,” Mayer and colleagues concluded. “The results of the PALLAS study remind us that benefits observed in the metastatic setting do not necessarily translate into the adjuvant setting, underscoring the importance of doing well-designed adjuvant trials to determine the potential efficacy of such therapies.”