Terbinafine for Biochemically Recurrent Prostate Cancer (TerbinaPro)

TerbinaPro is a phase II drug-repurposing study evaluating oral Terbinafine in patients with biochemical recurrence of prostate cancer after prior local treatment with curative intent. When local salvage strategies have been exhausted, recurrence usually reflects micro-metastatic disease without clearly visible metastases on imaging. Standard therapy with androgen deprivation or androgen-receptor pathway inhibitors can effectively control disease but is associated with substantial side effects and negative impact on quality of life. Terbinafine is a long-licensed, generic antifungal drug that inhibits squalene epoxidase (SQLE), an enzyme that may play a role in prostate cancer progression. Preclinical and limited clinical data suggest potential anti-cancer activity.

About 20-50% of patients with prostate cancer will develop biochemical recurrence within 10 years after local treatment with initial curative intent. After exhaustion of local salvage strategies such as radiotherapy to the prostate bed, biochemical recurrence usually indicates micro metastatic locoregional or distant disease, mostly no longer amenable to curative strategies. Evidence on how to treat these patients without clearly visible metastatic disease on imaging is very limited. Eventually, patients will be started on androgen deprivation therapy and/or androgen-receptor pathway inhibitors. These treatments however have well-known side effects and negative impact on quality of life such as causing hot flushes, reduction of bone and muscle mass and affecting sexual function and psychological wellbeing. Many patients therefore have an interest to postpone initiation of androgen deprivation and new treatment options are needed. Terbinafine is a long-licensed and generic anti-fungal drug used to treat fungal infections of nails and skin with a very favorable side-effect profile. Its mode of action is inhibition of the fungal enzyme squalene epoxidase (SQLE) which results in accumulation of squalene and consecutive fungal cell death. SQLE is also present in mammalian cells and a growing amount of preclinical and limited clinical study data suggests that SQLE may play a role in development and progression of different cancer types. In prostate cancer, overexpression of SQLE has been documented and shown to be associated with adverse outcomes. Tissue culture and xenograft models show inhibition of prostate cancer cells by Terbinafine, including models resistant to androgen-receptor pathway inhibitors. Limited clinical and retrospective population-based data also suggest activity of Terbinafine in patients with prostate cancer. However, so far, the drug has not been tested systematically in prostate cancer patients and based on our knowledge, no such trials are currently ongoing. TerbinaPro is a drug repurposing phase II study to assess activity of Terbinafine in biochemical recurrence of prostate cancer. The primary objective of the trial is to demonstrate efficacy of Terbinafine in biochemically recurrent prostate cancer. Secondary objectives are exploration of an active oncological dose and safety of treatment.