Target trial emulation of first-line ribociclib versus palbociclib in hormone receptor-positive, HER2-negative...

Head-to-head randomized trials of CDK4/6 inhibitors are lacking. We emulated a target trial of first-line ribociclib versus palbociclib in hormone receptor-positive, HER2-negative metastatic breast cancer.

Using TriNetX (January 2014-March 2025), adults initiating first-line endocrine therapy plus ribociclib or palbociclib underwent 1:1 propensity score matching. The primary outcome was all-cause mortality. The co-primary calendar-restricted survival analysis applied a year-level restriction beginning January 1, 2017, the calendar year of ribociclib market entry.

The prescription-confirmed cohort comprised 11,685 patients; 4394 were matched (2197 per group; mean age 60.2 years; 97.9% female). In the whole-period co-primary analysis, ribociclib was associated with longer overall survival (hazard ratio [HR] 0.82, 95% CI 0.73-0.92) and a 48-month restricted mean survival difference of 1.7 months (95% CI 0.5-2.8). The all-initiator analysis removing the second-prescription requirement yielded HR 0.86 (95% CI 0.75-0.99) but did not restrict calendar time. The separately matched calendar-restricted co-primary analysis (from 2017; 1924 per arm) yielded HR 0.90 (95% CI 0.82-0.99); residual temporal confounding could favor ribociclib. Exploratory analyses showed lower cause-specific hazards of recorded hematologic events (neutropenia HR 0.69, thrombocytopenia HR 0.52, anemia HR 0.80) and higher hazards of recorded QT prolongation and dermatologic events (HR 1.61 and 1.41); no detectable differences were observed for healthcare utilization or severe infections.

Both co-primary analyses showed an association with longer overall survival for ribociclib, with attenuation in the calendar-restricted analysis (HR 0.90, 95% CI 0.82-0.99). These findings are hypothesis-generating, not evidence of superiority, and require randomized confirmation.