Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2.

LBA1003 Background: PAL was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for ER+/HER2– ABC based on the randomized, phase 2 PALOMA-1 study. PALOMA-2 is a randomized, double-blind, phase 3 trial in first-line ER+/HER2– ABC that confirmed a clinically and statistically significant improvement in progression-free survival (PFS) with PAL+LET versus PBO+LET (median PFS, 27.6 vs 14.5 months; hazard ratio, 0.56 [95% CI, 0.46–0.69]; P<0.0001). At the time of the final PFS analysis, OS data were not mature. Herein, we report OS results. Methods: 666 postmenopausal women with ER+/HER2– ABC who had not received prior systemic therapy for advanced disease were randomized 2:1 to receive PAL (125 mg/d orally, 3/1 week schedule) plus LET (2.5 mg/d orally, continuously) or PBO+LET. The primary endpoint was investigator-assessed PFS and a key secondary endpoint was OS. Per study design, 390 OS events are required to have 80% power to detect a hazard ratio <0.74 at a significance level of 0.025 (1-sided) using a stratified log-rank test. The planned final OS analysis was conducted when the number of events required for the analysis was observed. Results: At data cut-off (November 15, 2021), with a median follow-up of 90 months, 43 patients (pts; 10%) remained on PAL+LET and 5 pts (2%) on PBO+LET. With 405 deaths, median OS (95% CI) was 53.9 months (49.8–60.8) in the PAL+LET arm and 51.2 months (43.7 –58.9) in the PBO+LET arm (hazard ratio, 0.956 [95% CI, 0.777–1.177]; stratified 1-sided P=0.3378). In this OS analysis, a proportion of pts were not available for follow-up (withdrew consent or lost to follow-up) and were censored: 21% in the PBO+LET arm versus 13% in the PAL+LET arm. A posthoc sensitivity analysis excluding these pts resulted in a median OS (95% CI) of 51.6 months (46.9–57.1) with PAL+LET and 44.6 months (37.0–52.3) with PBO+LET (hazard ratio, 0.869 [95% CI, 0.706–1.069]). Of the pts who discontinued study treatment, 81% in the PAL+LET arm and 88% in the PBO+LET arm received post-study systemic therapy; 12% and 27% of pts who discontinued received CDK4/6 inhibitor, respectively. In pts with disease-free interval (DFI) >12 months, median OS (95% CI) was 66.3 months (52.1–79.7) in the PAL+LET arm (n=179) and 47.4 months (37.7–57.0) in the PBO+LET arm (n=93); hazard ratio, 0.728 (95% CI, 0.528-1.005). No new safety findings were observed. Conclusions: PALOMA-2 met its primary endpoint of improving PFS but not the secondary endpoint of OS. Pts receiving PAL+LET had numerically longer OS compared to PBO+LET, but the results were not statistically significant. Funding: Pfizer Inc (NCT01740427) Clinical trial information: NCT01740427.