Original article
Efficacy of enzalutamide and apalutamide in the treatment of non-metastasic castration-resistant prostate cancer: Indirect comparison
Enzalutamida y apalutamida en el tratamiento del cáncer de próstata no metastásico resistente a la castración: comparación indirecta de la eficacia
P. Nieto-Gómez
, R. Ubago-Pérez, J. Cabeza-Barrera
Corresponding author
Unidad de Gestión Clínica de Farmacia Hospitalaria, Hospital Universitario San Cecilio, Granada, Spain
Read
1
Timeswas read the article
0
Total PDF
1
Total HTML
Share statistics
array:24 [ "pii" => "S2173578619300794" "issn" => "21735786" "doi" => "10.1016/j.acuroe.2019.03.011" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "1170" "copyright" => "AEU" "copyrightAnyo" => "2019" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Actas Urol Esp. 2019;43:355-63" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0210480619300713" "issn" => "02104806" "doi" => "10.1016/j.acuro.2019.03.007" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "1170" "copyright" => "AEU" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Actas Urol Esp. 2019;43:355-63" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 163 "formatos" => array:2 [ "HTML" => 122 "PDF" => 41 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Artículo original</span>" "titulo" => "Enzalutamida y apalutamida en el tratamiento del cáncer de próstata no metastásico resistente a la castración: comparación indirecta de la eficacia" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "355" "paginaFinal" => "363" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Efficacy of enzalutamide and apalutamide in the treatment of non-metastasic castration-resistant prostate cancer: Indirect comparison" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "P. Nieto-Gómez, R. Ubago-Pérez, J. Cabeza-Barrera" "autores" => array:3 [ 0 => array:2 [ "nombre" => "P." "apellidos" => "Nieto-Gómez" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Ubago-Pérez" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Cabeza-Barrera" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173578619300794" "doi" => "10.1016/j.acuroe.2019.03.011" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173578619300794?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210480619300713?idApp=UINPBA00004N" "url" => "/02104806/0000004300000007/v1_201909021027/S0210480619300713/v1_201909021027/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2173578619300769" "issn" => "21735786" "doi" => "10.1016/j.acuroe.2019.03.010" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "1163" "copyright" => "AEU" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Actas Urol Esp. 2019;43:364-70" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "364" "paginaFinal" => "370" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Seguridad de nivolumab en pacientes con carcinoma de células renales metastásico: experiencia española en urología en la práctica clínica real" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Amores Bermúdez, I. Osman García, M. Unda Urzáiz, P. Jiménez Marrero, M.J. Ledo Cepero, R. Llarena, J. Flores Martín, J.I. Abad Vivas-Pérez, M. Rodrigo Aliaga, A. Juarez Soto" "autores" => array:10 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Amores Bermúdez" ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Osman García" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Unda Urzáiz" ] 3 => array:2 [ "nombre" => "P." "apellidos" => "Jiménez Marrero" ] 4 => array:2 [ "nombre" => "M.J." "apellidos" => "Ledo Cepero" ] 5 => array:2 [ "nombre" => "R." "apellidos" => "Llarena" ] 6 => array:2 [ "nombre" => "J." "apellidos" => "Flores Martín" ] 7 => array:2 [ "nombre" => "J.I." "apellidos" => "Abad Vivas-Pérez" ] 8 => array:2 [ "nombre" => "M." "apellidos" => "Rodrigo Aliaga" ] 9 => array:2 [ "nombre" => "A." "apellidos" => "Juarez Soto" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S021048061930049X" "doi" => "10.1016/j.acuro.2019.03.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S021048061930049X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173578619300769?idApp=UINPBA00004N" "url" => "/21735786/0000004300000007/v1_201909021029/S2173578619300769/v1_201909021029/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173578619300782" "issn" => "21735786" "doi" => "10.1016/j.acuroe.2019.07.001" "estado" => "S300" "fechaPublicacion" => "2019-09-01" "aid" => "1168" "copyright" => "AEU" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Actas Urol Esp. 2019;43:348-54" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Validation of a new artificial model for simulated training of a laparoscopic vesicourethral anastomosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "348" "paginaFinal" => "354" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Validación de un nuevo modelo de simulación inorgánica para la anastomosis uretrovesical laparoscópica" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1413 "Ancho" => 1593 "Tamanyo" => 134675 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Time to perform prostate resection, “task 1” and urethrovesical anastomosis, “task 2” of the E and N groups.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "B. Fernández-Tomé, I. Díaz-Güemes, S. Enciso Sanz, B. Naranjo Moreno, L. Correa, M.A. Sánchez-Hurtado, J. Usón, J. Bachiller, A. Serrano, F.M. Sánchez-Margallo" "autores" => array:10 [ 0 => array:2 [ "nombre" => "B." "apellidos" => "Fernández-Tomé" ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Díaz-Güemes" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Enciso Sanz" ] 3 => array:2 [ "nombre" => "B." "apellidos" => "Naranjo Moreno" ] 4 => array:2 [ "nombre" => "L." "apellidos" => "Correa" ] 5 => array:2 [ "nombre" => "M.A." "apellidos" => "Sánchez-Hurtado" ] 6 => array:2 [ "nombre" => "J." "apellidos" => "Usón" ] 7 => array:2 [ "nombre" => "J." "apellidos" => "Bachiller" ] 8 => array:2 [ "nombre" => "A." "apellidos" => "Serrano" ] 9 => array:2 [ "nombre" => "F.M." "apellidos" => "Sánchez-Margallo" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210480619300695" "doi" => "10.1016/j.acuro.2019.03.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210480619300695?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173578619300782?idApp=UINPBA00004N" "url" => "/21735786/0000004300000007/v1_201909021029/S2173578619300782/v1_201909021029/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Efficacy of enzalutamide and apalutamide in the treatment of non-metastasic castration-resistant prostate cancer: Indirect comparison" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "355" "paginaFinal" => "363" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "P. Nieto-Gómez, R. Ubago-Pérez, J. Cabeza-Barrera" "autores" => array:3 [ 0 => array:4 [ "nombre" => "P." "apellidos" => "Nieto-Gómez" "email" => array:1 [ 0 => "pnietog90@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Ubago-Pérez" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Cabeza-Barrera" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Gestión Clínica de Farmacia Hospitalaria, Hospital Universitario San Cecilio, Granada, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enzalutamida y apalutamida en el tratamiento del cáncer de próstata no metastásico resistente a la castración: comparación indirecta de la eficacia" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">According to the International Agency for Research on Cancer (IARC), prostate cancer is the neoplasm with the highest incidence and prevalence in Spain (data from 2012).