Double-Drug attack on bone metastases in prostate cancer

NCT ID NCT02194842

Disease control Sponsor: European Organisation for Research and Treatment of Cancer - EORTC Source: ClinicalTrials.gov ↗

First seen Jun 26, 2026 · Last updated Jun 26, 2026

Summary

This phase 3 trial compares enzalutamide alone versus enzalutamide plus radium-223 in 446 men with castration-resistant prostate cancer that has spread to bone. The goal is to see if the combination delays cancer progression better than enzalutamide alone. Participants must have at least 4 bone metastases and be asymptomatic or mildly symptomatic.

What this could mean

Our plain-language read of the trial. This is informational only, not medical advice or a prediction.

Active substance: enzalutamide and radium-223 (Ra223)
What this could lead to: If successful, this combination could slow cancer progression in the bone better than enzalutamide alone, offering a new standard of care for this patient group.
What could go wrong: This is an advanced trial, but the combination may not improve outcomes enough to justify added side effects. Results are not yet available, and the benefit may be limited to certain patients.

This is an AI summary of the original study and may miss details. Read our disclaimer.

Study facts

What this study's own registry entry says, in plain language.

Phase

Phase 3

Large-scale testing in a bigger group. Usually the last step before a treatment can be approved.

Participants

446 people

The number who actually took part.

Started

Oct 2015

Expected to finish

Dec 2028

An estimate. End dates often move.

Lead sponsor

A research network

The lead sponsor is a research network or cooperative group.

Who can take part

This study's own entry requirements. Only the study team can say for certain whether you qualify.

Ages

18 years and older

Sex

Male participants only

Healthy volunteers

Not accepted

This study is not open to healthy volunteers. The entry requirements below say who it is open to.

