A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.

Conditions: Castration resistant prostate cancer patients metastatic to bone.
MedDRA version: 18.0Level: PTClassification code 10036909Term: Prostate cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-001787-36-ES

Lead Sponsor: European Organisation for Research and Treatment of Cancer (EORTC)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Male

Target Recruitment: 560

Inclusion Criteria

?Histologically confirmed diagnosis of prostate adenocarcinoma
? Asymptomatic or mildly symptomatic (defined as no opioids and Brief Pain Inventory score, i.e. short form question #3 worst pain must be < 4)
? Metastatic to bone with ? 2 bone metastases (area of increased uptake on 99mTC Bone Scan (BS) confirmed by standard X-Ray, CT, or MRI) with or without additional lymph node metastases. Patients with visceral metastases are not allowed
? Progressive CRPC according to Prostate Cancer Working Group 2 (PCWG2) i.e. either:
-For patients who manifest disease progression solely as a rising PSA level, PCWG2 criteria require documentation of a sequence of rising PSA values at a minimum of 1-week intervals with the last value ? 2 ng/ml.
-For patients with disease progression manifest in the bone, irrespective of progression by rising PSA, PCWG2 guidelines require appearance of 2 or more new lesions. Ambiguous results should be confirmed by other imaging modalities than bone scan and X-Ray (e.g.: CT-scan or MRI).
-For patients with disease progression manifest at nodal sites, irrespective of progression by rising PSA, PCWG2 requires progression according to RECIST 1.1.
? Ongoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy.
Patients must be at least 18 years old
? WHO Performance status 0-1
? Charlson score ? 3
? Castrate serum levels of testosterone < 50 ng/dL
? Biochemistry and hematology
-Adequate bone marrow function (absolute neutrophil count (ANC) ? 1.5 109/L; platelets ?100 109/L, and hemoglobin ? 10.0 g/dl.).
-Total bilirubin level ? 1.5 x institutional upper limit of normal (ULN), except for patient with Gilbert?s disease ? 5.0 × ULN.
-Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 x ULN.
-Creatinine ? 1.5 x ULN
-Albumin > 25 g/L
? Normal cardiac function according to local standard by 12-lead ECG (complete, standardized 12-lead recording).
? Able to swallow the study drug and comply with study requirements
? Prior or concomitant therapy.
-Prior docetaxel is permitted under the following conditions: started within 2 months of ADT initiation, given for a maximum of 6 cycles and progression after 6 months of the last dose of docetaxel.
-Previous treatment with bicalutamide, flutamide, prednisone, or dexamethasone is allowed if it was stopped at least 4 weeks prior to randomization.
? Patients taking bisphosphonates or denosumab are eligible if they have received a stable dose for 4 weeks or more prior to randomization. (These treatments may then be continued on study).
? Drugs known to lower the seizure threshold or prolong QT interval are not permitted.
? 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 enzalutamide and 6 months after the last dose of Ra223. 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.
? Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
? Before patient randomization, written informed consent must be given

Exclusion Criteria

? Known central nervous system metastases or leptomeningeal tumor spread.
? Significant cardiovascular disease including:
-Myocardial infarction within 6 months prior to screening.
-Uncontrolled angina within 3 months prior to screening.
-Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ? 45%
-History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes).
-History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
-Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 millimeters of mercury (mm Hg) or diastolic blood pressure > 105 mm Hg at screening.
-Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening.
-Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening ECG and on physical examination.
? Prior treatment with enzalutamide or Ra223.
? Prior or concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole.
? Prior hemibody external radiotherapy. Patients who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count and platelets.
? Prior therapy with other radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188).
? Involvement in another therapeutic trial involving an experimental drug.
? Anticancer therapy (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization.
? Known hypersensitivity to compounds related to enzalutamide or Ra223 .
? Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin, in-situ carcinoma or low-grade superficial bladder cancer), or the patient has been free of malignancy for a period of 3 years prior to randomization date.
? History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack within 12 months of randomization, OR any condition that may pre-dispose to seizure (e.g., prior stroke, brain arterio-venous malformation, head trauma with loss of consciousness requiring hospitalization).
? Major surgery within 4 weeks prior to treatment.
? Drug or alcohol abuse.
? Other serious illness or medical condition, such as but not limited to:
-Any infection ? Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.
-No gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease).
-Crohn?s disease or ulcerative colitis.
-Bone marrow dysplasia.
-Fecal incontinence.
-Life-threatening illness unrelated to cancer.
? Condition which, in the investigator?s opinion, makes the patient unsuitable for trial participation.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival (rPFS1) compared to enzalutamide single agent in CRPC patients metastatic to bone.;Secondary Objective: To assess if upfront combination of enzalutamide with Ra223 (experimental arm) offers further benefits over enzalutamide alone in terms of the secondary efficacy endpoints listed below, to compare the safety profile of the approaches and to document their impact on patient reported outcomes (pain and quality of life (QoL).;Primary end point(s): Radiological Progression free survival (rPFS1);Timepoint(s) of evaluation of this end point: Radiological Progression free survival (rPFS1) counted from randomization to the first progression defined as per the Prostate Cancer clinical trials Working Group version 2 and referred to as the PCWG2 for the setting delay/prevent progression or to death from any cause.

Secondary Outcome Measures

Name	Time	Method