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Clinical Trial
. 2019 Jan 7;19(1):12.
doi: 10.1186/s12885-018-5203-y.

Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program

Axel Heidenreich  1 , Silke Gillessen  2   3   4 , Daniel Heinrich  5 , Daniel Keizman  6 , Joe M O'Sullivan  7 , Joan Carles  8 , Manfred Wirth  9 , Kurt Miller  10 , John Reeves  11 , Monica Seger  11 , Sten Nilsson  12 , Fred Saad  13
Affiliations
Clinical Trial

Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program

Axel Heidenreich et al. BMC Cancer. .

Abstract

Background: Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking.

Methods: This was a prospective, single-arm phase 3b study. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6 cm was allowed, visceral disease was excluded) received radium-223, 55 kBq/kg intravenously, every 4 weeks for up to 6 cycles. Co-primary endpoints were safety and overall survival. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Asymptomatic status was defined as no pain and no opioid use at baseline.

Results: Seven hundred eight patients received ≥1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%). A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. Overall survival (hazard ratio [HR] 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3-4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). There were two treatment-related deaths, both in patients with baseline symptomatic disease.

Conclusions: Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies.

Trial registration: The study was registered with ClinicalTrials.gov , number NCT01618370 on June 13, 2012 and the European Union Clinical Trials Register, EudraCT number 2012-000075-16 on April 4, 2012.

Keywords: Bone metastases; Radium-223; Symptomatic; mCRPC, asymptomatic.

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Conflict of interest statement

Ethics approval and consent to participate

The protocol and all protocol amendments were reviewed and approved by each study site’s Independent Ethics Committee/Institutional Review Board before the start of the study (listed below). All patients provided written informed consent prior to entry into the international, prospective, interventional, open-label, single-arm, phase 3b study that was conducted in compliance with the Declaration of Helsinki, International Conference on Harmonisation Guidelines for Good Clinical Practice and all local legal and regulatory requirements.

