Antacid co-treatment and pregnane X receptor genetic polymorphisms are survival determinants in patients treated with palbociclib.

BACKGROUND

Palbociclib is the more extensively evaluated CDK4-6 inhibitor in term of safety, efficacy and sources of pharmacokinetic variability. However, real-life data on the correlation between palbociclib plasma concentration, drug-drug interactions, gene polymorphisms and efficacy remain scarce. We previously characterized the effects of co-medications (CYP3A4 and P-glycoprotein inhibitors and antacid drugs) on palbociclib plasma concentration, and here we wanted to identify factors that influence progression-free survival in the same cohort of patients.

METHODS

This multicentric prospective clinical trial included patients with metastatic breast cancer treated with first-line palbociclib and an aromatase inhibitor. Efficacy (progression-free survival) and safety (high-grade neutropenia during the first two cycles) were reported, and the influence of covariates, such as drug-drug interactions, palbociclib plasma concentration and specific gene variants, were analyzed.

RESULTS

In the 58 included patients, drug-drug interactions (antacid drugs) and pregnane X receptor (NR1I2) single nucleotide polymorphisms (SNP) were identified as survival prognostic factors, but not palbociclib concentration and high-grade neutropenia (p = 0.4 and p = 0.5). Concomitant antacid treatment reduced progression-free survival (26.2 vs. 32.6 months, p = 0.059) and the NR1I2 rs10934498 and rs2276707 SNPs affected survival (p = 0.002 and 0.004).

CONCLUSION

This study consolidated the data on palbociclib as first-line metastatic breast cancer treatment and identified factors that negatively influence survival (co-treatment with antacid drugs and NR1I2 SNPs).

TRIAL REGISTRATION: NCT04025541, Registration Date 2019-07-16.