Show the full entry requirements

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * Histologically confirmed diagnosis of prostate adenocarcinoma * Asymptomatic or mildly symptomatic (defined as short form question #3 in Brief Pain Inventory worst pain must be \< 4, see Appendix E) * Metastatic to bone with ≥ 4 bone metastases (ambiguous areas of increased uptake on 99mTc Bone Scan (BS) should be confirmed by CT or MRI) with or without additional lymph node metastases. Patients with visceral metastases are not allowed. Patients with multifocal bone lesions are allowed; while patients with diffuse confluent bone lesions (superscan) are not allowed in the trial. * Note: Patients must start treatment with a bone protecting agent (at doses used to reduce the incidence of skeletal related events) ideally before or at the time of randomization, if patient is not already on one. A minimum of two doses is recommended before the first administration of Ra223 in the experimental arm. The first administration of Ra223 should be scheduled at least 6 weeks after the first administration of bone protecting agent. * Note: For French sites only, patients must not have undergone a PET/CT scan for restaging prostate cancer using radiopharmaceuticals such as 18F-FDG, 18F-fluoride, 18F-Fluorocholine or a PSMA (prostate-specific membrane antigen) ligand or any other tracer. * Progressive CRPC according to Prostate Cancer Working Group 3 (PCWG3) (Ref. 22) i.e. either: * For patients who manifest disease progression solely as a rising PSA level, PCWG3 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, PCWG3 guidelines require appearance of 2 or more new lesions. Ambiguous results should be confirmed by other imaging modalities than bone scan (e.g.: CT-scan or MRI) * For patients with disease progression manifest at nodal sites, irrespective of progression by rising PSA, PCWG3 requires progression according to RECIST 1.1 * Ongoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy * No known central nervous system metastases or leptomeningeal tumor spread. * Patients must be at least 18 years old * WHO Performance status 0-1(see Appendix C) * Charlson score ≤ 3 (see Appendix G) * T-score ≥ -2.5 on a DXA scan done in the past 12 months Note: For French sites only, DXA scan done within 6 weeks of randomization * 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 where ≤ 5.0 × ULN applies * 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) * No 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 \> 140 millimeters of mercury (mm Hg) or diastolic blood pressure \> 90 mm Hg at screening. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to randomization. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from all blood pressure assessment timepoints must be ≤140/90 mm Hg in order for a patient to be eligible for the study. * 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 * Uncontrolled hyperglycemia as indicated by a fasting glucose ≥ 7 mmol/L * Able to swallow the study drug and comply with study requirements * Prior or concomitant therapy * Prior docetaxel is permitted if given in the castration sensitive state and if it was started within 4 months of ADT initiation Note: patients having received docetaxel for CRPC are excluded. * Prior use of abiraterone is permitted if the patient had a response or stable disease on abiraterone for a minimum of 1 year for metastatic castration sensitive prostate cancer * Note: patients having received abiraterone for CRPC are excluded. Prior treatment with abiraterone is allowed if it was stopped at least 4 weeks prior to randomization * No prior treatment with enzalutamide, apalutamide, darolutamide or Ra223 * No concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole * Previous treatment with bicalutamide or flutamide is allowed if it was stopped at least 48 hours prior to randomization * Corticosteroids are allowed only at a dose ≤ 10 mg of prednisone (or equivalent) no matter the indication * No 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 * No prior therapy with other radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188) * No involvement in another therapeutic trial involving an experimental drug * No anticancer therapy (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization * No known hypersensitivity to compounds related to enzalutamide or Ra223 (refer to Investigator's brochures) * No 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 * No 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) * Drugs known to lower the seizure threshold or prolong QT interval are not permitted (refer to section 5.9.3.2) * No major surgery within 4 weeks prior to treatment * No drug or alcohol abuse * No 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 * Osteonecrosis of the jaw * Any bone disease with an osteoblastic activity * Bone marrow dysplasia * Fecal incontinence * Life-threatening illness unrelated to cancer * No condition which, in the investigator's opinion, makes the patient unsuitable for trial participation * Participants who have pregnant partners must use a condom and those with partners of childbearing potential must use a condom and another adequate birth control measure if engaging in sexual activities 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 according to ICH/GCP, and national/local regulations * For participation in translational research, specific consent must be given. Important note: All eligibility criteria must be adhered to, in case of deviation discussion with EORTC Headquarters and study coordinator is mandatory Exclusion Criteria: * No known history of central nervous system metastases or leptomeningeal tumor spread. * No significant cardiovascular disease including: 1. Myocardial infarction within 6 months prior to screening 2. Uncontrolled angina within 3 months prior to screening 3. 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% 4. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes) 5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place 6. Uncontrolled hypertension as indicated by a resting systolic blood pressure \> 170 mm Hg or diastolic blood pressure \> 105 mm Hg at screening 7. Hypotension as indicated by systolic blood pressure \< 86 millimeters of mercury (mm Hg) at screening 8. Bradycardia as indicated by a heart rate of \< 45 beats per minute on the screening ECG and on physical examination * patients having received docetaxel for CRPC are excluded. * No prior treatment with enzalutamide or Ra223 * No prior and concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole * No 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 * No prior therapy with other radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188) * No involvement in another therapeutic trial involving an experimental drug * No anticancer therapy or treatment with another investigational agent within the last 4 weeks prior to randomization * No known hypersensitivity to compounds related to enzalutamide or Ra223 * No 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 * No history of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack within 12 months of enrollment (registration date), 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) * No major surgery within 4 weeks prior to treatment * No intake of narcotic analgesia for bone pain * No drug or alcohol abuse * No other serious illness or medical condition, such as but not limited to: 1. Any infection ≥ Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 2. No gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease) 3. Crohn's disease or ulcerative colitis 4. Bone marrow dysplasia 5. Fecal incontinence 6. Life-threatening illness unrelated to cancer * No condition which, in the investigator's opinion, makes the patient unsuitable for trial participation

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Conditions

The condition(s) this trial relates to.

castration-resistant prostate carcinoma Neoplasm Metastasis prostate cancer

As listed by the trial registrant

The condition terms exactly as the trial's registrant entered them.

Prostate cancer

Contacts and locations

Locations

AZ Groeninge Kortrijk

Kortrijk, Belgium
AZ Turnhout

Turnhout, Belgium
Assistance Publique - Hopitaux de Paris - CHU Henri Mondor

Créteil, 94000, France
CHU Dinant Godinne - UCL Namur

Yvoir, 5530, Belgium
CHUM - Centre Hospitalier de l'Université de Montreal - Pavillon Saint-Luc

Montreal, Quebec, H2X 3J4, Canada
Centre Francois Baclesse

Caen, 14076, France
Centre Leon Berard

Lyon, 69008, France
Centre de sante et de services sociaux de Chicoutimi

Chicoutimi, Quebec, G7H 5H6, Canada
Centro Pesquisas Oncologicas

Florianópolis, 88034000, Brazil
Centro de Estudos e Pesquisa Hematologia e Oncologia