Local ethics committees (central ethics committees) — Belgium: (Central) CU Saint-Luc/UZ St-Luc, Comité d’Ethique Hospitalo-Facultaire, Brussels (trial unit [TU] 28,001); Institut Jules Bordet/Jules Bordet Instituut Comité Ethique/Ethisch Comité, Brussels (TU 28002); UZ Gent Ethisch Comité, Gent (TU 28003); UZ Leuven Gasthuisberg Commissie voor Medische Ethiek/klinisch Onderzoek, Leuven (TU 28007); UZ Brussel Comité Ethique/Ethisch Comité, Brussels (TU 28009). Canada: Princess Margaret Hospital-University Health Network, University Health Network Research Ethics Board, Toronto (TU 26004); British Columbia Cancer Agency-Vancouver Centre Research Ethics Board, Vancouver (TU 26005); Sunnybrook Health Sciences Centre, Sunnybrook Research Ethics Board Research Ethics Office, Toronto (TU 26006); Ottawa Health Science Network Research Ethics Board, Ottawa (TU 26007); CHUM - Hopital Notre-Dame, Comité d’évaluation scientifique et d’éthique de la recherche du CHUM, Montreal (TU 26008). Finland: (Central) HUS Tutkimuseettiset toimikunnat Operatiivinen eettinen toimikunta Biomedicum, Helsinki (TU 59002, 59,003, 59,004, 59,005). Germany: (Central) Landesamt für Gesundheit und Soziales Geschäftsstelle der Ethik-Kommission des Landes, Berlin (TU 10001, 10,014, 10,025); Fakultät Carl Gustav Carus, Ethik-Kommission der Technischen Universität Dresden, Dresden (TU 10002); Universitätsklinikum Aachen Ethik-Kommission, Aachen (TU 10003); Ethik-Kommission des Fachbereichs Medizin der Johann Wolfgang Goethe-Universität, Frankfurt (TU 10006); Klinikum der Universität München Großhadern, Ethikkommission der LMU, Munich (TU 10007); Ethikkommission der Fakultät für Medizin der Technischen Universität München, Munich (TU 10010); Ethik-Kommission der Landesärztekammer Rheinland-Pfalz, Mainz (TU 10011); Universität Rostock - Medizinische Fakultät Ethikkommission an der Medizinischen Fakultät, Rostock (TU 10013); Ethikkommission des Landes Bremen Institut für Klinische Pharmakologie Klinikum Bremen-Mitte gGmbH, Bremen (TU 10016); Universitätsklinikum Erlangen Ethik-Kommission der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen (TU 10017); Medizinische Medizinische Fakultät der Otto-von-Guericke Universität Ethikkommission, Magdeburg (TU 10018); Ethik-Kommision der Medizinischen Fakultät der Eberhard-Karls-Universität und am Universitätsklinikum Tübingen, Tübingen (TU 10019); Ethik-Kommission der Friedrich-Schiller-Universität Jena, Jena (TU 10020); Ethikkommission an der Medizinischen Fakultät der Heinrich-Heine-Universität, Düsseldorf (TU 10021); Ethik-Kommission des Fachbereichs Medizin der Philipps-Universität Marburg (TU 10026); Ethik-Kommission der Landesärztekammer Baden-Württemberg, Stuttgart (TU 10027); Universitätsklinikum Ulm Ethik-Kommission, Ulm (TU 10029); Ethik-Kommission der Ärztekammer Hamburg, Hamburg (TU 10030). Ireland: Clinical Research Ethics Committee of the Cork Teaching Hospital, Cork (TU 80001, 80,002, 80,003). Israel: Soroka University Medical Center Ethics Committee, Beer Sheva (TU 39001); Meir Medical Center Ethics Committee, Kafar Saba (TU 39002); Ethic Committee, Rambam Medical Center Tamar, Hafia (TU 39003); Assaf Harofeh Medical Center Ethics Committee, Zrifin (TU 39004); Hadassah Hebrew University Hospital Ein Kerem Helsinki Committee, Hadassah University Medical Center, Jerusalem (TU 39005); Rabin Medical Center - Beilinson Campus Ethics Committee, Petah Tikva (TU 39006); Tel-Aviv Sourasky Medical Center Ethics Committee, Tel-Aviv (TU 39007); Chaim Sheba Medical Center Ethics Committee, Ramat Gan (TU 39009). Italy: IRST Istituto Scientifico Romagnolo per studio e cura Tumori CE IRST IRCCS-AVR: Comitato Etico IRST IRCCS e Area Vasta Romagna, Forli (TU 22001); Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Comitato Etico Centrale IRCCS Lombardia sezione IRCCS Istituto Nazionale Tumori, Milano (TU 22002); A.O.U. Pisana Ceavno: Comitato Etico di Area Vasta Nord Ovest Toscana, Pisa (TU 22005); IRCCS Istituto Clinico Humanitas - Humanitas Mirasole S.p.A. Comitato Etico IRCCS Lombardia Sezione Istituto Clinico Humanitas, Milano (TU 22007); Azienda Policlinico Umberto I Comitato Etico Universita’ La Sapienza, Roma (TU 22008); A.O.U. Policlinico G. Martino Comitato Etico Interaziendale Provincia Di Messina, Messina (TU 22009); A.O.U. San Luigi Gonzaga CEI: Comitato Etico Interaziendale A.O.U. San Luigi Gonzagsa e ASL TO2 TO3 TO4 TO5, Orbassano, Torino (TU 22010); E.O. Ospedali Galliera Comitato Etico Regione Liguria Sezione 2 Sperimentazioni Adulti, Genova (TU 22012); AULSS 09 Treviso CESC: Comitato Etico Sperimentazione Clinica Province Trevisobelluno, Treviso (TU 22017); Comitato Etico Di Area Vasta Sud Est Toscana - Sezione di Arezzo, Arezzo (TU 22018); APSS Trento – Trentino Comitato Etico Sperimentazioni Cliniche Azienda Provinciale per i Servizi Sanitari (APSS), Trento (TU 22021). A.O. Sant’Andrea Comitato Etico Universita’ La Sapienza, Roma (TU 22028): A.O. San Camillo-Forlanini Comitato Etico Lazio 1, Roma (TU 22029). Norway: (Central) Regional komité for medisinsk og helsefaglig forskningsetikk, Oslo (TU 36001, 36,002, 36,003, 36,004, 36,006); Netherlands: (Central) Commissie Mensgebonden Onderzoek (CMO) UMC St-Radboud, Nijmegen (TU 30003, 30,004). Poland: Komisja Bioetyczna przy Centrum Onkologii Centrum Onkologii - Instytut im. M. Sklodowskiej-Curie, Warszawa (TU 18001, 18,006). Russian Federation: National Medical Research Radiology Center, Local ethical committee for clinical trials Medical Radiological Research Centre of RAMS, Obninsk (TU 51002); EC at Oncological Scientific Center n.a N.N. Blokhin 24, Kashirskoe shosse, Moscow (TU 51003). Spain: (Central) Ciutat Sanitària i Universitaria de la Vall d’Hebron Comité Étic d’Investigació Clínica, Barcelona (TU 24001); Clínica Universidad de Navarra CUN, Comité Ético de Investigación Clínica de Navarra, Pamplona (TU 24002); Hospital General Universitario Gregorio Marañón Comité Ético de Investigación Clínica Secretaría CEIC, Madrid (TU 24008); CEIC Hospital Ramón y Cajal, Madrid (TU 24004); Hospital Clínico Universitario de Santiago de Compostela Comité Etico de Investigación Clínica SERGAS, Santiago de Compostela (TU 24006); CEIC Investigación Biomédica de Andalucían, Consejeria de Salud Secretaria General de Calidad y Eficiencia, Sevilla (24,014, 24,028); Hospital Virgen de la Victoria Comité Etico de Investigación Clínica, Malaga (TU 24007); Fundación Hospital Alcorcón Comité Ético de Investigación Clínica, Alcorcón (TU 24009); Hospital de la Santa Creu i de Sant Pau Comité Ético de Investigación Clínica, Barcelona (TU 24010); Hospital Clínic i Provincial de Barcelona Comité Ético de Investigación Clínica, Agencia de Ensayos Clínicos, Barcelona (TU 24011); Hospital Universitari Son Espases Comité Ético de Investigación Clínica de las Islas Baleares Conselleria de Salut i Consum, Palma de Mallorca (TU 24012); Hospital Universitario “La Paz” CEIC Área 5 - H.U. La Paz, Madrid (TU 24013); Comité Ético de Investigación Clinica de Navarra, Hospital de Navarra, Pamplona (TU 24015); Ciutat Sanitària i Universitària de Bellvitge, Comité Ético de Investigación Clínica Secretaria Administrativa/Unitat de Recerca, L’Hospitalet de Llobregat, Barcelona (TU 24017); Hospital Universitario “Marqués de Valdecilla” Comité Etico de Investigación Clínica, Santander (TU 24023); Hospital Universitario 12 de Octubre Comité Ético de Investigación Clínica, Madrid (TU 24024); Hospital Central de Asturias Secretaría del Comité Ético de Investigación Clínica, Oviedo (TU 24032); Hospital Universitari i Politècnic La Fe Comité Etico de Investigación Clínica, Valencia (TU 24033). Sweden: (Central) Etikprövningsnämnden Regionala etikprövningsnämnden i Stockholm, Karolinska Institutet, Stockholm (TU 34001–34,009, 340,011). Switzerland: Commission cantonale d’éthique de la recherche sur l’être humain, Lausanne (TU 58001); Ethikkommission St. Gallen, Kantonspital St. Gallen, St. Gallen (TU 58002); Kantonale Ethikkommission Zürich, Zürich (TU 58003); Kantonale Ethikkommission Aargau, Departement Gesundheit und Soziales, Aarau (TU 58004); Ethikkommission NordWest- und Zentralschweiz, Basel (TU 58005); Kantonale Ethikkommission Bern – KEK Institut für Pathophysiologie, Bern (TU 58007); Commission cantonale d’éthique de la recherche CCER, Genève (TU 58009). United Kingdom: National Research Ethics Service (NRES) Committee South West – Central Bristol South West Research Ethics Committee Centre, Bristol (TU 12006, 12,011, 12,015, 12,019, 12,020, 12,021, 12,024, 12,026).