<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> The age-standardized incidence rate is 96.8 and the mortality rate is 15.2 per 100,000 inhabitants/year.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">1,2</span></a> Worldwide, there are 1,600,000 cases and 366,000 annual deaths.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Approximately one third of these patients will develop advanced disease, and all of them will eventually progress to castration-resistant prostate carcinoma (CRPC). This is defined as clinical, radiographic and biochemical progression of the disease, despite maintaining plasma testosterone levels below 50<span class="elsevierStyleHsp" style=""></span>ng/dl.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">4,5</span></a> In these cases who are resistant to castration (nmCRPC) with no signs of distant metastasis, the baseline PSA level and the PSA doubling time (PSADT) have been associated with the time to first bone metastasis, bone metastasis-free survival (BMFS) and overall survival (OS).<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Until the development of the second-generation antiandrogens, with androgen deprivation therapy (ADT) and surveillance as reference treatments, there was no effective treatment for nmCRPC.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Apalutamide and enzalutamide are second-generation antiandrogens that have been shown to increase MFS in their pivotal phase 3 trials. However, definitive OS data are not yet available.</p><p id="par0025" class="elsevierStylePara elsevierViewall">After their recent approval by the Food and Drug Administration (FDA), enzalutamide and apalutamide have been authorized as an additional therapy for ADT in patients with nmCRPC in the United States. In the international context, the use of these drugs has been included in the main clinical practice guidelines of oncology and urology published in 2018.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">4,7,8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">On the other hand, apalutamide and enzalutamide have received a positive opinion from the European Medicines Agency (EMA) for the indication of “treatment of adult men with non-metastatic castration-resistant prostate cancer with high risk of developing metastatic disease”.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">9,10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Considering the absence of randomized clinical trials (RCTs) with a direct comparison between these 2 drugs (indicated for the same therapeutic niche), the availability of an indirect comparison between them is considered of high interest for health decision making. However, a study comparing 2 drugs with a higher level of evidence is always a direct comparison through RCTs.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Adjusted indirect comparisons confront different treatments adjusted according to the results of their direct comparison with a common comparator. Therefore, the strength of randomized trials is fairly preserved.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Objective</span><p id="par0045" class="elsevierStylePara elsevierViewall">The objective of this study is to perform an adjusted indirect comparison of the relative efficacy of enzalutamide and apalutamide in patients with nmCRPC with a high risk of progression to metastatic disease.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methodology</span><p id="par0050" class="elsevierStylePara elsevierViewall">For the identification of relevant published studies, a search was carried out (October 25, 2018) in Medline (through PubMed), The Cochrane Library and Center for Reviews and Dissemination (CRD) databases. The search terms were enzalutamide, apalutamide, prostate cancer and nonmetastatic prostate cancer. We included articles published only in 2017 and 2018. We also searched the websites of EMA, FDA and the most relevant Spanish and English speaking agencies of Health Technology Assessment (HTA): Catalan Agency for Health Information, Evaluation and Quality. (AQuAS), National Institute for Health and Care Excellence (NICE), European Network for Health Technology Assessment (EUnetHTA), Canadian Agency for Drugs and Technologies in Health (CADTH) and Agency for Healthcare Research and Quality (AHRQ). The search engines of the International Network of Agencies for HTA (INAHTA) were also explored.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The inclusion criteria in this review, which responded to the research question in PICO (D) format (Population, Intervention, Comparator, Outcomes, Study Design), is presented below:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0060" class="elsevierStylePara elsevierViewall">Population of interest: Adult male patients with nmCRPC with high risk of progression to metastatic disease despite having a condition of biochemical castration with serum testosterone levels below 50<span class="elsevierStyleHsp" style=""></span>ng/dl.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0065" class="elsevierStylePara elsevierViewall">Intervention: apalutamide or enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0070" class="elsevierStylePara elsevierViewall">Comparator or control: placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">•</span><p id="par0075" class="elsevierStylePara elsevierViewall">Outcomes: OS, MFS (defined as the time from randomization to the first detection of distant metastasis in an imaging test [evaluated by a blind independent central review]) and PSA response rate (PSARR, defined as the percentage of patients who had a decreased PSA level from baseline of at least 50% [according to the criteria of the Prostate Cancer Working Group 2]).</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">•</span><p id="par0080" class="elsevierStylePara elsevierViewall">Design: RCT.</p></li></ul></p><p id="par0085" class="elsevierStylePara elsevierViewall">Two independent evaluators made the selection of the articles, the critical reading, the data extraction and the qualitative and quantitative synthesis of the results.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The Cochrane risk-of-bias tool<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> was employed for the selected RCTs.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The methodological and clinical similarity between the combined studies was assessed based on the baseline characteristics of the patients, the measurement units and time in measuring the outcomes, the protocol (e.g. complementary therapies), treatment duration, follow-up time, lost to follow-up management, etc.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The method of Bucher et al.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a> was employed to perform the adjusted indirect comparison. The comparisons were based upon the relative effects of each drug against a common comparator. We used the indirect comparisons software developed by the CADTH for the calculation of the hazard ratio [HR] for MFS and relative risk [RR] for PSARR) (95% CI).<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0105" class="elsevierStylePara elsevierViewall">A total of 13 articles and one health technology assessment report were included.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The evaluation of enzalutamide included 4 articles from Medline: 3 review articles and one article describing the PROSPER trial. The pivotal PROSPER<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> trial was selected, for it was the only trial that followed the PICO (D) question. The other articles referred to this trial in a narrative way.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Regarding the evaluation of apalutamide, the SPARTAN<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> pivotal trial, 8 narrative review articles in Medline and an evaluation report of the CADTH<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">17</span></a> were included. Finally, this report was adapted following the EUnetHTA HTA Adaptation Toolkit & Glossary.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">18</span></a> This evaluation report only identified as relevant and evaluated the SPARTAN pivotal trial.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Thus, the 2 pivotal phase 3 trials finally included for indirect comparison were PROSPER for enzalutamide and SPARTAN for apalutamide.</p><p id="par0125" class="elsevierStylePara elsevierViewall">PROSPER<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> was an international, multicenter, double-blind, phase 3 RCT with a placebo comparator to evaluate the efficacy and safety of enzalutamide in the treatment of nmCRPC in patients with high risk of progression to metastatic disease. The primary outcome of this study was the MFS. This study included 1401 patients.</p><p id="par0130" class="elsevierStylePara elsevierViewall">In a similar way, SPARTAN<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> was an international, multicenter, double-blind, phase 3 RCT with a placebo comparator to evaluate the efficacy and safety of apalutamide in the treatment of nmCRPC in patients with high risk of progression to metastatic disease. The primary outcome of this study was also MFS, and 1207 patients were included.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Regarding the methodological quality of the studies, there was a low risk of bias in a global way. For the section of “missing data bias”, the risk of bias was unclear, since OS data have not been obtained yet. However, these will be provided in subsequent analyses.</p><p id="par0140" class="elsevierStylePara elsevierViewall">There was also a risk of unclear bias in the section “other sources of bias”, by the employment relationship maintained by 5 of the investigators of the PROSPER trial with the laboratory funding the trial and 7 people from SPARTAN are also job related or have received fees or payments from it.</p><p id="par0145" class="elsevierStylePara elsevierViewall">The summary of the main features of both trials is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Taking these characteristics into account, it was possible to verify that the assumptions of clinical and methodological similarity were fulfilled.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Two outcomes were selected to estimate the relative efficacy of both treatments: the primary outcome for both RCTs was MFS, and the secondary outcome was PSARR. The OS could not be used for the comparison since the data was still not available.</p><p id="par0155" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the efficacy results of both clinical trials as well as those from the indirect comparison performed for the selected outcomes. We can observe that:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">•</span><p id="par0160" class="elsevierStylePara elsevierViewall">For MFS, enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs. apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, the HR (95% CI) was 1.036 (0.781–1.373). No statistically significant differences were observed for MFS between the 2 treatments.</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">•</span><p id="par0165" class="elsevierStylePara elsevierViewall">For PSARR, enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs. apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT the HR (95% CI) was 0.81 (0.339–1.938). No statistically significant differences were observed for PSARR between both treatments.</p></li></ul></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0170" class="elsevierStylePara elsevierViewall">The need to position drugs presented a priori as alternatives for the same indication and population is inherent to public health systems, given that resources are limited, and these must ensure the best health outcomes in the most efficient way.</p><p id="par0175" class="elsevierStylePara elsevierViewall">In the ideal scenario, the data with the highest level of evidence to perform the mentioned positioning would be those from an RCT in which the 2 drugs intended for the same therapeutic objective were directly compared.</p><p id="par0180" class="elsevierStylePara elsevierViewall">In many cases, thehealth systems are forced to position drugs when such RCTs do not yet exist, and they have to employ other strategies of lesser evidence to perform such task.</p><p id="par0185" class="elsevierStylePara elsevierViewall">An adjusted indirect comparison is an appropriate approximation for the assessment of 2 recently approved drugs, which are destined for the same target population and for which there are no RCTs, as in the case of enzalutamide and apalutamide. The statistical approach used is widely accepted by agencies such as NICE and CADTH. However, some clinicians may not be familiar with this approach and there are few guidelines available to critically evaluate these comparisons.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Both RCTs concerning the evidence of these drugs for the indication considered are very similar in terms of the population included, the interventions performed, the follow-up of the patients and the inclusion and exclusion criteria. The measured efficacy outcomes and their form and times of collection are similar, as well as the number and management of loss to follow-up cases. Considering these aspects, we can assure that the internal validity of the comparison is high.