In a preplanned final analysis of the PENELOPE-B study, after a median follow-up of 77.8 months, adding one year of palbociclib to standard adjuvant endocrine treatment showed no improvement in overall survival (OS) or invasive disease-free survival (iDFS) compared to placebo in patients with high-risk hormone receptor (HR)-positive, HER2-negative primary breast cancer with residual disease after neoadjuvant chemotherapy (NACT).
Results were consistent across subgroups, except for patients with lobular breast cancer, in which the study team observed a trend for improved iDFS and OS for palbociclib. The findings were published by Prof. Sibylle Loibl of the German Breast Group in Neu-Isenburg, Germany and colleagues on 24 March 2025 in the Annals of Oncology.
Patients with HR-positive, HER2-negative breast cancer and residual disease after NACT have a substantial relapse risk. After a median follow-up of 42.8 months in the PENELOPE-B study, the addition of palbociclib compared to placebo for one year did not improve iDFS (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; p = 0.52) nor OS (hazard ratio 0.87, 95% CI 0.61-1.22; p = 0.42). In the latest article, published in the Annals of Oncology, the study investigators reported the final OS analysis and updated iDFS analysis and other time to event endpoints after prolonged follow-up.
High relapse risk was defined as presence of clinical and pathologic stage and oestrogen receptor status and histologic grade score ≥ 3 or 2 and ypN+ after taxane-based NACT. A total of 1250 patients were randomly assigned to receive either palbociclib 125 mg or placebo from day 1 to 21 in 4 week cycles for 13 cycles in addition to endocrine treatment.
After a median follow-up of 77.8 months, the study investigators recorded 225 deaths (108 in the palbociclib arm and 117 in the placebo arm) with 6-year OS rate of 82.4% in the palbociclib arm versus 80.3% in the placebo arm (hazard ratio 0.87, 95% CI 0.67-1.14; p = 0.31]. No significant improvement was noted for palbociclib versus placebo for iDFS, distant disease-free survival or locoregional relapse rate, even with longer follow-up.
Upon stratified analysis, the study team found no benefits across major subgroups. However, exploratory post-hoc analyses of the lobular breast cancer subgroup indicated a trend towards better survival outcomes in favour of palbociclib with hazard ratio of 0.45 (95% CI 0.19-1.07; p=0.062) for OS and 0.52 (95% CI 0.28-0.97; p=0.035) for iDFS.
To further elaborate the potential benefits of palbociclib in patients with lobular breast cancer, the study team classified patients according to E-cadherin expression. In the subgroup of patients with lobular breast cancer with low E-cadherin expression, the difference between the treatment arms was clearly visible with hazard ratio for OS of 0.30 (95% CI 0.07-1.25; p=0.08) and hazard ratio for iDFS of 0.33 (95% CI 0.09-1.17; p=0.07).
The authors commented that the patients with lobular breast cancer, particularly those with reduced E-cadherin expression, may derive benefit from addition of one year adjuvant palbociclib to standard of care or endocrine treatment. Further research is essential to identify precise biomarkers to refine patient selection and determine subgroups that will benefit from adjuvant treatment with CDK4/6 inhibition.
The study was funded by Pfizer Inc.
Reference
Loibl S, Martin M, Bonnefoi H, et al. Final Survival Results from the Penelope-B trial investigating palbociclib vs placebo for patients with high-risk HR+/HER2- breast cancer and residual disease after neoadjuvant chemotherapy – PENELOPE-B. Annals of Oncology; Published online 24 March 2025. DOI: 10.1016/j.annonc.2025.03.010