Efficacy of Systemic Treatment in Prostate Cancer Patients With Visceral Metastasis: A Systematic Review, Meta-analysis, and Network Meta-analysis

You have accessJournal of UrologyReview Articles1 Sep 2023Efficacy of Systemic Treatment in Prostate Cancer Patients With Visceral Metastasis: A Systematic Review, Meta-analysis, and Network Meta-analysisThis article is commented on by the following:Editorial Comment Takafumi Yanagisawa, Pawel Rajwa, Tatsushi Kawada, Keiichiro Mori, Wataru Fukuokaya, Patrik Petrov, Fahad Quhal, Ekaterina Laukhtina, Markus von Deimling, Alberto Bianchi, Muhammad Majdoub, Benjamin Pradere, Gero Kramer, Takahiro Kimura, and Shahrokh F. Shariat Takafumi YanagisawaTakafumi Yanagisawa https://orcid.org/0000-0002-7410-0712 Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, The Jikei University School of Medicine, Tokyo, Japan , Pawel RajwaPawel Rajwa Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, Medical University of Silesia, Zabrze, Poland , Tatsushi KawadaTatsushi Kawada Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan , Keiichiro MoriKeiichiro Mori Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, The Jikei University School of Medicine, Tokyo, Japan , Wataru FukuokayaWataru Fukuokaya Department of Urology, The Jikei University School of Medicine, Tokyo, Japan , Patrik PetrovPatrik Petrov Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria , Fahad QuhalFahad Quhal Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia , Ekaterina LaukhtinaEkaterina Laukhtina Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia , Markus von DeimlingMarkus von Deimling Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany , Alberto BianchiAlberto Bianchi Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy , Muhammad MajdoubMuhammad Majdoub Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, Hillel Yaffe Medical Center, Hadera, Israel , Benjamin PradereBenjamin Pradere Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Urology, La Croix Du Sud Hospital, Quint Fonsegrives, France , Gero KramerGero Kramer Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria , Takahiro KimuraTakahiro Kimura Department of Urology, The Jikei University School of Medicine, Tokyo, Japan , and Shahrokh F. ShariatShahrokh F. Shariat *Correspondence: Department of Urology, Medical University of Vienna, Wahringer Gurtel 43 18-20, Vienna1090, Austria telephone: +4314040026150; E-mail Address: [email protected] Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic Department of Urology, Weill Cornell Medical College, New York, New York Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria View All Author Informationhttps://doi.org/10.1097/JU.0000000000003594AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: There are limited pooled data showing the impact of visceral metastasis on oncologic outcomes in metastatic prostate cancer patients treated with combination systemic therapies. We aimed to analyze and compare the efficacy of combination systemic therapies in metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer with or without visceral metastasis. Materials and Methods: Three databases were queried in July 2022 for randomized, controlled trials analyzing metastatic prostate cancer patients treated with combination systemic therapy (androgen receptor signaling inhibitor and/or docetaxel plus androgen deprivation therapy) to standard of care. We analyzed the association between presence of visceral metastases and efficacy of systemic therapies in metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer patients. The main and secondary outcomes of interest were overall survival and progression-free survival, respectively. Formal meta-analysis using fixed-effect model and network meta-analysis using random-effect model were conducted. We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and AMSTAR (A MeaSurement Tool to Assess systematic Reviews) guidelines. Results: Overall, 12 and 8 randomized, controlled trials were included for systematic review and meta-analyses/network meta-analyses, respectively. In metastatic hormone-sensitive prostate cancer patients, adding androgen receptor signaling inhibitor to standard of care improved overall survival in patients with visceral metastasis (pooled HR: 0.77, 95% CI: 0.64-0.94) as well as in those without (pooled HR: 0.66, 95% CI: 0.60-0.72; no differences in both across- and within-trial approach; P = .13 and