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

Sponsor

Universitaire Ziekenhuizen Leuven (Other)

Overall Status

Recruiting

CT.gov ID

NCT03080116

Collaborator

(none)

Enrollment

Location

Arms

33.1

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer Neoadjuvant Therapy Androgen Antagonists Prostatectomy	Drug: ARN-509 Drug: Degarelix Other: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

84 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 28, 2019

Anticipated Primary Completion Date :

Jun 30, 2021

Anticipated Study Completion Date :

Dec 30, 2021

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: ARN-509 + degarelix

Treatment period of 12 weeks before RP + PLND.

Drug: ARN-509

240mg/day (4x60mg tablets, Oral administration: OS)

Other Names:

apalutamide

Drug: Degarelix

1st injection: 120mg Subcutaneous administration (SC) x2, 2nd-3rd SC injection 80mg monthly

Active Comparator: placebo + degarelix

Treatment period of 12 weeks before RP + PLND.

Drug: Degarelix

1st injection: 120mg Subcutaneous administration (SC) x2, 2nd-3rd SC injection 80mg monthly

Other: Placebo

4 tablets, per OS

Outcome Measures

Primary Outcome Measures

Minimal Residual Disease (MRD) [After 12 weeks of neoadjuvant therapy + RP + PLND]
Proportions of MRD between arms. MRD: tumor volume ≤ 0.25 cm3

Secondary Outcome Measures

Difference in proportions of pathological downstage [After 12 weeks of neoadjuvant therapy + RP + PLND]
Any decrease in T stage from clinical to pathological stage
Complete pathological response rates [After 12 weeks of neoadjuvant therapy + RP + PLND]
Difference in proportions of complete pathological response (no evidence of tumour in the postoperative specimen) between arms.
Difference in proportions of patients with pN1 disease. [After 12 weeks of neoadjuvant therapy + RP + PLND]
Difference in proportions of lymph node invasion between arms
Proteins expression in prostatic tumour TMA's (tissue microarrays) [After 12 weeks of neoadjuvant therapy + RP + PLND]
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.
Transcriptome analysis by microarray expression platform [At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND]
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.
Pathway profiling and Gene Set Enrichment Analyses [At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND]
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.
Genomic subtyping by exome-sequencing [At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND]
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.
PSA kinetics [Up to 40 months]
Changes of PSA during time and comparison of PSA values and changes between arms.
Testosterone kinetics [Up to 40 months]
Comparison of total and free serum testosterone and testosterone change between arms
PSA nadir </=0.3ng/ml after neoadjuvant treatment [After 12 weeks of neoadjuvant therapy before RP + PLND]
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.
Peri-operative features [up to (about) 5 hours]
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.
Differences in proportions of surgical complications between arms [Up to 6 weeks post RP + PLND]
Clavien-Dindo classification will be implemented to assess differences in surgical complications between the two arms.
Continence [Up to 40 months]
Assessment of continence rates through validated preoperative and postoperative questionnaire (ICIQ)
Quality of life [Up to 40 months]
Assessment of Quality of life through validated preoperative and postoperative questionnaire (EORTC QLQ-C30)
Erection state [Up to 40 months]
Assessment of erection state through validated preoperative and postoperative questionnaire (IEEF5)
Survival [Up to 36 months]
Three years biochemical recurrence free survival
Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR per arm [At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND]
Standardized Uptake Value (SUV) change (delta) per arm comparing SUV values before and after treatment
Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR between arms [After 12 weeks of neoadjuvant therapy + RP + PLND]
SUV delta between the two arms.
Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR and tumour volume [After 12 weeks of neoadjuvant therapy + RP + PLND]
Correlation between SUV values and the tumour volume (TV) in the RP correspondent volume of interest (VOI) at definitive pathology
Standardized Uptake Value (SUV) on prostate [68]Ga PSMA PET/MR and Immunohistochemistry [After 12 weeks of neoadjuvant therapy + RP + PLND]
Correlation between SUV values and PSMA expression at Immunohistochemistry
Magnetic resonance (MR) and tumor volume (TV) per arm [At baseline and after12 weeks of neoadjuvant therapy + RP + PLND]
Change of magnetic resonance (MR) tumor volume (TV): Tumor volume (TV) change (delta) per arm comparing TV values before and after treatment
Magnetic resonance (MR) and tumor volume (TV) between arms [At baseline and after12 weeks of neoadjuvant therapy + RP + PLND]
Change of magnetic resonance (MR) tumor volume (TV):TV deltas between the two arms.
PI-RADS between arms at MR [After 12 weeks of neoadjuvant therapy + RP + PLND]
Proportion of PI-RADS between arms
PI-RADS score and Gleason score [After 12 weeks of neoadjuvant therapy + RP + PLND]
Correlation between PI-RADS score and pathology Gleason score
Down-staging at imaging [At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND]
Proportion of down-staging
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [From patient inclusion until RP + PLND]
Frequencies of adverse events (AE), severe adverse events (SAE) and Suspected Unexpected Serious Adverse Reaction (SUSAR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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