Immune checkpoint inhibitor (ICI)-based combination therapies have become the standard first-line treatment for metastatic renal cell carcinoma (mRCC). Proton-pump inhibitors (PPIs), frequently used to treat gastrointestinal conditions, have been implicated in modulating ICI efficacy, potentially through gut microbiome dysbiosis. However, the impact of PPIs on ICI-based therapies for mRCC remains unclear.
This multicenter retrospective cohort study analyzed 427 patients with mRCC classified as intermediate or poor risk according to the IMDC criteria treated with first-line IO-IO (ipilimumab plus nivolumab) or IO-TKI (ICI plus tyrosine kinase inhibitor) therapies. Patients were stratified by PPI use during the 30 days before and including the day of ICI initiation. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were compared between PPI users and nonusers.
PPI use was significantly associated with shorter OS in patients receiving IO-IO therapy (median OS, 23.34 months vs. not reached; P = .002), but not in those receiving IO-TKI therapy (P = .909). Multivariate analysis confirmed PPIs as an independent prognostic factor for OS in the IO-IO group (HR, 1.647; 95% CI, 1.007-2.693; P = .046). No significant differences in PFS or ORR were observed between PPI users and nonusers in either group, although the complete response rate was notably lower in PPI users treated with IO-IO (1.6% vs. 10.3%; P = .025).
PPI use was associated with inferior survival in mRCC patients receiving IO-IO therapy, potentially through microbiome modulation and other immunologic or clinical mechanisms; however, these findings are based on retrospective data and should be regarded as hypothesis-generating. Caution is advised when prescribing PPIs to patients undergoing ICI-based therapy, particularly IO-IO regimens, and prospective studies are needed to confirm whether avoiding unnecessary PPI use can improve clinical outcomes.
Clinical genitourinary cancer. 2026 Jan 03 [Epub ahead of print]
Lan Inoki, Shingo Toyoda, Wataru Fukuokaya, Takafumi Yanagisawa, Teruo Inamoto, Takuhisa Nukaya, Kiyoshi Takahara, Takuya Tsujino, Ryoichi Maenosono, Kazumasa Komura, Kensuke Bekku, Motoo Araki, Takehiro Iwata, Kazutoshi Fujita, JK-FOOT study group
Department of Urology, Kindai University Faculty of Medicine, Sakai City, Osaka Prefecture, Japan., Department of Urology, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan., Department of Urology, Hamamatsu University School of Medicine, Hamamatsu City, Shizuoka Prefecture, Japan., Department of Urology, Fujita-Health University School of Medicine, Toyoake-shi, Aichi, Japan., Department of Urology, Osaka Medical and Pharmaceutical University, Takatsukishi, Osaka, Japan., Department of Urology, Kawasaki Medical School, Kurashiki City, Okayama Prefecture, Japan., Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama Prefecture, Japan., Department of Urology, Kindai University Faculty of Medicine, Sakai City, Osaka Prefecture, Japan. Electronic address: .