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Given that there are currently no direct comparisons between both treatments, the external validity and consistency of this comparison cannot be evaluated.</p><p id="par0200" class="elsevierStylePara elsevierViewall">However, there are some differences which imply certain limitations in this indirect comparison. For example, the PSA and PSADT baseline values are different for the patient groups of both drugs. The median values of baseline PSA are higher for enzalutamide in the control group and in the treatment group. The baseline PSADT values for the control and enzalutamide treatment groups are lower than those for both groups of apalutamide.</p><p id="par0205" class="elsevierStylePara elsevierViewall">The baseline PSA level does not seem to be as clinically relevant as the PSADT when determining the risk of progression, so the differences found at this respect would not be determinant.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a> However, these variations in the baseline characteristics could be related to the results observed for the PSARR outcome and may partly explain the differences found for the PSARR RR calculated for both RCTs and the wide confidence interval of the subsequent indirect comparison.</p><p id="par0210" class="elsevierStylePara elsevierViewall">Another limitation of this indirect comparison, perhaps the most relevant one, is the fact that it was not possible to compare the OS efficacy outcome, since the OS data are not yet mature and have not been published.</p><p id="par0215" class="elsevierStylePara elsevierViewall">Therefore, we have selected the common efficacy surrogated outcomes available for both RCTs. Although they are correlated with OS, these are not the optimal outcomes to determine efficacy, and they are uncertain to some extent.</p><p id="par0220" class="elsevierStylePara elsevierViewall">The outcome MFS is adequate (primary outcome of both pivotal tests) because, despite being surrogated, it measures the delay of developing a metastatic disease, with the consequent patient deterioration (pain, bone fractures, worsening of general health condition, need for radiotherapy, etc.). In addition, this correlates with the OS outcome and allows us to obtain information about the efficacy of these drugs in a shorter time. Despite this, there are some considerations to take into account regarding this outcome.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">20</span></a> The first one is that the correlation between MFS and OS was assessed by the Intermediate Clinical Endpoints in Cancer of the Prostate<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> study, which included patients with localized prostate cancer between 1987 and 2011. However, this study did not take into account that OS has changed in the recent years with the approval of new drugs in the setting of metastatic prostate cancer. Moreover, OS varies according to the type of metastasis developed, lower in the cases of visceral metastases.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">22</span></a> Finally, MFS does not distinguish between symptomatic or asymptomatic metastases, which has different consequences on the functional status and quality of life of patients.</p><p id="par0225" class="elsevierStylePara elsevierViewall">The second evaluated outcome is PSARR which, is not only a surrogate outcome with a lower clinical value, but it is considered as exploratory in the SPARTAN trial. Despite this, it has been selected for the indirect comparison as it is present in both trials. As previously mentioned, there are differences between the 2 studies in the RR calculated for this outcome that, although they are not significant, seem remarkable to us. These could be explained by different measurement times or by the variations in baseline PSA levels that we have previously suggested. As a consequence, the confidence interval of the subsequent indirect comparison for this outcome is wide, with a less precise estimate.</p><p id="par0230" class="elsevierStylePara elsevierViewall">Finally, we must emphasize that RCTs of direct comparison would be the most appropriate study design (together with systematic reviews) for the correct evaluation of efficacy and safety of these two drugs.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusions</span><p id="par0235" class="elsevierStylePara elsevierViewall">The adjusted indirect comparison carried out in this study shows that there are no statistically significant differences in terms of efficacy regarding MFS and PSARR, between enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT and apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT in patients with nmCRPC with high risk of progression to metastatic disease.</p><p id="par0240" class="elsevierStylePara elsevierViewall">However, an independent trial with direct comparison between these 2 drugs should be designed to confirm these results.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1237815" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1148994" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1237816" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1148993" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Objective" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Methodology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-01-22" "fechaAceptado" => "2019-03-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1148994" "palabras" => array:5 [ 0 => "Prostate cancer" 1 => "Enzalutamide" 2 => "Apalutamide" 3 => "Metastasis-free survival" 4 => "Indirect comparison" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1148993" "palabras" => array:5 [ 0 => "Cáncer de próstata" 1 => "Enzalutamida" 2 => "Apalutamida" 3 => "Supervivencia libre de metástasis" 4 => "Comparación indirecta" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To perform an adjusted indirect comparison of the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with a high risk of progression to metastatic disease.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">After carrying out a literature search, we performed an adjusted indirect comparison (Bucher et al.) of the relative efficacy of enzalutamide and apalutamide in patients with nmCRPC with a high risk of progression to metastatic disease. The outcomes included were metastasis-free survival (MFS) and PSA response rate (PSARR).</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">There were no statistically significant differences between enzalutamide and apalutamide regarding the analysed outcomes. For the comparison enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs. apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT: MFS a HR (95% <span class="elsevierStyleSmallCaps">C</span>I)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.036 (0.781–1.373) was obtained. For PSARR, a RR (95% CI)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.81 (0.339–1.938) was obtained.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The adjusted indirect comparison performed in this study shows that there are no statistically significant differences in terms of efficacy regarding MFS and PSARR between enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT and apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT in patients with nmCRPC with a high risk of progression to metastatic disease. However, in order to confirm these results, an independent trial with direct comparison between both drugs would be required.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Realizar una comparación indirecta ajustada de la eficacia relativa de enzalutamida y apalutamida en pacientes con cáncer de próstata no metastásico resistente a la castración (CPRCnm) con alto riesgo de progresión a enfermedad metastásica.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Tras realizar una búsqueda bibliográfica se llevó a cabo una comparación indirecta ajustada de la eficacia relativa de enzalutamida y apalutamida en pacientes con CPRCnm con alto riesgo de progresión a enfermedad metastásica siguiendo el método de Bucher et al. Como variables se seleccionaron la supervivencia libre de metástasis (SLM) y la tasa de respuesta al PSA (TRPSA).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">No se observaron diferencias estadísticamente significativas para las variables evaluadas entre enzalutamida y apalutamida. Para la comparación enzalutamida<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>TDA vs. apalutamida<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>TDA: SLM obtuvo un HR (IC95%)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1,036 (0,781-1,373) y TRPSA obtuvo un RR (IC95%)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,81 (0,339-1,938).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La comparación indirecta ajustada realizada en este estudio muestra que no existen diferencias estadísticamente significativas en términos de eficacia, a nivel de SLM y TRPSA, entre enzalutamida<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>TDA y apalutamida<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>TDA en pacientes con CPRCnm con alto riesgo de progresión a enfermedad metastásica. Sin embargo, se debería diseñar un ensayo independiente en el que se comparasen directamente ambos fármacos para confirmar estos resultados.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Nieto-Gómez P, Ubago-Pérez R, Cabeza-Barrera J. Enzalutamida y apalutamida en el tratamiento del cáncer de próstata no metastásico resistente a la castración: comparación indirecta de la eficacia. Actas Urol Esp. 2019;43:355–363.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">RCT: randomized clinical trial; ECOG: Eastern Cooperative Oncology Group scale; EQ-5D-5L: European Quality of Life-5 Dimensions-5 Levels health questionnaire; FACT-P: Functional Assessment of Cancer Therapy-Prostate global score; PSA: prostate-specific antigen; PSADT: PSA doubling time QLQ-PR25: Quality of Life Questionnaire-Prostate 25; RECIST: Response Evaluation Criteria In Solid Tumors; ADT: androgen deprivation therapy.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RCT enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs. placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT (PROSPER) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RCT apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT (SPARTAN) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Selection criteria n \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.401 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.207 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ratio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2:1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Patients with castration-resistant prostate cancer (defined by increased PSA despite serum levels below 50<span class="elsevierStyleHsp" style=""></span>ng/ml)• Patients should be receiving ADT with GnRH agonists or antagonists or bilateral orchiectomy• Patients had to have 3 increased PSA tests separated by at least one week, a serum PSA level greater than or equal to 2<span class="elsevierStyleHsp" style=""></span>ng/ml and a PSADT less than or equal to 10 months• There could be no evidence of soft-tissue metastases demonstrated by computed tomography or MRI and of bone-metastases shown at a whole-body radionuclide scan• 0 or 1 ECOG• N0 or N1• Confirmed absence of distant metastasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Patients had to be older than 18 years of age• Histological or cytological confirmation of high-risk metastatic castration-resistant prostate adenocarcinoma (PSADT less than or equal to 10 months)• N0 or N1• 0–1 ECOG• Patients should be receiving ADT with GnRH agonists or antagonists or bilateral orchiectomy• Confirmed absence of distant metastasis• Patients with castration-resistant prostate cancer (defined by 50% PSA rise in 2/3 determinations and with the last PSA level<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>ng/ml, despite continuing with ADT/postorchiectomy) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Metastasis-free survival:</span> assessed by an independent group of radiologists, according to the RECIST criteria, version 1.1, or death during the study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Metastasis-free survival:</span> assessed by an independent group of radiologists, according to the RECIST criteria, version 1.1, or death during the study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Secondary outcomes</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Overall survival:</span> time from randomization to death from any cause \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Time to metastasis:</span> time since randomization until the detection of the first bone or soft tissue metastasis, determined by an independent group of radiologists following the RECIST criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Time to PSA progression:</span> with <span class="elsevierStyleItalic">Prostate Cancer Working Group</span> 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Progression-free survival:</span> time since randomization until detection of local or distant metastasis (determined by an independent group of radiologists following the RECIST criteria) or death by any cause \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PSA response rate:</span> defined as decreased PSA level by 50% or more from baseline level \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Time to symptom progression:</span> time from randomization to some event related to the skeleton, progression of pain, worsening of disease symptoms that lead to chemotherapy administration, or time until clinically relevant symptoms occur due to local or regional progression that lead to surgery or radiotherapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Time to a subsequent chemotherapy:</span> time from randomization until documentation of new chemotherapy administered to the patient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Overall survival:</span> time from randomization to death from any cause \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Quality of life:</span> evaluated with the questionnaires EQ-5D-5L, QLQ-PR25 and FACT-P <span class="elsevierStyleItalic">global score</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Time to a subsequent chemotherapy:</span> time from randomization until documented new chemotherapy regimen administered to the patient \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Safety</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Exploratory outcome:</span>• <span class="elsevierStyleItalic">Quality of life</span>: evaluated with the FACT-P and EQ-5D questionnaires• <span class="elsevierStyleItalic">Adverse events</span>• <span class="elsevierStyleItalic">PSA response rate</span>: percentage of patients with a decreased PSA level of 50% or more from baseline, <span class="elsevierStyleItalic">Prostate Cancer Working Group</span> 2• <span class="elsevierStyleItalic">Time to PSA</span> progression: following the <span class="elsevierStyleItalic">Prostate Cancer Working Group</span> 2 criteria•<span class="elsevierStyleItalic">Second progression-free survival</span>: time from randomization of allocation to an evaluation of the progression of the disease by a researcher during the first subsequent chemotherapy until progression or death, before the second subsequent chemotherapy, whichever occurs first \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="9" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baseline characteristics of the population</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, median (years): 74 vs. 73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median of age, years: 74 vs. 74 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ECOG, <span class="elsevierStyleItalic">n</span>/<span class="elsevierStyleItalic">N</span> total (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ECOG, <span class="elsevierStyleItalic">n</span>/<span class="elsevierStyleItalic">N</span> total (%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0: 747/933 (80) vs. 382/468 (82) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0: 623/806 (77,3) vs. 311/401 (77,8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1: 185/933 (20) vs. 85/468 (18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0: 183/806 (22,7) vs. 89/401 (22,3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSADT, <span class="elsevierStyleItalic">n</span>/<span class="elsevierStyleItalic">N</span> (%) 3,8 vs. 3,6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSADT, median (months) 4.4 vs. 4,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><6 months: 715/933 (77) vs. 361/468 (77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤6 months: 576/806 (71,5) vs. 284/401 (70,8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥6 months: 217/933 (23) vs. 107/468 (23) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>6 months: 230/806 (28.5) vs. 117/401 (29,2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum PSA value (ng/ml), median 11.1 vs. 10.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum PSA value (ng/ml), median 7.78 vs. 7.76 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Use of bone antiresorptive agents (number (%))Yes 105/933 (11) vs 48/468 (10)No 828/933 (89) vs 420/468 (90) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Use of bone antiresorptive agents (number (%))Yes 82/806 (10.2) vs 39/401 (9.7)No 724/806 (89.8) vs 362/401 (90.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Enzalutamide 160<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h with ADT according to its previous continuous therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apalutamide 240<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h with ADT according to previous continuous therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Control group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo/24<span class="elsevierStyleHsp" style=""></span>h with ADT according to their previous continuous therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo/24<span class="elsevierStyleHsp" style=""></span>h with ADT according to previous therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Study design</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Randomized 2:1, phase 3, multicenter, multinational, double-blind, placebo-controlled clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Randomized 3, 2:1, phase 3, multicenter, multinational, double-blind, placebo-controlled clinical trial \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Randomized patients:• Enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>933• Placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>468 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Randomized patients:• Apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>806• Placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>401 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treated patients:• Enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>930• Placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>465 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treated patients:• Apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>803• Placebo<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>398 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Withdrawal due to toxicity or progression was allowed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Withdrawal due to toxicity or progression was allowed \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stratified randomization was performed to patients according to:• PSADT<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>6 months or PSADT<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>6 months• Use of antiresorptives (yes or no) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Three groups were pre-specified to perform stratified randomization:• PSADT<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>6 months or PSADT<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>6 months• Use of antiresorptive agents (yes or no)• N0 or N1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Duration of the study (evaluation of the primary outcome and follow-up) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The study was suspended when the primary outcome occurred in 447 patients. The median follow-up was 18.4 months for the enzalutamide group and 15.1 months for the placebo group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The primary analysis was made when the primary outcome occurred in 378 cases. Patients had a median follow-up of 20.3 months \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2114461.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Main characteristics of the PROSPER and SPARTAN RCTs.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">HR: hazard ratio; CI: confidence interval; NR: not reached; NE: non-estimable; NS: non-significant; PSA: prostate-specific antigen; RR: relative risk; MFS: metastasis-free survival; ADT: androgen deprivation therapy; PSARR: PSA response rate.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results of randomized clinical trials versus placeboMFS (months)</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results of randomized clinical trials versus placeboPSARR (%)</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment, median (months) (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control, median (months) (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RR<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>(95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Enzalutamide</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">+</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADT</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36.6 (33.1-NR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.7 (14.2–15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.29 (0.24–0.35)<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic"><</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0.001</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32.47(18.09–58.28)<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Apalutamide</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">+</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADT</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40.5 (NE) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.2 (14.6–18.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.28 (0.23–0.35)<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic"><</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0.001</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40.09(20.987–76.582)<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Results of the indirect comparison</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs. Apalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MFSHR (95% CI)1.036 (0.781–1.373)<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>NS</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSARRRR (95% CI)0.81 (0.339–1.938)<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>NS</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2114462.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">RR (PSARR from enzalutamide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ADT vs. ADT) estimated by the authors.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Efficacy results.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0115" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Ferlay" 1 => "I. Soerjomataram" 2 => "R. Dikshit" 3 => "S. Eser" 4 => "C. Mathers" 5 => "M. Rebelo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ijc.29210" "Revista" => array:6 [ "tituloSerie" => "Int J Cancer" "fecha" => "2015" "volumen" => "136" "paginaInicial" => "E359" "paginaFinal" => "E386" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25220842" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0120" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Ferlay" 1 => "E. Steliarova-Foucher" 2 => "J. Lortet-Tieulent" 3 => "S. Rosso" 4 => "J.W. Coebergh" 5 => "H. Comber" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejca.2012.12.027" "Revista" => array:6 [ "tituloSerie" => "Eur J Cancer" "fecha" => "2013" "volumen" => "49" "paginaInicial" => "1374" "paginaFinal" => "1403" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23485231" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0125" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990–2015: a systematic analysis for the Global Burden of Disease Study" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Global Burden of Disease Cancer Collaboration" "etal" => true "autores" => array:5 [ 0 => "C. Fitzmaurice" 1 => "C. Allen" 2 => "R.M. Barber" 3 => "L. Barregard" 4 => "Z.A. Bhutta" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2017" "volumen" => "3" "paginaInicial" => "524" "paginaFinal" => "548" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0130" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "NCCN (Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer. Version 4.2018 [Internet]. Fort Washington: NCCN; 2018. Available from: <a target="_blank" href="https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf">https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf</a> [accessed 17.10.18]." ] ] ] 4 => array:3 [ "identificador" => "bib0135" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.R. Smith" 1 => "F. Kabbinavar" 2 => "F. Saad" 3 => "A. Hussain" 4 => "M.C. Gittelman" 5 => "D.L. Bilhartz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2005.01.529" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2005" "volumen" => "23" "paginaInicial" => "2918" "paginaFinal" => "2925" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15860850" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0140" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.R. Smith" 1 => "R. Cook" 2 => "K.A. Lee" 3 => "J.B. Nelson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.25762" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "2011" "volumen" => "117" "paginaInicial" => "2077" "paginaFinal" => "2085" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21523719" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0145" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Castration-resistant prostate cancer: AUA Guideline" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.S. Cookson" 1 => "B.J. Roth" 2 => "P. Dahm" 3 => "C. Engstrom" 4 => "S.J. Freedland" 5 => "M. Hussain" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.juro.2013.05.005" "Revista" => array:7 [ "tituloSerie" => "J Urol" "fecha" => "2013" "volumen" => "190" "paginaInicial" => "429" "paginaFinal" => "438" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23665272" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0920996416302754" "estado" => "S300" "issn" => "09209964" ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0150" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Managing nonmetastatic castration-resistant prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Mateo" 1 => "K. Fizazi" 2 => "S. Gillessen" 3 => "A. Heidenreich" 4 => "R. Perez-Lopez" 5 => "W.J.G. Oyen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.eururo.2018.07.035" "Revista" => array:6 [ "tituloSerie" => "Eur Urol" "fecha" => "2019" "volumen" => "75" "paginaInicial" => "285" "paginaFinal" => "293" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30119985" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0155" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "European