SGLT2i may delay hormone therapy failure in prostate cancer

Intention-to-treat (ITT) SGLT2 inhibitor (SGLTi) use was associated with reduced risk of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (APRI) failure, according to findings of a population-based study in Hong Kong.

ADT and ARPI are essential prostate cancer treatments that suppress androgen-driven tumour growth. However, 45–75 percent of patients develop drug resistance within 24 months. [Sci Rep 2025;doi:10.1038/s41598-025-93136-9] At the same time, more than half of patients receiving long-term ADT develop metabolic syndrome with symptoms like hyperglycaemia and obesity, contributing to elevated risks of diabetes and cardiovascular disease, which in turn may be treated with SGLT2i. [J Clin Oncol 2006;24:3979-3983]

Emerging clinical and in vitro evidence suggests that SGLT2i may confer anticancer benefits beyond their cardio-renal-metabolic effects, including an association with prostate-specific antigen responses and inhibition of prostate cancer cell proliferation. [Biomedicines 2023;11:1867; Prostate 2025;85:391-394; CommunBiol 2023;6:919] “This evidence raises the possibility of repurposing SGLT2i as adjunctive agents in prostate cancer management,” hypothesized the researchers from the University of Hong Kong. [JAMA Oncol 2026;doi:10.1001/jamaoncol.2025.5869]

The study used a sequential target trial emulation (TTE) design to evaluate the impact of SGLT2i among patients with prostate cancer receiving hormone therapy. Eligible patients were 14,223 men diagnosed with prostate cancer in Hong Kong between January 1993 and April 2025 who received ADT (leuprorelin, goserelin, triptorelin, degarelix) with or without combined androgen blockade (CAB; flutamide, bicalutamide). Patients who were given ARPI (abiraterone, enzalutamide, darolutamide, apalutamide) upfront (ie, within 1 month after ADT/CAB initiation) were excluded.

At a median follow-up of 66 months, 44.0 percent of patients experienced ADT failure, with a median time to failure of 55 months. Among 3,358 patients who received subsequent ARPI, 57.5 percent experienced treatment failure, with a median time to failure of 50 months.

In the ITT analysis, receiving vs not receiving SGLT2i was associated with significantly improved disease control during ADT treatment (hazard ratio [HR], 0.63; 95 percent confidence interval [CI], 0.41–0.95; p=0.03), resulting in an 11.1 percent decrease of the 10-year cumulative event rate.  Similarly, use of SGLT2i was associated with a significantly delayed time to failure of APRI (HR, 0.44; 95 percent CI, 0.20–0.97; p=0.04), with an 8.4 percent decrease of the cumulative event rate at 10 years. Subgroup analyses comparing dapagliflozin and empagliflozin did not reveal substantial differences in their associations with prostate cancer outcomes.

In a sensitivity analysis, patients using SGLT2i vs those receiving other glucose-lowering agents had a longer time to ADT failure (HR, 0.62; 95 percent CI, 0.42–0.90; p=0.01). The association with time to ARPI failure was also significantly in favour of SGLTi in this analysis (HR, 0.45; 95 percent CI, 0.20–0.99; p=0.04)

Although the associations with disease-specific survival and overall survival (OS) were not statistically significant, the point estimates suggested a favourable trend among those who used SGLT2i.

In a subgroup analysis comparing patients receiving metformin with patients without diabetes, no statistically significant association was found between metformin use and ADT or APRI failure. However, metformin use was associated with improved OS in this analysis (HR, 0.59; 95 percent CI, 0.42–0.83; p=0.002). “Considering that SGLT2i are often prescribed together with metformin, this suggests they may have improved prostate cancer hormone therapy outcomes via pathways other than glucose control, consistent with previous genetic findings,” wrote the researchers. [Cell Rep Med 2024;5:101688]