Santo André, 09060-650, Brazil
Centro de Pesquisas Clinicas em Oncologia - Hospital Sao Lucas

Porto Alegre, 90610 000, Brazil
Centro de Tratamentos de Tumores Botafogo

Rio de Janeiro, 22250-040, Brazil
Chuq-Pavillon Hotel-Dieu De Quebec

Québec, Quebec, G1R 2J6, Canada
Cliniques Universitaires Saint-Luc

Brussels, 1200, Belgium
Clínica Oncológica - CLION

Salvador, 41810-570, Brazil
Complejo Hospitalario de Navarra

Pamplona, 31008, Spain
Cork University Hospital

Cork, TI2DC4A, Ireland
Corporacio Sanitaria Parc Tauli

Sabadell, Spain
Gustave Roussy

Villejuif, 94805, France
Hamilton And District Urology Association

Hamilton, Ontario, L8N 1T8, Canada
Hopital Universitaire Brugmann

Brussels, 1020, Belgium
Hopitaux Universitaires Bordet-Erasme - Hopital Universitaire Erasme

Brussels, 1070, Belgium
Hopitaux Universitaires de Strasbourg - Hôpitaux Universitaires de Strasbourg - Hôpital civil

Strasbourg, 67091, France
Hospital Beneficencia Portuguesa

São Paulo, 01321-000, Brazil
Hospital Clinic Universitari de Barcelona

Barcelona, 08036, Spain
Hospital De La Santa Creu I Sant Pau

Barcelona, 08041, Spain
Hospital Del Mar

Barcelona, 08003, Spain
Hospital Erasto Gaertner

Curitiba, 81520-060, Brazil
Hospital Moinhos de Vento

Porto Alegre, 90035-001, Brazil
Hospital Paulistano

São Paulo, 01321-001, Brazil
Hospital Universitario QuironSalud

Madrid, 28223, Spain
Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain
Hospital Universitario de La Princesa

Madrid, 28006, Spain
Hospital Universitario de Salamanca

Salamanca, 37007, Spain
Hospital de Amor

Barretos, 14.784-400, Brazil
Institut de Cancerologie de l'Ouest (ICO) - Centre Paul Papin

Angers, 49055, France
Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau

Saint-Herblain, 44805, France
Institut régional du Cancer Montpellier

Montpellier, 34298, France
Instituto de Medicina Integral Professor Fernando Figueira - IMIP

Recife, 50070-550, Brazil
Istituto Europeo di Oncologia

Milan, Italy
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Italy
Kantonsspital St Gallen

Sankt Gallen, Switzerland
London Regional Cancer Center

London, Ontario, N6A 4L6, Canada
Maria Sklodowska-Curie Memorial Cancer Centre

Warsaw, Poland
Nottingham University Hospitals NHS Trust - City Hospital

Nottingham, United Kingdom
Odette Cancer Centre - Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada
Oncocentro

Fortaleza, 60130-241, Brazil
Oncology Institute of Southern Switzerland - Ospedale San Giovanni

Bellinzona, 6500, Switzerland
Ospedale B.Ramazzini

Carpi, 41012, Italy
Rigshospitalet

Copenhagen, Denmark
Royal Marsden Hospital - Chelsea, London

London, SW3 6JJ, United Kingdom
Saint John Regional Hospital

Saint John, New Brunswick, E2L 4, Canada
Sao Camilo Oncologia - Instituto Brasileiro de Controle do Cancer

São Paulo, 03.102-002, Brazil
Soerlandet Sykehus-Kristiansand

Kristiansand, 4604, Norway
St. Vincent's University Hospital

Dublin, Ireland
Tallaght University Hospital

Dublin, Ireland
The Christie NHS Foundation Trust

Manchester, United Kingdom
U.Z. Leuven - Campus Gasthuisberg

Leuven, 3000, Belgium
United Lincolnshire Hospitals NHS Trust - Lincoln County Hospital

Lincoln, LN2 5QY, United Kingdom
UniversitaetsSpital Zurich

Zurich, 8091, Switzerland
Universitair Ziekenhuis Antwerpen

Edegem, 2650, Belgium
University Health Network - Oci Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada
University Hospital of North Norway

Tromsø, N-9038, Norway
Vall d'Hebron Institut d'Oncologia

Barcelona, 08035, Spain

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