Should PPIs be avoided in mHSPC patients treated with upfront docetaxel?

A landmark analysis of data from a Hong Kong prostate cancer database found that use of proton-pump inhibitors (PPIs) was associated with inferior oncological outcomes in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who received upfront docetaxel.

Most patients with advanced prostate cancer have multiple comorbidities that require various comedications, including PPIs, which are widely used to manage gastrointestinal adverse effects (AEs) caused by anticancer and other therapies. [Prostate 2024;84:1138-1145; Ther Adv Drug Saf 2019;doi:10.1177/2042098618809927] While several studies have demonstrated PPIs’ negative effect on outcomes with abiraterone plus androgen deprivation therapy (ADT) in both mHSPC and metastatic castration-resistant prostate cancer (mCRPC), there is less evidence on their potential impact on the efficacy of docetaxel. [Prostate Cancer Prostatic Dis 2024;27:444-450; Prostate 2024;84:1329-1335; J Clin Oncol 2020;doi:10.1200/JCO.2020.38.6_suppl.309; Curr Oncol 2021;28:783-799]

“Therefore, this study aimed to investigate the impact of PPI use on the efficacy of docetaxel plus ADT in patients with mHSPC,” wrote the researchers from the Chinese University of Hong Kong (CUHK). [Cancers (Basel) 2025;doi:10.3390/cancers17172879]

The researchers analyzed data from the Hong Kong Prostate Cancer Study Group Database, a prospective registry that includes consecutive prostate cancer patients from five hospitals in Hong Kong. A total of 101 patients diagnosed with de novo mHSPC between 2016 and 2022 and treated with upfront docetaxel (ie, initiated within 6 months of starting ADT) were included in the analysis. All patients were classified as having high-risk and high-volume disease. Among them, 21.8 percent were taking a PPI (pantoprazole, lansoprazole, esomeprazole, or omeprazole) at ADT initiation (PPI group), while the remaining 78.8 percent were not (no PPI group). Both groups shared similar pretherapy characteristics.

Compared with patients who were taking a PPI, a significantly higher proportion of patients in the no PPI group achieved a PSA nadir of <0.1 ng/mL (19.0 vs 4.5 percent; p=0.041) at landmark analysis at 6 months. On the other hand, the two groups had no significant difference in rates of achieving PSA90 or PSA95. The median time to mCRPC was also similar between groups (14.2 vs 12.7 months).

The Kaplan–Meier median overall survival (OS) estimates were 81.1 months for the no PPI group vs 38.6 months for the PPI group (hazard ratio [HR], 2.28; p=0.025). “Multivariate regression analysis identified PPI use as the only statistically significant factor associated with OS [p=0.036],” highlighted the researchers.

At the same time, the researchers noted that despite efforts to mitigate confounding factors through multivariate regression analysis, uncontrollable confounders, such as comedications apart from PPIs and next-line therapies, remained inevitable.

“PPIs exert their effects by inducing cell cycle progression, increasing the expression of oncoproteins and antiapoptotic proteins and inhibiting prostate phosphatases. These changes could conceivably make cancer cells less susceptible to chemotherapy-induced death,” they explained. [Prostate Cancer Prostatic Dis 2020;23:622-629] “[However,] methodologically, a causal relationship could not be established, and further high-quality clinical data are required to better elucidate the effect of PPI use on the efficacy of prostate cancer chemotherapeutic agents.”

“Based on real-world data from prostate cancer patients, the use of PPIs was found to be associated with inferior OS in de novo mHSPC treated with upfront docetaxel. Clinicians are advised to carefully evaluate the indication for PPI use when managing patients with mHSPC,” suggested the researchers.