P = .06, respectively). On the other hand, the progression-free survival benefit from androgen receptor signaling inhibitor + androgen deprivation therapy was significantly lower in patients with visceral metastasis using across-trial approach (P = .03), while it did not reach statistical significance using within-trial approach (P = .14). Analysis of treatment ranking in metastatic hormone-sensitive prostate cancer showed that darolutamide + docetaxel + androgen deprivation therapy had the highest likelihood of improved overall survival irrespective of visceral metastasis. In post-docetaxel metastatic castration-resistant prostate cancer patients, adding androgen receptor signaling inhibitor to androgen deprivation therapy significantly improved overall survival in both patients with visceral metastasis (pooled HR: 0.79, 95% CI: 0.63-0.98) and those without (pooled HR: 0.63, 95% CI: 0.55-0.72). No randomized, controlled trials reported the differential oncologic outcomes stratified by lung vs liver metastases. Conclusions: Despite aggressive clinical behavior and worse trajectory of metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer with visceral metastasis, the effectiveness of novel systemic therapies is similar in both metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer patients with and without visceral metastasis. Further well-designed studies with detailed visceral metastatic sites and number will enrich the clinical decision-making. The landscape of therapy for metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) has transformed during the past 10 years as a result of emerging combination systemic therapies.1 Combination therapies using androgen receptor signaling inhibitor (ARSI) and/or docetaxel (DOC) plus androgen deprivation therapy (ADT) have evolved, changing guideline recommendations for both mHSPC and mCRPC.2-6 However, due to toxicity, related costs, and potential limited survival advantages in some patients, therapy intensification in the clinical context should be personalized to deliver the right therapy for the right tumor in the right patient at the right time.7,8 Numerous trials demonstrated a survival benefit for ARSI and DOC in patients stratified by tumor burden, defined as low- vs high-volume disease.4,6,9,10,11,12 Visceral metastasis, an essential component of "high-volume" disease, is often considered the prognostically worst site for metastasis, resulting in the poorest overall survival (OS) in both mHSPC and mCRPC patients.13-15 However, although several previous meta-analyses showed pooled data on mHSPC treatment stratified by disease burden,16,17 survival outcomes of metastatic prostate cancer (mPCa) patients stratified by the presence or absence of visceral metastases have not been studied yet due to the relative rarity. According to some experts, DOC should be used in patients with visceral metastasis and others prefer ARSI. Therefore, we conducted this systematic review, meta-analysis, and network meta-analysis (NMA) to assess the differential efficacy of the different combination therapies on survival outcomes of mPCa patients with visceral metastasis. METHODS The protocol has been registered in the International Prospective Register of Systematic Reviews database (PROSPERO: CRD42022352440). Search Strategy This systematic review, meta-analysis, and NMA was conducted according to the guidelines of the Preferred Reporting Items for Meta-analyses of Observational Studies in Epidemiology Statement (Supplementary Table 1, https://www.jurology.com).18 A literature search on PubMed, Web of Science, and Scopus databases was performed in July 2022 to identify studies investigating the oncologic outcomes of systemic therapy for mPCa. The detailed search strategy is described in Supplementary Appendix 1 (https://www.jurology.com). Furthermore, we also reviewed abstracts presented at recent major conferences such as the American Society of Clinical Oncology and the European Society for Medical Oncology to include unpublished randomized, controlled trials (RCTs) and trials' updates. Additional literature search on ClinicalTrial.gov was performed in January 2023. The primary outcome of interest was OS and the secondary outcome of interest was progression-free survival (PFS). The initial screening based on the titles and abstracts was performed to identify eligible studies by 2 investigators. Potentially relevant studies were subjected to a