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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Prostate Cancer, Neoadjuvant Therapy, Androgen Antagonists, Prostatectomy

Intervention / Treatment
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* Drug: ARN-509
* Drug: Degarelix
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations Male aged 18 years or older (within 80 years) Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features 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. Patient amenable for open or robotic radical prostatectomy + pelvic lymph node dissection ECOG performance status: 0-1 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: Previous surgical/endoscopic treatments for prostatic disease Herbal and non-herbal products that in the opinion of the investigator may decrease PSA levels cM1 disease Any contraindication for PET or MR investigations 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) Medications known to lower the seizure threshold 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 Any other condition that, in the opinion of the Investigator, would impair the patient's ability to comply with study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARN-509 + degarelix<br>Treatment period of 12 weeks before RP + PLND. | Drug: ARN-509<br>* 240mg/day (4x60mg tablets, Oral administration: OS)<br>* Other names: apalutamide;Drug: Degarelix<br>* 1st injection: 120mg Subcutaneous administration (SC) x2, 2nd-3rd SC injection 80mg monthly<br>|
| Active Comparator: placebo + degarelix<br>Treatment period of 12 weeks before RP + PLND. | Drug: Degarelix<br>* 1st injection: 120mg Subcutaneous administration (SC) x2, 2nd-3rd SC injection 80mg monthly<br>Other: Placebo<br>* 4 tablets, per OS<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) | Proportions of MRD between arms. MRD: tumor volume ≤ 0.25 cm3 | After 12 weeks of neoadjuvant therapy + RP + PLND | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in proportions of pathological downstage | Any decrease in T stage from clinical to pathological stage | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Complete pathological response rates | Difference in proportions of complete pathological response (no evidence of tumour in the postoperative specimen) between arms. | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Difference in proportions of patients with pN1 disease. | Difference in proportions of lymph node invasion between arms | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Proteins expression in prostatic tumour TMA's (tissue microarrays) | Intensity of immunoreactivity and percentage of immunoreactive cells for, selected markers between arms. The TMA's will be produced from the formalin-fixed paraffin-embedded (FFPE) specimen of the RP. | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Transcriptome analysis by microarray expression platform | To assess differences in the transcriptome in tumour tissue on formalin-fixed paraffin-embedded (FFPE) specimens: clinical-grade high-density oligonucleotide microarray expression platform and cloud-based informatics pipeline to interrogate 1.4M probe sets representing all known  46K genes and non-coding RNAs. | At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND | 
| Pathway profiling and Gene Set Enrichment Analyses | To assess differences in the transcriptome in tumour tissue on formalin-fixed paraffin-embedded (FFPE) specimens. Pathway profiling and Gene Set Enrichment Analyses will also be used to generate pathway scores for the 'androgen receptor signaling pathway'; determination of pathway scores for the DNA damage checkpoints and the different DNA repair pathways. | At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND | 
| Genomic subtyping by exome-sequencing | Genomic subtyping (e.g., ERG, SPINK1, SPOP, FOXA1, PTEN, circulating nucleic acids (CNA) data...) will be performed based on exome-sequencing data. The exome and CNA data will be linked with the transcriptome data on androgen regulation and DNA repair pathways. | At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND | 
| PSA kinetics | Changes of PSA during time and comparison of PSA values and changes between arms. | Up to 40 months | 
| Testosterone kinetics | Comparison of total and free serum testosterone and testosterone change between arms | Up to 40 months | 
| PSA nadir </=0.3ng/ml after neoadjuvant treatment | Differences in proportions of PSA nadir </=0.3ng/ml after neoadjuvant treatment. PSA nadir after neoadjuvant therapy and before external beam radiotherapy (EBRT) is an important biomarker of hormonal response and an independent prognostic factor of prostate cancer survival. | After 12 weeks of neoadjuvant therapy before RP + PLND | 
| Peri-operative features | Differences in peri-operative features (operative time, blood loss, grade of surgical difficulty...) will be collected to evaluate the possible effect of treatment on surgical intervention. | up to (about) 5 hours | 
| Differences in proportions of surgical complications between arms | Clavien-Dindo classification will be implemented to assess differences in surgical complications between the two arms. | Up to 6 weeks post RP + PLND | 
| Continence | Assessment of continence rates through validated preoperative and postoperative questionnaire (ICIQ) | Up to 40 months | 
| Quality of life | Assessment of Quality of life through validated preoperative and postoperative questionnaire (EORTC QLQ-C30) | Up to 40 months | 
| Erection state | Assessment of erection state through validated preoperative and postoperative questionnaire (IEEF5) | Up to 40 months | 
| Survival | Three years biochemical recurrence free survival | Up to 36 months | 
| Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR per arm | Standardized Uptake Value (SUV) change (delta) per arm comparing SUV values before and after treatment | At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND | 
| Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR between arms | SUV delta between the two arms. | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR and tumour volume | Correlation between SUV values and the tumour volume (TV) in the RP correspondent volume of interest (VOI) at definitive pathology | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Standardized Uptake Value (SUV) on prostate [68]Ga PSMA PET/MR and Immunohistochemistry | Correlation between SUV values and PSMA expression at Immunohistochemistry | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Magnetic resonance (MR) and tumor volume (TV) per arm | Change of magnetic resonance (MR) tumor volume (TV): Tumor volume (TV) change (delta) per arm comparing TV values before and after treatment | At baseline and after12 weeks of neoadjuvant therapy + RP + PLND | 
| Magnetic resonance (MR) and tumor volume (TV) between arms | Change of magnetic resonance (MR) tumor volume (TV):TV deltas between the two arms. | At baseline and after12 weeks of neoadjuvant therapy + RP + PLND | 
| PI-RADS between arms at MR | Proportion of PI-RADS between arms | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| PI-RADS score and Gleason score | Correlation between PI-RADS score and pathology Gleason score | After 12 weeks of neoadjuvant therapy + RP + PLND | 
| Down-staging at imaging | Proportion of down-staging | At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Frequencies of adverse events (AE), severe adverse events (SAE) and Suspected Unexpected Serious Adverse Reaction (SUSAR) | From patient inclusion until RP + PLND | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Placebo-controlled, Neoadjuvant, Androgen deprivation, Antiandrogen, Radical Prostatectomy