A Randomized Trial of Neoadjuvant Leuprorelin, Darolutamide or Both Prior to Radical Prostatectomy for Intermediate or High-risk Prostate Cancer. Prospective, randomized, parallel group, open-label with blinded endpoint adjudication multicenter clinical trial.To assess, among patients with unfavorable intermediate to high-risk prostate cancer, whether a neoadjuvant combined treatment with leuprorelin (Leuprorelin) and darolutamide is superior to monotherapy in terms of complete or almost complete pathological response.A total of 144 patients with unfavorable intermediate to high-risk prostate cancer scheduled for radical prostatectomy with extended pelvic lymph node dissection will be randomized 1:1:1 to oral darolutamide, SC leuprorelin (Leuprorelin) or both (48 patients per arm) for 24 weeks.

Inclusion Criteria:

• Men ≥18 years of age;

• Histologically confirmed unfavorable intermediate or high/very high risk non metastatic (by conventional imaging) prostate adenocarcinoma intended for surgery without neuroendocrine differentiation or small cell features;

• Unfavorable intermediate-risk:

  • ISUP grade 3, and/or > 50% positive biopsy cores and/or at least two intermediate-risk factors. Intermediate-risk factors:

    • Clinical tumor stage T2b or T2c (MRI based);
    • ISUP grade 2 or 3;
    • Prostate-specific antigen (PSA) level of 10-20 ng/mL.

• High-risk or very high-risk:

  • ≥cT3a (MRI based) or ISUP 4-5 or PSA>20 ng/mL;
  • cN1.

• ECOG 0-1;

• Baseline testosterone > 230 ng/dL;

• No prior prostate cancer treatment;

• Sexually active male subjects must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with darolutamide and for 1 week after the end of treatment with darolutamide to prevent pregnancy;

• Written informed consent.

Exclusion Criteria:

• Unresectable prostate cancer;
• Histology of small cell carcinoma prostate cancer or adenocarcinoma with neuroendocrine features;
• Any prior prostate cancer treatment;
• Any active infection requiring IV antibiotics;
• Known additional malignancy that has a life-expectancy < 2 years;
• Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, heart failure with New York Heart Association Class Functional III or IV;
• Uncontrolled severe hypertension as indicated by a resting systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg despite medical management;
• A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of darolutamide;
• Inability to swallow oral medications;
• Receipt of medications (e.g. finasteride, dutasteride) or agents that are likely to alter serum PSA levels within <= 42 days or 5 half-lives prior to registration, whichever is shorter.