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

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.

Study Overview

• Status: Unknown
• Conditions: Prostate Cancer; Neoadjuvant Therapy; Prostatectomy; Androgen Antagonists
• Intervention / Treatment: Drug: ARN-509; Drug: Degarelix; Other: Placebo

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 Type: Interventional
• Enrollment (Anticipated): 84
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Steven Joniau, MD PhD; Phone Number: +32 16 34 66 87; Email: steven.joniau@uzleuven.be
• Study Contact Backup: Name: Lorenzo Tosco, MD; Phone Number: +32 16 34 66 87; Email: lorenzo.tosco@uzleuven.be

Study Locations

• Belgium
  • Vlaams-brabant
    • Leuven, Vlaams-brabant, Belgium, 3000
      • Recruiting
      • University Hospitals Leuven
      • Contact: Gaëtan Devos, MD; Email: gaetan.devos@uzleuven.be
      • Contact: Steven Joniau, Prof. MD; Email: steven.joniau@uzleuven.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Steven Joniau, UZ Leuven

Publications and helpful links

General Publications

• Tosco L, Laenen A, Gevaert T, Salmon I, Decaestecker C, Davicioni E, Buerki C, Claessens F, Swinnen J, Goffin K, Oyen R, Everaerts W, Moris L, De Meerleer G, Haustermans K, Joniau S; P.E.A.R.L. (ProstatE cAncer Research Leuven). Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial. BMC Cancer. 2018 Apr 2;18(1):354. doi: 10.1186/s12885-018-4275-z.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 28, 2019
• Primary Completion (ANTICIPATED): June 30, 2021
• Study Completion (ANTICIPATED): December 30, 2021

Study Registration Dates

• First Submitted: February 14, 2017
• First Submitted That Met QC Criteria: March 8, 2017
• First Posted (ACTUAL): March 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): December 24, 2020
• Last Update Submitted That Met QC Criteria: December 23, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Placebo-controlled; Randomized; Neoadjuvant; Radical Prostatectomy; Androgen deprivation; Antiandrogen
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: S58827; 2016-002854-19 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes