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

Phase IIIb randomized stratified open-label comparative 2-arm superiority study with a pre-set non-inferiority boundary.

Registered GnRH antagonists, degarelix, will be given at the dose of 240 mg given as two subcutaneous injections of 120 mg at a concentration of 40 mg/mL on day 1, followed by 80 mg given as one subcutaneous injection at a concentration of 20 mg/mL every 28 days (±2 days).

External beam radiotherapy (EBRT) to a total dose of 78-80 Gy, delivered as one daily fraction, five days a week, started between d1 and months 6 of the androgen deprivation therapy as per institution policy. The irradiation is the same as in the reference therapy arm.

The minimum duration of androgen deprivation with GnRH agonist or antagonist therapy is 18 months.

For each patient, the duration of therapy must be elected upfront by the treating physician among three possible options: 18, 24 or 36 months. The institution shall also declare upfront the duration of the neoadjuvant treatment they intend to deliver to each patient (between 0 and 6 months).

The primary endpoint is 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 endpoints:

• Clinical progression-free survival
• Time to next systemic anticancer therapy (including secondary hormonal manipulation)
• Proportion of patients 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 six 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 - CCE (i.e. arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease) in patients who had cardiovascular events before entering the trial and in those without such events.
• Incidence of urinary tract infection

Inclusion criteria

• Histologically confirmed diagnosis of prostate adenocarcinoma
• PSA ≥ 10 ng/ml and two of the following 4 criteria:
• PSA ≥ 20 ng/ml,
• Gleason sum ≥ 8,
• cN1 (regional LN with a short axis length >10mm 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 one of the other 3 risk factors is needed)
• M0 by standard imaging work-up (see chapter 6.1.1.1)
• 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 0-1
• Age ≥ 18 and ≤ 80 years
• Participants 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 deprivation therapy (ADT), 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 gastro-intestinal 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 evidence 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 BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive 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