The international phase III PALLAS trial has demonstrated that adding palbociclib to standard adjuvant endocrine therapy fails to improve outcomes in hormone receptor-positive (HR+), HER2-negative early breast cancer patients, regardless of disease stage.
The study, which enrolled 5,796 patients, including 1,010 with stage IIA disease, reached a median follow-up of 50 months for stage IIA patients and 43.1 months overall. Results showed no significant benefit from palbociclib across all disease stages and endpoints.
For stage IIA patients, the 4-year invasive disease-free survival (iDFS) was 92.9% in the palbociclib plus endocrine therapy arm versus 92.1% for endocrine therapy alone (HR 0.75, 95% CI 0.48–1.19, p = 0.23). Similarly, stage IIB/III patients showed no significant improvement, with 4-year iDFS rates of 85.3% versus 83.6% respectively (HR 0.91, 95% CI 0.77–1.07, p = 0.24).
Contrasting Results with Other CDK4/6 Inhibitor Trials
The PALLAS findings stand in marked contrast to positive results from similar trials. The MONARCH-E trial with abemaciclib and the NATALEE trial with ribociclib both demonstrated significant improvements in invasive disease-free survival. The divergent outcomes might be attributed to differences in CDK target potency or varying risk profiles among study populations.
Patient Population and Risk Stratification
A key distinction of the PALLAS trial was its inclusion of lower-risk, node-negative stage IIA patients without additional high-risk features. Unlike MONARCH-E and NATALEE, which required specific risk factors such as high Ki-67 or genomic risk scores, PALLAS eligibility was based solely on pathologic stage.
Secondary Endpoints and Subgroup Analysis
The study found no benefit from palbociclib across multiple secondary endpoints for stage IIA patients, including:
- Invasive breast cancer-free survival (94.8% vs. 94.2%)
- Locoregional relapse-free survival (98.1% vs. 98.2%)
- Distant relapse-free survival (95.3% vs. 95.2%)
- Overall survival (97.7% vs. 98.1%)
Future Implications and Research Direction
The trial results suggest that the era of large adjuvant trials based solely on clinical stage may be ending. The PALLAS investigators are now conducting correlative analyses of RNA-based gene expression profiles, germline DNA, and circulating biomarkers to identify potential subgroups who might benefit from palbociclib.
The TRANS-PALLAS biospecimen bank, containing tumor blocks and serial blood samples from all participants, will be crucial for investigating:
- Genomic predictors of poor prognosis
- Endocrine therapy response markers
- Longitudinal assessment of circulating tumor DNA
- Mechanisms of tumor dormancy and reactivation
These analyses may help develop biomarker-enriched trial designs and identify patients who truly need treatment escalation, potentially transforming the approach to adjuvant therapy in HR+ breast cancer.
