Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study

Abstract

Introduction Approximately 20–33% of all cancer patients are treated with acid-reducing agents (ARAs), most commonly proton pump inhibitors (PPIs), to reduce gastroesophageal reflux disease symptoms. Palbociclib and ribociclib are weak bases so their solubility depends on different pH. The solubility of palbociclib dramatically decreases to < 0.5 mg/ml when pH is above 4,5 but ribociclibs’ solubility decreases when pH increases above 6,5. In the current study, we aimed to investigate the effects of concurrent PPIs on palbociclib and ribociclib efficacy in terms of progression-free survival in metastatic breast cancer (mBC) patients. Patients and methods We enrolled hormone receptor-positive, HER2-negative mBC patients treated with endocrine treatment (letrozole or fulvestrant) combined palbociclib or ribociclib alone or with PPI accompanying our observational study. During palbociclib/ribociclib therapy, patients should be treated with "concurrent PPIs" defined as all or more than half of treatment with palbociclib/ribociclib, If no PPI was applied, it was defined as ‘no concurrent PPI’, those who used PPI but less than half were excluded from the study. All data was collected from real-life retrospectively. Results Our study included 217 patients, 105 of whom received palbociclib and 112 received ribociclib treatment. In the study population CDK inhibitor treatment was added to fulvestrant 102 patients ( 47%), to letrozole 115 patients (53%). In the Palbociclib arm fulvestrant/letrozole ratio was 53.3/46.7%, in the ribociclib arm it was 41.07/58.93%. Of 105 patients who received palbociclib, 65 were on concomitant PPI therapy, 40 were not. Of the 112 patients who received ribociclib, 61 were on concomitant PPI therapy, 51 were not. In the palbociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (13.04 months vs. unreachable, p < 0.001). It was determined that taking PPIs was an independent predictor of shortening PFS (p < 0.001) in the multivariate analysis, In the ribociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (12.64 months vs. unreachable, p = 0.003). It was determined that taking PPIs was single statistically independent predictor of shortening PFS (p = 0.003, univariate analysis). Conclusions Our study demonstrated that concomitant usage of PPIs was associated with shorter PFS in mBC treated with both ribociclib and especially palbociclib. If it needs to be used, PPI selection should be made carefully and low-strength PPI or other ARAs (eg H2 antagonists, antacids) should be preferred.

The effect of concomitant use of proton pump inhibitors with CDK 4/6 inhibitors on survival in metastatic breast cancer

“…It has been revealed in previous studies that, in metastatic breast cancer patients receiving palbociclib, compared to non-use, concomitant PPI use reduces PFS [17,20]. In addition, these studies demonstrated that concomitant PPI use is an independent risk factor for a shorter PFS [17,20].…”

Concomitant administration of proton pump inhibitors does not significantly affect clinical outcomes in metastatic breast cancer patients treated with ribociclib

“…This appears to be of particular clinical relevance when a dose reduction of ribociclib may be required because of toxicity. Noteworthy, the results from a recently published observational study suggest the opposite conclusion that PPIs may reduce the efficacy of ribociclib in metastatic breast cancer patients [ 21 ]. However, the higher doses of PPIs (twice the drug doses administered in our work) and heterogeneity of drugs used in that work, compared to our study, might partially account for such a difference.…”

“…Subgroup analysis carried out in our cohort suggests that PPIs do not affect PFS, regardless of the endocrine resistance or sensitivity. Although a two-way classification (PPI yes/no, endocrine resistance yes/no) may have reduced sample size, such an approach has also been applied in previously published works [ 13 , 21 ]. Other unknown factors that could influence clinical outcomes were a different lifestyle in PPI users compared to non-users, e.g., alimentary disorders or unhealthy conditions associated with worse outcomes in breast cancer, and the lack of information about fed or fasting conditions during PPI administration.…”

Physicians lectuar abstracts

“…Several studies apostrophize detrimental effects on PFS due to concomitant use of PPIs and CDK 4/6 inhibitors. (5,6) Suppression of gastric acidity changes the composition of the gut microbiome, inducing a higher risk of enteric infections or impaired absorption of some micronutrients. Ergo, the possible direct impact on the impaired response to immunotherapy.…”

“…Nekoliko studija ističe kako istodobno korištenje IPP-ova i CDK 4/6 inhibitora ima negativan utjecaj na vrijeme do progresije bolesti. (5,6) Smanjenjem lučenja želučane kiseline mijenja se sastav crijevnog mikrobioma, mogući je veći rizik enteralnih infekcija te je slabija apsorpcija mikronutijenata. Opisano se pret postavlja uzrokom slabijeg odgovora na imunoterapiju.…”