Pre-surgical, window-of-opportunity trials provide a suitable model to assess the activity of preventive interventions in a cost-effective manner using tissue biomarkers as surrogate endpoints. Finasteride has been shown to reduce prostate cancer development in a large phase III trial, and flutamide has a well-known anticancer effect in advanced prostate cancer at the dose of 750 mg/day.

In this randomized, phase IIB, double blind, placebo controlled, multicenter, pre-surgical, window-of-opportunity trial we compared the effects of finasteride (5 mg/day) versus low-dose flutamide (250 mg/day) or placebo on tissue biomarkers in patients with prostate cancer who were candidate to radical surgery. Specifically, the effects of both drugs on the change in epithelial cell nuclear area in prostate cancer tissue between pre- and post-treatment biopsies was evaluated (primary endpoint). Moreover, the changes of the proliferation marker Ki-67 and of karyometric parameters in benign, dysplastic (HG-PIN) and malignant tissues were evaluated (secondary endpoints). Additional endpoints include the changes of serum PSA and testosterone, assessment of toxicity, overall survival, recurrence-free survival and event-free (recurrence + death) survival. Patients with intracapsular biopsy proven prostate cancer were randomized to either flutamide, 250 mg/day, or finasteride, 5 mg/day, or placebo for 4-6 weeks before radical prostatectomy. Blood samples were taken before and after treatment. At surgery, end-of-study ex-vivo biopsies were obtained from the prostatectomy specimens to assess the treatment changes in nuclear area (primary endpoint), Ki-67, topoisomerase-II-α and a 20-feature karyometric discrimant function in normal, high-grade PIN and malignant tissue. After surgery patients were followed up for at least 15 years to assess recurrence and/or mortality. We also plan to follow-up patients by telephone interview to assess their vital status for up to 20 years.

Inclusion Criteria:

• Patients aged > 18 years

• Patients with a biopsy proven, clinically intracapsular PCa who are candidates to radical retropubic prostatectomy

• ECOG performance status ≤ 2

• Satisfactory hematological and biochemical functions:

  • Platelets ≥100 x 10^9/L
  • AST and ALT in the normal range

• Able to understand and sign an informed consent

Exclusion Criteria:

• Previous hormone treatment during the 8 weeks before enrollment
• Neurologic and psychiatric diseases precluding patient participation in the study
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with the study procedures.

The drugs and placebo were purchased through the Galliera Hospital Pharmacy, encapsulated to preserve blinding, then packaged and labelled for the study under GMP.