Trial of Abiraterone Acetate Plus LHRH-therapy Versus Abiraterone Acetate Sparing LHRH-therapy in Patients With Progressive Chemotherapy-naïve Castration-resistant Prostate Cancer (SPARE)

Inclusion criteria

• Willing and able to provide written informed consent
• Written Data Protection Consent has been obtained
• Male aged 18 years and above
• Histologically or cytologically confirmed adenocarcinoma of the prostate
• Metastatic disease documented by positive CT/MRI and/or bone scan (both must be performed). If lymph node metastasis is the only evidence of metastasis, it must be ≥2 cm in diameter
• Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria
• Asymptomatic or mildly symptomatic from prostate cancer. A score of 0-1 for the question of worst pain within last 24 hours (Appendix 8) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic.
• Medically castrated, with testosterone levels of <20-50 ng/dl (< 2.0 nM).
• Combined androgen blockade is permitted, but not required. If patients received combined androgen blockade with an anti-androgen they must have shown PSA progression after discontinuing the anti-androgen prior to enrollment (≥4 weeks since last flutamide, ≥6 weeks since last bicalutamide or nilutamide).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2 (Appendix 6)
• Hemoglobin ≥9.0 g/dL independent of transfusion
• Platelet count ≥100,000 /μl
• Serum albumin ≥3.0 g/dl
• Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥60 ml/min (Appendix 7)
• Serum potassium ≥3.5 mmol/l
• Liver function:

• Serum bilirubin <1.5 x ULN (except for patients with documented Gilbert's disease)
• AST or ALT <2.5 x ULN
• Able to swallow the study drug whole as a tablet
• Life expectancy of at least 6 months
• Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 1 week after last study drug administration.

Exclusion criteria

• Surgical castration (i.e. orchiectomy).
• Application of any LHRH-therapy (LHRH-analogue or LHRH-antagonist) within 3 months (for patients receiving a 3-months formulation) or 1 months (for patients receiving a 1-month formulation) prior to Cycle 1 day 1.
• Patients receiving a 6- or 12-months formulation of LHRH-therapy
• Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
• Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid.
• Pathological finding consistent with small cell carcinoma of the prostate
• Liver or visceral organ metastasis
• Known brain metastasis
• Use of opiate analgesics for cancer-related pain, including codeine, tramadol, tilidin and others (see Appendix 9), currently or anytime within 4 weeks of Cycle 1 Day 1.
• Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC
• Radiation therapy for treatment of the primary tumour within 6 weeks of Cycle 1, Day 1
• Radiation or radionuclide therapy for treatment of metastatic CRPC
• Prior treatment with Abiraterone acetate or other CYP17 inhibitors (ketoconazole, TAK700, TOK001) ), Enzalutamide (Xtandi) or investigational agents targeting the androgen receptor for prostate cancer for more than 7 days
• Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1
• Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1)
• Bicalutamide (Casodex), nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day1)
• Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg). Patients with a history of hypertension are allowed provided that blood pressure is controlled by anti- hypertensive treatment
• Active or symptomatic viral hepatitis or chronic liver disease
• History of pituitary or adrenal dysfunction
• 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 II-IV heart disease or cardiac ejection fraction measurement of <50 % at baseline
• Any condition that requires treatment with Digoxin, digitoxin, and other digitalis drugs
• Atrial Fibrillation, or other cardiac arrhythmia requiring therapy
• Other malignancy with a ≥30 % probability of recurrence within 24 months, except non- melanoma skin cancer.
• Administration of an investigational therapy within 30 days of Cycle 1, Day 1
• Any condition, which, in the opinion of the investigator, would preclude participation in this trial.