Stage-specific quality of life and tolerability of CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer: a narrative review.

BACKGROUND

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor tolerability should be interpreted alongside treatment benefit, patient-reported outcomes (PROs), and treatment continuation. This narrative review examines these outcomes in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic and early breast cancer.

SUMMARY: In MONALEESA-2, median overall survival (OS) was 63.9 versus 51.4 months with ribociclib plus letrozole versus letrozole alone (hazard ratio [HR] 0.76), while global health-related quality of life (HRQoL) was maintained. PALOMA-2 and MONARCH 3 improved progression-free survival (HRs 0.58 and 0.540) without demonstrated OS improvement. Earlier CDK4/6 inhibitor use in SONIA increased exposure and toxicity without demonstrating improved OS or global HRQoL. In monarchE, with abemaciclib plus endocrine therapy versus endocrine therapy alone, seven-year invasive disease-free survival (iDFS) was 77.4% versus 70.9% (HR 0.734), and OS was 86.8% versus 85.0% (HR 0.842). NATALEE showed a 4.5-percentage-point five-year iDFS difference; its OS estimate remained uncertain. Three-year mean global-health-status changes in NATALEE were -3.10 versus -1.96 points with ribociclib plus a nonsteroidal aromatase inhibitor versus the aromatase inhibitor alone. Grade ≥3 diarrhea occurred in 7.8% of abemaciclib-treated monarchE patients. PALLAS and PENELOPE-B did not demonstrate improved iDFS; 42.2% of PALLAS palbociclib initiators discontinued early, including 27.2% because of adverse events.

KEY MESSAGES: Global HRQoL, individual symptoms, and continuation answer different questions. Discussions about metastatic treatment should integrate disease control and sequencing; discussions about adjuvant treatment should address absolute recurrence reduction and planned duration. Both require consideration of baseline symptoms, uncertainty, and individual priorities.