full-text review. Disagreements were resolved by consensus with coauthors. Inclusion and Exclusion Criteria Studies were included if they investigated mPCa patients stratified by visceral metastasis status (Population), and compared the efficacy of the currently available combination systemic therapy (Interventions) with the efficacy of standard systemic treatment at the time of study enrollment (Comparisons) to assess their differential effects on OS and/or PFS (Outcome) in an RCT (Study design). Studies lacking original patient data, reviews, letters, editorial comments, replies from authors, case reports, and articles not written in English were excluded. References of all papers included were scanned for additional studies of interest. Data Extraction Two authors independently extracted the following data: studies and the first author's name, publication year, inclusion criteria, agents, number of patients, follow-up duration, number of patients and median OS stratified by visceral metastasis status. Subsequently, the HRs and 95% CIs from Cox regression models for OS and PFS were retrieved. All discrepancies were resolved by consensus with coauthors. Risk of Bias Assessment Assessment of study quality and risk of bias (RoB) was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions RoB tool (version 2; Supplementary Figure 1, https://www.jurology.com).19 The RoB figure was created using Review Manager 5.3 Software. The RoB assessment of each study was performed independently by 2 authors. Statistical Analyses We followed the guidelines for reporting of statistics, figures, and tables for clinical research in urology.20,21 For meta-analysis, forest plots with HRs were used to analyze the association between systemic therapy and survival outcomes. PFS was defined as the time from treatment initiation to radiological progression, clinical progression, or death. Based on possible homogeneity between eligible studies owing to the nature of international phase Ⅲ RCTs, fixed-effect model was used for calculations of HRs.22 For reliable assessment of treatment effects across patients' subgroups, we subsequently calculated interaction HRs for OS and PFS between mHSPC patients with visceral metastasis and those without in each trial and then pooled them.23 For network meta-analysis, we used random-effect models with a frequentist approach for direct and indirect treatment comparisons with regards to OS and PFS.24,25 In the assessment of survival outcomes, contrast-based analyses were applied with estimated differences in the log HR and the standard error calculated from the published HR and CI.26 The relative effects were presented as HRs and 95% CIs.24 We also estimated the relative ranking of the different regimens for OS and PFS using the surface under the cumulative ranking (SUCRA).24 Network plots were utilized to illustrate the connectivity of the treatment networks in terms of PFS and OS. Heterogeneity among the outcomes of included studies in this meta-analysis was assessed using Cochran's Q test. Following the Cochrane Handbook for Systematic Reviews of Interventions, significant heterogeneity was defined as P value of < .1 in the Cochran's Q test.27,28 Funnel plots were created using Review Manager 5.3 to assess publication bias (Supplementary Figure 2, https://www.jurology.com). All analyses were conducted using R version 4.0.5, and the statistical significance level was set at P < .05. RESULTS Study Selection and Characteristics Our initial search identified 4,794 records and additional literature search identified 128 RCTs. After removing duplicates, 2,664 records remained for screening titles and abstracts (Figure 1). After screening, a full-text review of 190 articles was performed. According to our inclusion criteria, we finally identified 12 RCTs eligible for systematic review,2,3,5,6,10,12,29-39 and 8 RCTs eligible for meta-analyses and NMAs.2,3,5,6,10,12,29-33,35,39 The demographics of each included study are shown in Table 1. Of the 12 RCTs, 6 included mHSPC patients and 6 included mCRPC patients. Figure 1. The Preferred Reporting Items for Systematic Reviews and Meta-analyses flow chart, detailing the article selection process. RCT indicates randomized, controlled trial. Table 1. Study Demographics and Oncologic Outcomes of Included Randomized, Controlled Trials Study name and first author Year Setting Treatment arm Control arm Total patients Total patients with visceral