Terbinafine: An Old Antifungal Enters a Phase 2 Prostate Cancer Trial

An inexpensive antifungal drug that has been used for decades is now being tested as a prostate cancer treatment. The phase 2 TerbinaPro trial is evaluating terbinafine in men whose prostate cancer has returned biochemically after previous treatment. Behind this unusual drug-repurposing trial lies an intriguing discovery about how prostate cancer produces cholesterol.

The target is an enzyme called squalene epoxidase (SQLE), which plays an important role in making cholesterol inside cells. This matters because prostate cancer does not simply depend on cholesterol circulating in the blood. Tumour cells can manufacture their own cholesterol, which can in turn help maintain androgen receptor signalling, one of the main engines driving prostate cancer.

A 2021 Nature Communications study found that SQLE becomes increasingly important as prostate cancer becomes more aggressive. High SQLE levels were associated with higher PSA, higher Gleason scores, lymph-node involvement and worse outcomes. The researchers also found that SQLE was increased in lymph-node metastases compared with the corresponding primary tumours.

Most importantly, blocking SQLE interfered with prostate cancer growth. The researchers tested terbinafine, a widely used antifungal drug that happens to inhibit SQLE. It reduced cholesterol production inside prostate cancer cells, weakened androgen receptor activity and slowed their growth. Interestingly, prostate cancer cells resistant to enzalutamide or abiraterone remained sensitive to SQLE inhibition.

The results were then reproduced in mice. Terbinafine reduced tumour growth and PSA while decreasing androgen receptor activity inside the tumours. Remarkably, it did this without lowering cholesterol levels in the blood, suggesting that the effect was related to disrupting cholesterol production inside the tumour rather than simply reducing cholesterol throughout the body.

The researchers even tried terbinafine off-label in four men with rapidly progressing, heavily pretreated metastatic prostate cancer who had very few treatment options left. Treatment lasted only two weeks in three patients and six weeks in one. PSA fell in three of the four men. This tiny experiment could not establish that terbinafine works against prostate cancer, but the signal was intriguing enough to support further investigation.

Five years later, that idea has reached a proper clinical trial. TerbinaPro is a randomised phase 2 study testing whether terbinafine can delay PSA progression in men with biochemically recurrent prostate cancer with no metastases or small local lymph-node metastases. The study will also measure PSA responses, including reductions of at least 30%, 50% and 90%.

The attraction of this strategy is not simply that terbinafine is an old and inexpensive drug. It attacks prostate cancer from an unusual direction. Instead of directly blocking androgen production or the androgen receptor, it attempts to interfere with a metabolic pathway that tumour cells may use to keep that signalling machinery running.

The trial will now provide the first controlled test of whether the striking laboratory findings translate into a meaningful effect in men with prostate cancer.

Source.

Clinical trial.