Consent for publication

Not applicable.

Competing interests

A.H. has received honoraria from Amgen, Astellas, Bayer, Dendreon, Ferring, Ipsen, Jansen, Pfizer, Sanofi, Takeda and has received research funding from Amgen, Astellas, and Sanofi; S.G. has compensated consultancy/advisory roles with AAA International, Active Biotech AB IDMC, Astellas Pharma, Bayer, Bristol-Myers Squibb, Clovis, Curevac, Dendron Corporation, Ferring, Innocrin Pharmaceuticals, Janssen-Cilag, MaxiVAX SA, Millennium, Pharmaceuticals, Novartis, Orion, Pfizer, Roche and Sanofi Aventis, and has participated in Speakers Bureaus (compensated) for Janssen and Novartis and has a patent application for a biomarker method (WO 2009138392 A1); D.H. has received honoraria from Janssen-Cilag, Astellas and Bayer, has compensated consultancy/advisory roles with Astellas, Bayer and Amgen and has had travel/accommodation expenses reimbursed from Bayer; D.K. has received honoraria from and has compensated consultancy/advisory roles with Pfizer, Sanofi, Bayer and Novartis and has had travel/accommodation/expenses reimbursed from Pfizer and Bayer; JMO has participated in advisory boards and speaker’s bureaus for Bayer, Janssen, Sanofi and has received research funding (institute) from Bayer; JC has a compensated consultancy role and has participated in scientific advisory boards for Johnson & Johnson, Astellas, Bayer, Amgen, Pfizer, BMS and has participated in speaker’s bureaus for Bayer and Johnson & Johnson; MW has compensated consultancy or advisory roles with ABX, Apogepha, Astellas, Amgen, Janssen-Cilag, Bayer, MSD and has provided expert testimony for ABX; KM has received honoraria from Bayer, Janssen and Amgen and has compensated consultancy/advisory roles with Astellas, Astra Zeneca, Bristol-Myers Squibb, Ferring, Janssen, MSD, Novartis, Roche and Sotio; J.R. and M.S. are salaried employees of Bayer; SN has received honoraria from Bayer, Astellas, Ipsen, Sanofi-Genzyme, Novartis, Roche and Janssen for advisory board participations and lectures; F.S. has a compensated consultancy role with, and has received research funding from, Bayer, Astellas, Janssen and Sanofi.

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Figures

Fig. 1
Fig. 1
Overall survival in radium-223 treated patients according to symptom status at baseline
Fig. 2
Fig. 2
Time to disease progression in radium-223 treated patients according to symptom status at baseline
Fig. 3
Fig. 3
Time to first symptomatic skeletal event in radium-223 treated patients according to symptom status at baseline
See this image and copyright information in PMC

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