metastasis No. (%) Median follow-up, mo No. patients (treatment/control arm) Median OS, mo (treatment/control arm) HR (95% CI) of survival outcomes (treatment arm vs control arm) No visceral metastasis Visceral metastasis No visceral metastasis Visceral metastasis No visceral metastasis Visceral metastasis mHSPC 1. Triplet therapy ARASENS, Smith et al 2022 mHSPC DAR + DOC + ADT DOC + ADT 1,305 229 (18) 43 517/520 111/118 ND ND OS: 0.67 (0.55-0.81) OS: 0.79 (0.55-1.14) 2. ARSI-based doublet therapy ARCHES, Armstrong et al 2019/2022 mHSPC ENZ + ADTa ADTa 1,150 128 (11) 44.6 510/512 64/64 NR/NR 48.5/50.3 OS: 0.60 (0.48-0.76) OS: 1.16 (0.67-2.00) ENZAMET, Davis et al 2019/2022 mHSPC ENZ + ADTa NSAA + ADTa 1,125 139 (12) 68 492/494 70/69 ND ND OS: 0.66 (0.55-0.81) cPFS: 0.38 (0.31-0.47) OS: 0.94 (0.58-1.51) cPFS: 0.58 (0.35-0.95) TITAN, Chi et al 2019/2021 mHSPC APA + ADTa ADTa 1,052 128 (12) 44 469/455 56/72 NR/52.2 40.8/30.1 OS: 0.65 (0.52-0.80) rPFS: 0.46 (0.37-0.59) OS: 0.76 (0.47-1.23) rPFS: 0.71 (0.43-1.18) LATITUDE, Fizzazi et al 2017/2019 High-risk de novo mHSPC ABI + ADT ADT 1,199 228 (19) Lung: 145 Liver: 62 51.8 483/488 114/114 NR/35.1b NR/32.3b OS: 0.69 (0.58-0.82) rPFS: 0.45 (0.38-0.55) OS: 0.58 (0.41-0.83) rPFS: 0.53 (0.37-0.76) 3. DOC-based doublet therapy CHAARTED, Sweeney et al and Kyriakopoulos et al 2015/2018 mHSPC DOC + ADT ADT 790 123 (16) 53.7 389c 123 ND ND OS: 0.65 (0.50-0.85) OS: 0.53 (0.30-0.92) mCRPC 1. Pre-ARSI PREVAIL, Beer et al 2014 Pre-DOC ENZ + ADT ADT 1,717 204 (12) 22 774/739 98/106 NR/30.2 27.8/22.8 OS: 0.69 (0.57-0.83) rPFS: 0.17 (0.14-0.22) OS: 0.82 (0.55-1.23) rPFS: 0.28 (0.16-0.49) AFFIRM, Scher et al 2012 Post-DOC ENZ + ADT ADT 1,199 278 (23) ND 921 278 NR/14.2 13.4/9.5 OS: 0.56 (0.46-0.69) OS: 0.78 (0.56-1.09) COU-AA-301, de Bono et al 2011 Post-DOC ABI + ADT ADT 1,195 120 (10)d 12.8 ND ND 17.1/12.3 12.9/8.3 OS: 0.69 (0.58-0.82) OS: 0.79 (0.59-1.05) 2. Post-ARSI PROfound, Hussain et al 2021 Either pre- or post- DOC OLA + ADT ARSI + ADT 245e 78 (32) ND 106/46 46/32 ND ND OS Bone only: 0.64 (0.35-1.22) Other: 0.62 (0.34-1.18) OS: 0.99 (0.57-1.74) CARD, de Wit et al 2019 Post-DOC CBZ + ADT ARSI + ADT 255 46 (18) 9.2 209 46 ND ND OS: 0.50 (0.36-0.69) OS: 0.79 (0.41-1.52) VISION, Sartor et al 2021 Post-DOC 177-Lu-PSMA -617 SOC 831 178 (21) Lung: 77 Liver: 101 20.9 503/246 48/34 ND ND OS: 0.62 (0.51-0.76)d OS: 0.87 (0.53-1.43)d Abbreviations: 177-Lu-PSMA-617, lutetium-177−prostate-specific membrane antigen-617; ABI, abiraterone; ADT, androgen deprivation therapy; APA, apalutamide; ARSI, androgen receptor signaling inhibitor; CBZ, cabazitaxel; CI, confidence interval; cPFS, clinical progression-free survival; DAR, darolutamide; DOC, docetaxel; ENZ, enzalutamide; HR, hazard ratio; mCRPC, metastatic castrate-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; ND, no data; NR, not reported; NSAA, nonsteroidal antiandrogen; OLA, olaparib; OS, overall survival; rPFS, radiographic progression-free survival; SOC, standard of care. ARCHES: 205 patients, ENZAMET: 503 patients, TITAN: 113 patients were allowed to use docetaxel before randomization or concomitantly. Data from interim analysis. High-volume disease with bone metastases alone. Described in liver metastasis. Described as Cohort A defined as patients with at least 1 alteration in BRCA1, BRCA2, or ATM. Across included studies, patients with visceral metastasis constantly constituted a minority of the included populations; the prevalence of patients with visceral metastasis ranged from 11%-19% in mHSPC patients and 12%-32% in mCRPC patients. Apart from the VISION trial, almost all included studies did not show the data of detailed visceral metastasis site (ie, lung or liver).38 RoB Assessment and Quality Assessment of the Study The RoB judgments of each domain for each included study are depicted in Supplementary Figure 1 (https://www.jurology.com). All included studies had a low RoB owing to the nature of prospective randomized phase 3 trials. The quality assessment of this meta-analysis was performed using the AMSTAR2 checklist; overall confidence in the results of this review was "High" (Supplementary Appendix 2, https://www.jurology.com).40 mHSPC Study Selection and Characteristics The study demographics and oncologic outcomes of included studies are shown in Table 1. Among studies including mHSPC patients, the ARASENS trial investigated the efficacy of adding darolutamide (DAR) to DOC + ADT; thus, the