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Clinical Trial
. 2024 Aug:76:103761.
doi: 10.1016/j.breast.2024.103761. Epub 2024 Jun 11.

Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer

Serena Di Cosimo  1 , José Manuel Pérez-García  2 , Meritxell Bellet  3 , Florence Dalenc  4 , Miguel J Gil Gil  5 , Manuel Ruiz-Borrego  6 , Joaquín Gavilá  7 , Elena Aguirre  8 , Peter Schmid  9 , Frederik Marmé  10 , Joseph Gligorov  11 , Andreas Schneeweiss  12 , Joan Albanell  13 , Pilar Zamora  14 , Duncan Wheatley  15 , Eduardo Martínez de Dueñas  16 , Kepa Amillano  17 , Eileen Shimizu  8 , Miguel Sampayo-Cordero  8 , Javier Cortés  18 , Antonio Llombart-Cussac  19
Affiliations
Clinical Trial

Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer

Serena Di Cosimo et al. Breast. 2024 Aug.

Abstract

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study.

Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive.

Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002).

Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.

Keywords: Absorption; Advanced breast cancer; Endocrine therapy; Palbociclib; Pharmacokinetic interaction; Proton pump inhibitors.

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Conflict of interest statement

Declaration of competing interest SDC reports consulting for MEDSIR and IQVIA and honoraria from Pierre-Fabre, Novartis, and AstraZeneca. JMPG reports consulting for Roche, Eiasi, Daichii Sankyo, AstraZeneca, Gilead, MSD and Seagen and travel expenses from Roche. MB reports consulting fees from Pfizer, Novartis, Lilly, and Steamline-Menarini; honoraria from Pfizer, Novartis, and Lilly; and trave support from Pfizer. FD reports travel grants for Daichii, Novartis, and Pfizer, and participation in monitor/advisory boards for Daiichi, Seagen, Novartis, Gilead, Lilly, and MSD. MGG reports honoraria from Pfizer, Novartis, and AstraZeneca, travel grants from Lilly, Daiichi-Sankyo, and Pfizer, and participation in monitoring/advisory boards for AstraZeneca, Seagen, and Gilead. MRB reports honoraria from Pfizer, Novartis, AstraZenca, and Daiichi Sankyo. JG reports consulting fees from Novartis, Pfizer, AstraZeneca; honoraria from Novartis; and travel support from Roche and AstraZeneca. EAO reports consulting for AstraZeneca, Daichii, Gilead, MSD, and Seagen; honoraria from AstraZeneca, Daichii, Lilly, MSD, and Seagen; travel support from Daichii, Lilly, Gilead, and AstraZeneca; and participation in monitor/advisory boards for Gilead, AstraZeneca, Seagen, and Dachii. PS reports honoraria from Pfizer, AstraZeneca, Novartis, Roche, Merck, and Boehringer Ingelheim; a consulting role for Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; and institutional grants from Roche, Genentech, Oncogenex, and Novartis. FM reports grants from Roche, Novartis, AstraZeneca, GSK, MSD, Clovis, Vaccibody, Gilead Sciences, and Esai; consulting fees from AstraZeneca, GSK, and Roche; honoraria from AstraZeneca, MSD, Lilly, Pfizer, Novartis, GSK, Clovis, Myriad, Daiich Sankyo, Seagen, Pierre-Fabre, and Agendia; travel support from AstraZeneca, GSK, Pfizer, and Roche; and participation in advisory boards for Palleos and Amgen. JG reports grant/research support from Roche, Eiasi, and Exact Science; honoraria or consultation fees from AstraZeneca, Daiichi, Eisai, Exact Science, Evapharm, GE Healthcare, Gilead, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Sothema and participation in company sponsored speaker's bureaus for Exact Science, Lilly, and Novartis. AS reports grants from Celgene, Roche, Abbvie; travel grants from Celgene, Roche, Pfizer, AstraZeneca, and honoraria from Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen, Pierre Fabre. JA reports trial funding from MEDSIR and consulting for Pfizer, Lilly, and Novartis. PZ reports honoraria from Pfizer, Novartis, Roche, and Pierre Fabre; and travel support from Pfizer, Novartis, Roche, and Lilly. DW reports honoraria from Pfizer, Novartis, AstraZeneca and travel grants from Roche, and Novartis. JC reports consulting for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo.; research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; stock shares for MEDSIR, Nektar Pharmaceuticals, Leuko (relative); Travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead; and Patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. LICENSED. ALC reports research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; consulting for Lilly, Roche, Pfizer, and Novartis; participation in speakers' bureaus for Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership in MEDSIR and Initia-Research. The remaining authors declare no conflicts of interest.

Figures

Fig. 1a
Fig. 1a
Progression-free survival between N-PPI and E-PPI users 95 % CI: 95 % confidence interval; HR: Hazard ratio; E-PPI, Early PPI user; N-PPI, PPI naïve; PFS: Progression-free survival; PPI: Proton pump inhibitors.
Fig. 1b
Fig. 1b
Progression-free survival between N-PPI and LT-PPI users. Abbreviations: 95 % CI, 95 % confidence interval; HR, Hazard ratio; LT-PPI, Long term PPI user; N-PPI, PPI naïve; PFS, progression-free survival; PPI, proton pump inhibitors.
Fig. 2
Fig. 2
Landmark analysis of progression-free survival at 3, 6, 12, 18, 24, and 30 months in N-PPI and PPI users. Abbreviations: 95 % CI, 95 % confidence interval; HR, Hazard ratio; Mo, months; N-PPI, PPI naïve; Nr, number; PFS, progression-free survival; PPI, proton pump inhibitors; Ref: reference category.
Fig. 3a
Fig. 3a
Overall survival between N-PPI and E-PPI users. 95 % CI: 95 % confidence interval; HR: Hazard ratio; E-PPI, Early PPI user; N-PPI, PPI naïve; OS: overall survival; PPI: Proton pump inhibitors.
Fig. 3b
Fig. 3b
Overall survival between N-PPI and LT-PPI users. 95 % CI: 95 % confidence interval; HR: Hazard ratio; LT-PPI, Long term PPI user; N-PPI, PPI naïve; OS, overall survival; PPI: Proton pump inhibitors.
Fig. 4
Fig. 4
Landmark analysis of overall survival at 3, 6, 12, 18, 24, and 30 months in N-PPI and PPI users. 95 % CI: 95 % confidence interval; HR: Hazard ratio; Mo: months; N-PPI, PPI naïve; Nr. Number; PFS: Progression-free survival; PPI: Proton pump inhibitors; ref: reference category.
Fig. 5
Fig. 5
Hematological adverse events in N-PPI and PPI users. Abbreviations: AEs, Adverse events; E-PPI, early PPI users; LT-PPI, Long-term PPI users; N-PPI, PPI naïve users; PPI: Proton pump inhibitors.
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