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

Phase 2

Active, not recruiting

• Conditions: Prostatectomy; Neoadjuvant Therapy; Prostate Cancer; Androgen Antagonists
• Interventions: Drug: ARN-509; Other: Placebo; Drug: Degarelix

• Registration Number: NCT03080116
• Lead Sponsor: Universitaire Ziekenhuizen KU Leuven

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.

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 Timeline

• Study First Submitted: 2017-02-14
• Study First Submitted QC: 2017-03-08
• Study First Posted: 2017-03-15
• Study Start: 2019-03-28
• Primary Completion: 2021-07-01
• Status Verified: 2024-07
• Study Completion: 2024-07-01
• Last Update Submitted: 2024-07-01
• Last Update Posted: 2024-07-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Male
• Target Recruitment: 90

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ARN-509 + degarelix	ARN-509	Treatment period of 12 weeks before RP + PLND.
placebo + degarelix	Placebo	Treatment period of 12 weeks before RP + PLND.
ARN-509 + degarelix	Degarelix	Treatment period of 12 weeks before RP + PLND.
placebo + degarelix	Degarelix	Treatment period of 12 weeks before RP + PLND.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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
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 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
Difference in proportions of pathological downstage	After 12 weeks of neoadjuvant therapy + RP + PLND	Any decrease in T stage from clinical to pathological stage
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.
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.
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.
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)
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.
Survival	Up to 36 months	Three years biochemical recurrence free survival
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.
PSA kinetics	Up to 40 months	Changes of PSA during time and comparison of PSA values and changes 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.
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)
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.
Testosterone kinetics	Up to 40 months	Comparison of total and free serum testosterone and testosterone change between arms
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.
Continence	Up to 40 months	Assessment of continence rates through validated preoperative and postoperative questionnaire (ICIQ)
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.
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
PI-RADS score and Gleason score	After 12 weeks of neoadjuvant therapy + RP + PLND	Correlation between PI-RADS score and pathology Gleason score
PI-RADS between arms at MR	After 12 weeks of neoadjuvant therapy + RP + PLND	Proportion of PI-RADS between arms
Down-staging at imaging	At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND	Proportion of down-staging

Trial Locations

Locations (1)

University Hospitals Leuven; 🇧🇪 Leuven, Vlaams-brabant, Belgium