RAndomized, open label, multicenter study of Docetaxel versus an Androgen Receptor-targeted agent (abiraterone orenzalutamide) as first-line of therapy in mCRPC patients with adverse prognostic factors (RADAR-1 CRPC)

Prior treatment

• Other malignancy with a previous diagnosis within 5 years (with the exclusions of NMIBC)
• Concomitant medications as reported in section 7
• Previous cytotoxic chemotherapy, or biologic therapies for the treatment of castrationsensitive or castration-resistant prostate cancer (prior use of bicalutamide is permitted). Previous use of new generation androgen receptor inhibitors for castration-sensitive disease is permitted if at least one year has passed since their discontinuation or if treatment has lasted longer than 36 months without evidence of biochemical and radiological progression
• 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 and CSPC

Other illness

• Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
• Active or symptomatic viral hepatitis or chronic liver disease
• Uncontrolled Atrial Fibrillation, or other uncontrolled cardiac arrhythmia requiring therapy
• Known hypersensitivity to docetaxel, abiraterone or enzalutamide active principles and any excipients
• Use of major opiate analgesics for cancer-related pain (codeine and tramadol are allowed)
• 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 antihypertensive treatment

Lab values

• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) or history of additional risk factors for “torsaides de pointes” (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval (at least those of class IA and III).
• 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

Other

• Pathological finding consistent with small cell carcinoma of the prostate greater than 10%
• Known brain metastasis
• Bicalutamide, nilutamide within 6 weeks of Cycle 1 Day 1

• Willing and able to provide written informed consent
• Adequate bone marrow and chemistry values defined as: a. Hemoglobin ≥ 10.0 g/dL independent of transfusion b. Neutrophil count ≥1500 x 109/L c. Platelet count ≥100,000/μL d. Serum albumin ≥ 3.5 g/dL e. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min f. Serum potassium ≥ 3.5 mmol/L g. 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 13 weeks after last study drug administration
• Male aged 18 years and above
• Histologically or cytological confirmed adenocarcinoma of the prostate
• Metastatic disease documented by positive bone scan or metastatic lesions other than liver or visceral metastasis on CT, MRI. If lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in diameter. Alternatively, metastatic disease can be diagnosed by PET-Choline or PSMA.
• Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria
• At least one negative prognostic features between: I. Mildly symptomatic prostate cancer defined as per BPI Question #3 (worst pain in last 24 hours) value 2 or 3 or II. Asymptomatic prostate cancer defined as per BPI Question #3 (worst pain in last 24 hours) value 0 or 1 and at least one between - PSA≥80 ng/dl ; - Gleason Score ≥ 8; - PSA doubling time ≤ 3 months; - Time from start ADT to CRPC less < 1 year
• No evidence of mutation in BRCA1 or genes or tumor tissue not evaluated for quality reasons (status unknown)
• Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 2