Heartburn treatment a poor match to cancer drug

Use of a common heartburn treatment in bladder cancer patients has been linked to significantly poorer health outcomes when patients are simultaneously taking a frequently prescribed immunotherapeutic drug.

Proton pump inhibitor (PPI) use was associated with worse outcomes in patients with the most common form of bladder cancer, urothelial cancer (which encompasses more than 80% of bladder cancers) when treated with the immunotherapeutic drug atezolizumab, compared with patients who did not use PPIs.

PPIs reduce acid production in the wall of the stomach and are commonly prescribed for acid reflux, heartburn and ulcers, and are used by around 30% of cancer patients. These medications are growing in use around the world and include esomeprazole (Nexium, Dexilant), lansoprazole (Zoton, Zopral), omeprazole (Losec, Maxor), pantoprazole (Somac, Ozpan) and rabeprazole (Parbezol, Pariet).

Recent evidence indicates they cause significant changes to the gut microbiome – which plays an important role in regulating immune function, explains Dr Ashley Hopkins, an early-career research fellow at the Precision Medicine Group at Flinders University.

“There is growing concern that an altered gut microbiome could negatively impact the efficacy of immune checkpoint inhibitors,” Dr Hopkins says.

“Given that approximately 30 percent of cancer patients use PPIs, often for extended time periods, there is an urgent need to determine if PPIs influence the efficacy of immune checkpoint inhibitors.”

In this study, Dr Hopkins and colleagues evaluated how PPI use impacted survival outcomes in patients with urothelial cancer who were treated with the immune checkpoint inhibitor atezolizumab or with chemotherapy. The researchers examined data from two clinical trials, which evaluated atezolizumab in almost 900 patients who had locally advanced or metastatic urothelial cancer.

Dr Hopkins and colleagues found that among patients treated with atezolizumab, those who used PPIs had a 68 percent greater risk of death, a 47 percent greater risk of disease progression and a 54 percent lower objective response rate than those who did not use PPIs.

PPI use was associated with worse outcomes even after adjusting for several patient and tumor characteristics. In contrast, use of the common heartburn medication did not significantly impact overall survival, progression-free survival, or the objective response rate for patients treated with chemotherapy.

Among patients who did not use PPIs, those treated with atezolizumab had a 31 percent lower risk of early death compared to those treated with chemotherapy. However, among PPI users, there were no significant differences in survival outcomes between patients treated with atezolizumab and chemotherapy, suggesting that PPI use impacted the magnitude of atezolizumab benefit.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50 percent, seemingly from a perspective that they will cause no harm,” says Dr Hopkins. “The findings from this study suggest that non-critical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer.”

He suggests future research could evaluate the impact of PPI use on other immune checkpoint inhibitors, additional cancer types, and different combinations of immune checkpoint inhibitors or chemotherapy regimens.

The research was published in Clinical Cancer Research, a journal of the American Association for Cancer Research. The study was supported by funds from the National Breast Cancer Foundation (Australia) and Cancer Council South Australia.

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