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

• ClinicalTrials.gov Identifier: NCT03080116
• Recruitment Status: Recruiting
• First Posted: March 15, 2017
• Last Update Posted: December 24, 2020
• Sponsor: Universitaire Ziekenhuizen Leuven
• Information provided by (Responsible Party): Universitaire Ziekenhuizen Leuven

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 (Clinical Trial)
• Estimated 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: March 28, 2019
• Estimated Primary Completion Date: June 30, 2021
• Estimated Study Completion Date: December 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 Name: 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 :

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

Secondary Outcome Measures :

1. Difference in proportions of pathological downstage [ Time Frame: After 12 weeks of neoadjuvant therapy + RP + PLND ]
   Any decrease in T stage from clinical to pathological stage
2. Complete pathological response rates [ Time Frame: 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.
3. Difference in proportions of patients with pN1 disease. [ Time Frame: After 12 weeks of neoadjuvant therapy + RP + PLND ]
   Difference in proportions of lymph node invasion between arms
4. Proteins expression in prostatic tumour TMA's (tissue microarrays) [ Time Frame: 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.
5. Transcriptome analysis by microarray expression platform [ Time Frame: 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.
6. Pathway profiling and Gene Set Enrichment Analyses [ Time Frame: 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.
7. Genomic subtyping by exome-sequencing [ Time Frame: 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.
8. PSA kinetics [ Time Frame: Up to 40 months ]
   Changes of PSA during time and comparison of PSA values and changes between arms.
9. Testosterone kinetics [ Time Frame: Up to 40 months ]
   Comparison of total and free serum testosterone and testosterone change between arms
10. PSA nadir </=0.3ng/ml after neoadjuvant treatment [ Time Frame: 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.

11. Peri-operative features [ Time Frame: 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.
12. Differences in proportions of surgical complications between arms [ Time Frame: Up to 6 weeks post RP + PLND ]
    Clavien-Dindo classification will be implemented to assess differences in surgical complications between the two arms.
13. Continence [ Time Frame: Up to 40 months ]
    Assessment of continence rates through validated preoperative and postoperative questionnaire (ICIQ)
14. Quality of life [ Time Frame: Up to 40 months ]
    Assessment of Quality of life through validated preoperative and postoperative questionnaire (EORTC QLQ-C30)
15. Erection state [ Time Frame: Up to 40 months ]
    Assessment of erection state through validated preoperative and postoperative questionnaire (IEEF5)
16. Survival [ Time Frame: Up to 36 months ]
    Three years biochemical recurrence free survival
17. Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR per arm [ Time Frame: 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
18. Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR between arms [ Time Frame: After 12 weeks of neoadjuvant therapy + RP + PLND ]
    SUV delta between the two arms.
19. Standardized Uptake Value (SUV) on pelvic [68]Ga PSMA PET/MR and tumour volume [ Time Frame: 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
20. Standardized Uptake Value (SUV) on prostate [68]Ga PSMA PET/MR and Immunohistochemistry [ Time Frame: After 12 weeks of neoadjuvant therapy + RP + PLND ]
    Correlation between SUV values and PSMA expression at Immunohistochemistry
21. Magnetic resonance (MR) and tumor volume (TV) per arm [ Time Frame: 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
22. Magnetic resonance (MR) and tumor volume (TV) between arms [ Time Frame: At baseline and after12 weeks of neoadjuvant therapy + RP + PLND ]
    Change of magnetic resonance (MR) tumor volume (TV):TV deltas between the two arms.
23. PI-RADS between arms at MR [ Time Frame: After 12 weeks of neoadjuvant therapy + RP + PLND ]
    Proportion of PI-RADS between arms
24. PI-RADS score and Gleason score [ Time Frame: After 12 weeks of neoadjuvant therapy + RP + PLND ]
    Correlation between PI-RADS score and pathology Gleason score
25. Down-staging at imaging [ Time Frame: At baseline and after 12 weeks of neoadjuvant therapy + RP + PLND ]
    Proportion of down-staging
26. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: From patient inclusion until RP + PLND ]
    Frequencies of adverse events (AE), severe adverse events (SAE) and Suspected Unexpected Serious Adverse Reaction (SUSAR)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Steven Joniau, MD PhD; +32 16 34 66 87; steven.joniau@uzleuven.be

Contact: Lorenzo Tosco, MD; +32 16 34 66 87; lorenzo.tosco@uzleuven.be

Locations

Belgium

University Hospitals Leuven; Recruiting

Leuven, Vlaams-brabant, Belgium, 3000

Contact: Gaëtan Devos, MD gaetan.devos@uzleuven.be

Contact: Steven Joniau, Prof. MD steven.joniau@uzleuven.be

Sponsors and Collaborators

Universitaire Ziekenhuizen Leuven

Investigators

• Principal Investigator: Steven Joniau; UZ Leuven

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Universitaire Ziekenhuizen Leuven
• ClinicalTrials.gov Identifier: NCT03080116
• Other Study ID Numbers: S58827; 2016-002854-19 ( EudraCT Number )
• First Posted: March 15, 2017
• Last Update Posted: December 24, 2020
• Last Verified: December 2020

• 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

Keywords provided by Universitaire Ziekenhuizen Leuven:

Randomized; Placebo-controlled; Neoadjuvant; Androgen deprivation; Antiandrogen; Radical Prostatectomy

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases