Dapagliflozin and Next-Generation Hormonal Agents: Targeting Metabolic Resistance in Metastatic Castrate-Resistant Prostate Cancer

A new phase 2 clinical trial is now underway to test whether adding dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, to next-generation hormonal agents (darolutamide, abiraterone, apalutamide, enzalutamide) can extend survival in metastatic castrate-resistant prostate cancer.

The rationale rests on a fundamental paradox in prostate cancer biology: while early tumors rely on oxidative metabolism and androgen signaling, advanced castration-resistant disease shifts to aerobic glycolysis, the Warburg effect, becoming addicted to glucose even in oxygen-rich environments. This metabolic reprogramming, paradoxically accelerated by hormonal therapies that block androgen receptor signaling, creates a vulnerability that dapagliflozin exploits by blocking glucose uptake directly into cancer cells.

(Note: we already talked about SGLT2 inhibition in this previous article)

Preclinical studies show SGLT2 inhibitors like dapagliflozin suppress proliferation in both androgen-sensitive and castrate-resistant prostate cancer cell lines, inducing cell cycle arrest, mitochondrial dysfunction, and apoptosis through AMPK activation and mTOR inhibition. Genetic evidence from Mendelian randomization further supports this: lifelong SGLT2 inhibition mimics a 44% reduction in prostate cancer risk, mediated partly by lowered uridine levels that fuel tumor growth. The trial’s design capitalizes on this synergy, pairing dapagliflozin with any first-line hormonal agent in chemotherapy-naïve patients, to attack both the androgen pathway and the glycolytic escape route tumors adopt under hormonal pressure. This approach addresses a key limitation of current therapies, where tumors adapt and progress despite androgen blockade. Beyond efficacy, dapagliflozin offers cardioprotective benefits that may counter the heart failure and metabolic risks of prolonged androgen deprivation, potentially improving quality of life without adding chemotherapy toxicity. Early data from related studies, including neoadjuvant dapagliflozin in localized disease and SGLT2 synergy with radiotherapy, reinforce the promise of metabolic targeting in prostate cancer. If successful, this combination could redefine first-line treatment for metastatic castrate-resistant prostate cancer, transforming a repurposed diabetes drug into a cornerstone of oncology through precise exploitation of tumor metabolic desperation.

Clinical trial.