SAKK 08/15 - PROMET - Salvage Radiotherapy +/- Metformin for Patients With Prostate Cancer After Prostatectomy

Inclusion Criteria:

* Written informed consent according to ICH/GCP regulations before registration and prior to any trial specific procedures
* Histologically confirmed adenocarcinoma of the prostate without small cell features
* Tumor stage pT2a-3b, pN0 or cN0, M0, R0-1 resection margins, according to UICC TNM 2009, Gleason score available
* Radical prostatectomy (RP) at least 12 weeks before registration
* PSA progression after RP defined as two consecutive rises with the final PSA \> 0.1 ng/mL or three consecutive rises. The first value must be measured earliest 4 weeks after RP
* PSA ≤ 2 ng/mL within 14 days prior to registration
* Age ≥ 18 years at time of registration
* WHO performance status 0-1
* Adequate hepatic function within 14 days prior to registration: bilirubin ≤ 1.5 x ULN (exception if Gilbert's syndrome ≤ 3 x ULN), AST and ALT ≤ 2.5 x ULN
* Adequate renal function within 14 days prior to registration: calculated corrected creatinine clearance ≥ 60 mL/min, according to the formula of corrected Cockcroft-Gault Patient agrees not to father a child and to use effective contraceptive methods during salvage radiotherapy and until 6 months after the last fraction of radiotherapy

Exclusion Criteria:

* Persistent PSA (\> 0.4 ng/mL) 4 to 20 weeks after RP
* Pelvic lymph node enlargement \> 0.8 cm in short axis diameter (cN positive) assessed by mpMRI within 12 weeks prior to registration, unless the enlarged lymph node is sampled and negative
* Evidence of macroscopic local recurrence assessed by mpMRI within 12 weeks prior to registration
* Palpable prostatic fossa mass suggestive of recurrence, unless an ultrasound guided biopsy is negative for malignancy
* Presence or history of prostate cancer metastases. In case of clinical suspicion (e.g. bone pain), imaging (e.g. bone scan, Choline-PET, PSMA-PET, whole body MRI) must be performed. The imaging method is at the discretion of the investigator.
* If PET/CT scan was performed, any metabolic uptake considered clinically suspicious for malignancy, unless biopsy proves to be negative.
* History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years from registration with the exception of curatively treated localized non-melanoma skin cancer
* Patients diagnosed with diabetes mellitus
* Treatment with metformin within the last 3 months prior to registration
* Prior pelvic radiotherapy
* Hormonal treatment as bilateral orchiectomy prior or following RP
* Usage of products known to affect PSA levels within 4 weeks prior to start of trial treatment
* Bilateral hip prosthesis
* Severe or active co-morbidity likely to impact on the advisability of salvage RT, e.g.:

  * History of inflammatory bowel disease or any malabsorption syndrome or conditions that would interfere with enteral absorption
  * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  * Transmural myocardial infarction within the last 6 months
  * Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
* Any condition associated with increased risk of lactic acidosis (e.g. alcohol abuse, congestive heart failure NYHA III or IV
* Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis
* Severe or uncontrolled kidney disease resulted in impaired kidney function (GFR \<60ml/min)
* Any acute or chronic condition that could cause tissue hypoxia (e.g. cardiac or respiratory insufficiency, recent myocardial infarction, shock)
* Treatment with any experimental drug or participation within a clinical trial within 30 days prior to registration (exception: concurrent participation in the biobank project SAKK 63/12 is allowed)
* Any concomitant drug contraindicated for use with metformin according to the approved product information
* Known hypersensitivity to metformin/placebo or to any of its components
* Hereditary intolerance to fructose; known galactose-1-phosphate uridyl transferase deficiency, UDP galactose 4 epimerase deficiency, galactokinase deficiency, Fanconi-Bickel syndrome, congenital lactase deficiency, or glucose-galactose malabsorption (due to the lactose-containing placebo)
* Inability or unwillingness to swallow oral medication
* Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications