NCT02799706.

Study name	Phase IIIb randomised trial comparing irradiation plus long term adjuvant androgen deprivation with GnRH antagonist versus GnRH agonist plus flare protection in patients with very high risk localized or locally advanced prostate cancer
Methods	Study design: parallel‐group randomized open‐label controlled clinical trial Setting: multicenter Country: Europe Follow‐up: unclear
Participants	Inclusion criteria: Histologically confirmed diagnosis of prostate adenocarcinoma PSA ≥ 10 ng/mL and 2 of the following 4 criteria: PSA ≥ 20 ng/mL; Gleason sum ≥ 8; cN1 (regional lymph nodes with a short axis length > 10 mm by CT scan or MRI) or pathologically confirmed lymph nodes (pN1); cT3‐T4 (by MRI or core biopsy) (i.e. if PSA ≥ 20 ng/mL, then only 1 of the other 3 risk factors is needed). M0 by standard imaging work‐up Testosterone ≥ 200 ng/dL Adequate renal function: calculated creatinine clearance ≥ 50 mL/min (Appendix D) Magnesium and potassium within normal limits of the institution or corrected to within normal limits prior to the first dose of treatment Patients with prolonged QT‐intervals due to prescribed Class IA (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmic medication must be carefully evaluated for GnRH agonist or GnRH antagonist use, because these drugs may prolong the QT‐interval. WHO performance status 0 to 1 Age ≥ 18 and ≤ 80 years Men who have partners of childbearing potential must use adequate birth control measures, as defined by the Investigator, during the study treatment period and for at least 3 months after last dose of study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Before patient registration/randomization, written informed consent must be given according to ICH/GCP and national/local regulations. Exclusion criteria: Previous use of androgen suppression therapy, antiandrogens. 5‐alpha reductase inhibitors are allowed if interrupted for more than 6 months prior to entering the study. History of severe untreated asthma, anaphylactic reactions, or severe urticaria and/or angioedema Hypersensitivity towards the investigational drug The following biological parameters: AST, ALT, total bilirubin, prothrombin time, serum albumin above upper level of normal range. No severe hepatic impairment (Child Pugh C) History of gastrointestinal disorders (medical disorder or extensive surgery) that may interfere with the absorption of the protocol treatment History of pituitary or adrenal dysfunction Uncontrolled diabetes mellitus History of ulcerative colitis, Crohn's disease, ataxia, telangiectasia, systemic lupus erythematous, or Fanconi anemia Clinically significant heart disease as evidenced by myocardial infarction or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < 50% at baseline Coronary revascularization (PCI or multivessel CABG), carotid artery or iliofemoral artery revascularization (percutaneous or surgical procedure) within the last 30 days prior to entering the trial Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointes ventricular arrhythmias (e.g. heart failure, hypokalemia, or a family history of a long QT syndrome), a QT or corrected QT (QTc) interval > 450 ms at baseline, or intake of medications that prolong the QT/QTc interval Uncontrolled hypertension (systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by antihypertensive treatment Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin), or the patient has been free of malignancy for a period of 3 years prior to first dose of study drug(s). Prior history of bladder cancer excludes the patient. Prior radical prostatectomy (TURP or suprapubic adenomectomy for benign prostatic hyperplasia is allowed) Prior brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields Any contraindication to external beam radiotherapy Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow‐up schedule, or any condition which, in the opinion of the Investigator, would preclude participation in this trial Target sample size: 885 Age (years): 18 to 80 Sex (M/F): male only
Interventions	Group 1 (sham comparator): GnRH agonist + radiation therapy (RT) As the study investigates the effect of a drug given concomitantly to radiotherapy, all men will be treated with the same treatment technique and target dose. The preferred treatment technique is intensity modulated radiotherapy + a GnRH agonist will be given for the duration selected for each participant. A non‐steroidal antiandrogen (e.g. flutamide, bicalutamide) will be given orally 1 week before the first injection of the GnRH agonist and will be continued for no longer than 8 weeks to protect against flare. Dose may vary due to availability of different brand names and pharmaceutical forms. The start of antiandrogen must be registered as Day 1 of treatment in the GnRH agonist arm. Group 2 (active comparator): degarelix + RT As the study investigates the effect of 2 drugs given concomitantly to radiotherapy, all men will be treated with the same treatment technique and target dose. The preferred treatment technique is intensity modulated radiotherapy + a GnRH antagonist will be given for a predefined duration of 18, 24, or 36 months as per institution policy. Each institution must adhere to the chosen duration of treatment for all participants throughout the study.
Outcomes	Primary outcomes: Progression‐free survival, defined as the time in days from randomization to death, clinical or biochemical progression, whichever comes first Where PSA progression based on Phoenix definition, i.e. a rise by 2 ng/mL or more above the nadir PSA (Ref. 17) confirmed by a second value measured minimum 3 months later Clinical progression is defined as onset of obstructive symptoms requiring local treatment and demonstrated to be caused by cancer progression or evidence of metastases detected by clinical symptoms and confirmed by imaging Start of another line of systemic therapy in absence of progression Death due to any cause Secondary outcomes: Clinical progression‐free survival Time to next systemic anticancer therapy (including secondary hormonal manipulation) Proportion of men switching from GnRH antagonists to GnRH agonists, and total effective duration of treatment with the originally allocated drug Overall survival Cancer‐specific survival PSA at 6 months after completion of RT Safety will be scored by the CTCAE version 4.0. The major safety endpoints in this study are the incidence of clinical cardiovascular events (i.e. arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease) in men who had cardiovascular events before entering the trial and in those without such events. Incidence of urinary tract infection
Starting date	April 2017
Contact information	Piotr Banski, PhD Telephone: 003227741553 Email: piotr.banski@eortc.be
Notes	Sponsors and collaborators: European Organisation for Research and Treatment of Cancer (EORTC) Principal Investigator: Dirk Boehmer, MD, PhD Charité ‐ Universitaetsmedizin Berlin ‐ Campus Benjamin Franklin Recruitment status: recruiting (checked on 14 August 2020) Estimated primary completion date: June 2024 (final data collection date for primary outcome measure) Trial ID: NCT02799706