PALOMA-2 confirmed the results of PALOMA-1 study with statistically and clinically significant improvement in progression-free survival (PFS) for palbociclib plus letrozole versus placebo plus letrozole in patients with ER-positive, HER2-negative advanced breast cancer. However, at the time of the final analysis of the primary endpoint of PFS, overall survival (OS) data were immature.
OS was a secondary endpoint and was not significantly longer in the palbociclib arm according to Prof. David J. Slamon of the David Geffen School of Medicine at University of California Los Angeles in Santa Monica, CA, US, and colleagues who published the final OS analysis and updated safety data from PALOMA-2 study on 22 January 2024 in the JCO.
The authors wrote in the background that since the initial development and approval of palbociclib, first-in-class CDK4/6 inhibitor, for ER-positive, HER2-negative advanced breast cancer based on PALOMA-1 in 2015, the CDK4/6 inhibitors have transformed the treatment landscape and, in combination with endocrine treatment, have become the standard-of-care in this setting.
In the latest article published in the JCO, the authors report results of the final OS analysis and updated safety data from PALOMA-2 study. OS was a secondary endpoint, and defined as the time from the date of random assignment to the date of death because of any cause. In the absence of confirmation of death, survival time was censored to the last date the patient was known to be alive.
The median OS was assumed to be 34 months in first-line treatment with letrozole for advanced breast cancer at the time of study design. The final OS analysis was planned to be performed after at least 390 events, providing an 80% power to detect a hazard ratio (HR) ≤0.74, using a stratified log-rank test with a one-sided significance level of 0.025.
OS analysis was conducted in the intent-to-treat population. Median OS was estimated using the Kaplan-Meier method with the one-sided stratified log-rank test adjusting for the disease site at the α = 0.025 overall significance level. The HRs and two-sided 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression stratified by disease site (visceral versus non-visceral). The proportional hazard assumption was evaluated using Schoenfeld’s residual test.
A total, 666 postmenopausal women with ER-positive, HER2-negative advanced breast cancer, who did not receive previous systemic therapy for advanced disease, were randomly assigned 2:1 to palbociclib plus letrozole or placebo plus letrozole. After a median follow-up of 90.1 months, 405 deaths were observed, and 155 patients were alive. The median OS was 53.9 months (95% CI 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI 43.7 to 58.9) with placebo plus letrozole (HR 0.96, 95% CI 0.78 to 1.18; stratified one-sided p = 0.34).
An imbalance in the number of patients with unknown survival outcome between the treatment arms (13.3% versus 21.2%) limited interpretation of OS results. With recovered survival data, the median OS was 53.8 (95% CI 49.8 to 59.2) versus 49.8 months (95% CI 42.3 to 56.4) and HR was 0.92 (95% CI 0.76 to 1.12; one sided p = 0.21).
The safety profile of palbociclib plus letrozole remained consistent with that reported in the primary analysis. Neutropenia was the most frequent adverse event with palbociclib plus letrozole, 82.2% versus 6.3% with placebo plus letrozole.
The authors concluded that PALOMA trials demonstrated a statistically significant and clinically meaningful benefit with palbociclib plus endocrine treatment in the primary endpoint of PFS compared with placebo plus endocrine treatment or endocrine treatment alone in this setting. OS was a secondary endpoint in all PALOMA studies and was not significantly longer in the palbociclib arm of PALOMA-1 (37.5 versus 34.5 months; HR 0.90), PALOMA-2, and PALOMA-3 (34.9 versus 28.0 months; HR 0.81).
Time to chemotherapy was longer in the palbociclib arm in all three PALOMA studies, delaying exposure to therapies associated with increased toxicity. Currently, only ribociclib has shown a statistically significant improvement in OS in this setting.
The findings were presented previously in part at the ASCO 2022 Annual Meeting (3-7 June; Chicago, IL, US).
The study was supported by Pfizer Inc.
Reference
Slamon DJ, Diéras V, Rugo HS, et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. JCO; Published online 22 January 2024. DOI: https://doi.org/10.1200/JCO.23.00137
