Neoadjuvant Degarelix With or Without Apalutamide (ARN-509) Followed by Radical Prostatectomy

Neoadjuvant Degarelix +/- Apalutamide (ARN-509) Followed by Radical Prostatectomy for Intermediate and High-risk Prostate Cancer: a Randomized, Placebo-controlled Trial

RATIONALE: Neoadjuvant hormonal therapy using luteinizing hormone releasing hormone (LHRH) agonists and/or anti-androgens has already demonstrated to downstage primary prostate cancer in patients treated by radical prostatectomy without a survival benefit. There is no evidence yet of a survival impact of LHRH antagonist (LHRHa) +/- new-generation anti-androgens in this setting. Thus novel studies are needed to assess this treatment combination.

PURPOSE: To assess the difference in treatment antitumor effect between arms by measuring pathological tumor volume with minimal residual disease (MRD) following radical prostatectomy + pelvic lymph-node dissection (RP + PLND) for intermediate or high-risk prostate cancer patients.

PRIMARY OBJECTIVE: To assess the difference in antitumor effect between the treatment arms by measuring MRD following radical prostatectomy.

SECONDARY OBJECTIVES: To measure differences between study arms in

• Proportions of post neoadjuvant prostate specific antigen (PSA) ≤ 0.3 ng/ml as a predictor of prostate cancer mortality
• T down-staging, complete pathological response, PSA kinetics, Testosterone kinetics, operation time, blood loss, grade of surgical difficulty
• New generation hybrid imaging 68Ga PSMA (Prostate-Specific Membrane Antigen) PET/MR (Positron emission tomography/Magnetic Resonance) derived parameters
• Early biochemical recurrence as prognostic factor of prostate cancer mortality
• Transcriptome and genome
• Tissue microarrays (TMA) protein expression (DNA repair, resistance etc.) by immunohistochemistry
• Perioperative safety and tolerability
• Quality of life, erection recovery, continence through validated preoperative and postoperative questionnaires pre and postop (IEEF5, ICIQ, EORTC QLQ-C30)

OUTLINE: interventional, single center, phase II, randomized, double blind, placebo controlled trial.

Inclusion Criteria:

1. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

2. Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

3. Male aged 18 years or older (within 80 years)

4. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features

5. Diagnosis of intermediate (at least 2 of the following factors: cT2b, biopsy GS 7, PSA 10-20ng/ml) or high-risk prostatic adenocarcinoma (clinical stage≥T2c and/or biopsy GS≥8 and/or PSA>20ng/ml), cN0-cN1, cM0.

6. Patient amenable for open or robotic radical prostatectomy + pelvic lymph node dissection

7. ECOG performance status: 0-1

8. Adequate organ function as defined by the following criteria:

   • White blood cells (WBC) ≥ 4.0 x109/L
   • Platelet count ≥ 100 x109/L
   • Hemoglobin ≥9 g/dl
   • Creatinine ≤ 2 x ULN
   • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normality (ULN)
   • Total serum bilirubin ≤1.5 x ULN.

Exclusion Criteria:

1. Previous surgical/endoscopic treatments for prostatic disease

2. Herbal and non-herbal products that in the opinion of the investigator may decrease PSA levels

3. cM1 disease

4. Any contraindication for PET or MR investigations

5. History of seizure or condition that may pre-dispose to seizure (e.g., prior stroke within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)

6. Medications known to lower the seizure threshold

7. History of:

   • Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer currently in complete remission) within 5 years prior to randomization
   • Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization
   • Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP ≥100 mmHg). Patients with a history of uncontrolled hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
   • Gastrointestinal disorder affecting absorption

8. Any other condition that, in the opinion of the Investigator, would impair the patient's ability to comply with study procedures.