UNLABELLED: The randomized phase II MA.38 trial estimated the relative progression-free survival (PFS) associated with second-line endocrine therapy plus palbociclib administered on a 100 mg continuous daily dosing (CDD) schedule compared with the standard dose schedule (SDS) of 125 mg (days 1-21 of a 28-day cycle). A total of 180 patients were allocated 1:1 to protocol therapy. Molecular profiling was performed on the archival tissue and cell-free DNA (cfDNA) at enrollment, 3 months, and 6 months. The primary analysis for PFS demonstrated a similar outcome for the CDD versus SDS treatment strategy: HR = 0.93 (90% confidence interval, 0.66-1.30). Secondary efficacy measures for CDD versus SDS included the following: overall survival, HR = 1.07 (90% confidence interval, 0.67-1.69); response rate, 16.1% versus 18.0% (P = 0.66); median duration of response, 4.2 months (range, 2.8-13.9 months) versus 5.6 months (range, 2.4-13.9 months; P = 0.86); and clinical benefit rate, 53.2% versus 57.3% (P = 0.89). cfDNA profiling of the baseline enrollment sample prior to palbociclib commencement showed low tumor fraction (HR = 2.28; P = 9.9 × 10-6); higher short/long fragment length ratios (HR = 1.19; P = 0.049) and cfDNA variants in FGFR4 (HR = 3.65; P = 0.012) were prognostic and associated with inferior PFS. Variants in TP53 (HR = 2.48; P = 0.006) and ESR1 (HR = 3.42; P = 0.005) detected at 12 weeks on treatment were also associated with poor PFS. CDD palbociclib 100 mg dosing was not associated with improved efficacy compared with the standard intermittent 125 mg dosing schedule. Additionally, we identified prognostic biomarkers in alignment with prior research and demonstrated the value of cfDNA dynamics, including fragment length ratios and tumor fraction as a measure of treatment response. SIGNIFICANCE: A continuous 100 mg dosing schedule of palbociclib was tolerable but not associated with improved efficacy signals versus the standard intermittent 125 mg (days 1-21 of a 28-day cycle) schedule. Mutations detected in liquid biopsies and changes in cfDNA dynamics were linked to poor outcomes and may identify patients with treatment-resistant cancer.