Medicine Agency (EMA). Summary of opinion (post authorisation) for Xtandi<span class="elsevierStyleSup">®</span> [Internet]. Londres: EMA; septiembre 2018. Available from: <a target="_blank" href="https://www.ema.europa.eu/documents/smop/chmp-post-authorisation-summary-positive-opinion-xtandi-ii-39-g_en.pdf">https://www.ema.europa.eu/documents/smop/chmp-post-authorisation-summary-positive-opinion-xtandi-ii-39-g_en.pdf</a> [accessed 17.10.18]." ] ] ] 9 => array:3 [ "identificador" => "bib0160" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "European Medicine Agency (EMA). Summary of opinion (post authorisation) for Erleada<span class="elsevierStyleSup">®</span> [Internet]. Londres: EMA; noviembre 2018. Available from: <a target="_blank" href="https://www.ema.europa.eu/documents/smop-initial/chmp-summary-positive-opinion-erleada_en.pdf">https://www.ema.europa.eu/documents/smop-initial/chmp-summary-positive-opinion-erleada_en.pdf</a> [accessed 7.01.18]." ] ] ] 10 => array:3 [ "identificador" => "bib0165" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Guidance document on reporting indirect comparisons. Ottawa: CADTH; 2015." ] ] ] 11 => array:3 [ "identificador" => "bib0170" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [actualizado Mar 2011]. The Cochrane Collaboration; 2011. Available from: <a target="_blank" href="http://www.cochrane-handbook.org/">www.cochrane-handbook.org</a> [accessed 7.01.19]." ] ] ] 12 => array:3 [ "identificador" => "bib0175" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H.C. Bucher" 1 => "G.H. Guyatt" 2 => "L.E. Griffith" 3 => "S.D. Walter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0895-4356(97)00049-8" "Revista" => array:6 [ "tituloSerie" => "J Clin Epidemiol" "fecha" => "1997" "volumen" => "50" "paginaInicial" => "683" "paginaFinal" => "691" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9250266" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0180" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Wells GA, Sultan SA, Chen L Khan M, Coyle D. Indirect Treatment Comparisons (ITC) [software on internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2012. Available from: <a target="_blank" href="http://www.cadth.ca/en/resources/about-this-guide/download-software">http://www.cadth.ca/en/resources/about-this-guide/download-software</a> [accessed 7.01.19]." ] ] ] 14 => array:3 [ "identificador" => "bib0185" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enzalutamide in men with nonmetastatic castration-resistant prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Hussain" 1 => "K. Fizazi" 2 => "F. Saad" 3 => "P. Rathenborg" 4 => "N. Shore" 5 => "U. Ferreira" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1800536" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2018" "volumen" => "378" "paginaInicial" => "2465" "paginaFinal" => "2474" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29949494" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0190" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Apalutamide treatment and metastasis-free survival in prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.R. Smith" 1 => "F. Saad" 2 => "S. Chowdhury" 3 => "S. Oudard" 4 => "B.A. Hadaschik" 5 => "J.N. Graff" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1715546" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2018" "volumen" => "378" "paginaInicial" => "1408" "paginaFinal" => "1418" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29420164" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0195" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Canadian Agency for Drugs and Tecnologies in Health (CADTH) [Internet]. Ottawa; noviembre 2018. Available from: <a target="_blank" href="https://www.cadth.ca/sites/default/files/pcodr/pcodr_apalutamide_erleada_crpc_in_cgr%20.pdf">https://www.cadth.ca/sites/default/files/pcodr/pcodr_apalutamide_erleada_crpc_in_cgr%20.pdf</a> [accessed 17.10.18]." ] ] ] 17 => array:3 [ "identificador" => "bib0200" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "European Network for Health Technology Assessment. EUnetHTA HTA Adaptation Toolkit & Glossary [Internet]. Diemen; 2018. Available from: <a target="_blank" href="https://www.eunethta.eu/wp-content/uploads/2011/01/EUnetHTA_adptation_toolkit_2011_version_5.pdf">https://www.eunethta.eu/wp-content/uploads/2011/01/EUnetHTA_adptation_toolkit_2011_version_5.pdf</a> [accessed 7.01.19]." ] ] ] 18 => array:3 [ "identificador" => "bib0205" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L.E. Howard" 1 => "D.M. Moreira" 2 => "A. De Hoedt" 3 => "W.J. Aronson" 4 => "C.J. Kane" 5 => "C.L. Amling" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bju.13856" "Revista" => array:6 [ "tituloSerie" => "BJU Int" "fecha" => "2017" "volumen" => "120" "paginaInicial" => "E80" "paginaFinal" => "E86" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28371163" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0210" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metastasis-free survival in prostate cancer: faster drug approvals. Better drugs?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.B. Parik" 1 => "V. Prasad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.18.01092" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2018" "volumen" => "37" "paginaInicial" => "266" "paginaFinal" => "268" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30532985" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0215" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Xie" 1 => "M.M. Regan" 2 => "M. Buyse" 3 => "S. Halabi" 4 => "P.W. Kantoff" 5 => "O. Sartor" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2017.73.9987" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2017" "volumen" => "35" "paginaInicial" => "3097" "paginaFinal" => "3104" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28796587" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0220" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of the site of metastases on survival in patients with metastatic prostate cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Gandalia" 1 => "P.I. Karakiewicz" 2 => "A. Briganti" 3 => "N.M. Passoni" 4 => "J. Schiffmann" 5 => "V. Trudeau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.eururo.2014.07.020" "Revista" => array:6 [ "tituloSerie" => "Eur Urol" "fecha" => "2015" "volumen" => "68" "paginaInicial" => "325" "paginaFinal" => "334" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25108577" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735786/0000004300000007/v1_201909021029/S2173578619300794/v1_201909021029/en/main.assets" "Apartado" => array:4 [ "identificador" => "6274" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735786/0000004300000007/v1_201909021029/S2173578619300794/v1_201909021029/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173578619300794?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2020 April | 1 | 0 | 1 |