control arm was DOC + ADT.5 The ENZAMET, ARCHES, and TITAN trials also allowed concomitant or pre-randomization use of DOC in both arms as adding DOC to ADT has become standard of care (SOC).2,3,10,29-31 The GETUG-15 study only provided the survival data stratified by presence of bone metastasis at diagnosis vs others which included both lymph node and visceral metastasis; thus, we excluded this study.11 Only the ARASENS trial provided the separate HRs of triplet therapy, DAR + DOC +ADT, for the visceral metastasis status,5 while the PEACE-1 trial did not; therefore, could not be included.4 The ARCHES, ENZAMET, TITAN, and LATITUDE trials provided the oncologic outcomes of ARSI-based doublet therapy,2,3,6,10,29-32 and the CHAARTED trial provided those of DOC-based doublet therapy.12,33 However, the arm C vs arm G of the STAMPEDE trial reported by Sydes et al did not provide data on subgroup analysis stratified by visceral metastasis; thus, this was excluded.41 We performed this meta-analysis to evaluate the efficacy of adding ARSI to SOC in both combination therapies including triplet therapy and only ARSI-based doublet therapy. NMAs were conducted including all currently available treatment regimens. The results of treatment rankings are summarized in Table 2. Table 2. Treatment Rankings for Overall Survival Based on Surface Under the Cumulative Ranking Analysis mHSPC Visceral DAR+DOC: 90%>DOC: 76%>ABI: 63%>APA: 41%>ADT: 17%>ENZ: 13% No visceral DAR+DOC: 98%>ENZ: 58%>APA: 57%>DOC: 48%>ABI: 39%>ADT: 0% mCRPC (post-DOC) Visceral ENZ: 77%> ABI: 63% No visceral ENZ: 97%> ABI: 53% Abbreviations: ABI, abiraterone acetate; ADT, androgen deprivation therapy; APA, apalutamide; DAR, darolutamide; DOC, docetaxel; ENZ, enzalutamide; mCRPC, metastatic castrate-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer. Meta-analysis of the Efficacy of ARSI-based Combination Therapy for mHSPC OS Among 5 RCTs providing the efficacy of adding ARSI to SOC, ARSI-based combination therapy significantly reduced the risk of overall mortality in mHSPC patients with visceral metastasis (HR: 0.77, 95% CI: 0.64-0.94) and those without (HR: 0.66, 95% CI: 0.60-0.72; Figure 2, A). There were no significant subgroup differences between patients with visceral metastasis and those without in terms of combination systemic therapy efficacy for OS using across-trial (P = .13, Figure 2, A) and within-trial approaches (P = .06; Supplementary Figure 3, https://www.jurology.com). Figure 2. Forest plots showing association of survival outcomes and androgen receptor signaling inhibitor (ARSI)–based systemic combination therapy stratified by with or without visceral metastasis. A, Overall survival for ARSI-based systemic combination therapy including triplet therapy. B, Overall survival for ARSI-based doublet therapy. C, Progression-free survival for ARSI-based doublet therapy. CI indicates confidence interval; HR, hazard ratio; SOC, standard of care. When limiting to ARSI-based doublet therapy, combination systemic therapy significantly reduced the risk of overall mortality in mHSPC patients with visceral metastasis (HR: 0.77, 95% CI: 0.61-0.96; Figure 2, B). There were also no significant differences between patients with visceral metastasis and those without in terms of combination systemic therapy efficacy for OS in both approaches. The Cochran's Q tests revealed no significant heterogeneity across all analyses. Sensitivity analyses of the drugs' differential pharmacodynamic action in mHSPC with visceral metastasis indicated that abiraterone (ABI) significantly reduced overall mortality (HR: 0.58, 95% CI: 0.41-0.83), while the other ARSIs did not (HR: 0.92: 95% CI: 0.69-1.23; Supplementary Figure 4, https://www.jurology.com). There was a significant difference between the types of agents in terms of the OS benefit of combination systemic therapy in patients with visceral metastasis (P = .045), while no differences were seen in those without (P = .5). The Cochran's Q tests revealed no significant heterogeneity among all analyses. PFS As shown in Figure 2, C, ARSI-based doublet therapy significantly reduced the risk of disease progression in mHSPC patients with visceral metastasis (HR: 0.58, 95% CI: 0.45-0.75) and those without (HR: 0.43, 95% CI: 0.38-0.48). There was a significant difference between patients with visceral metastasis and those without in terms of the PFS benefit of combination systemic therapy (P = .031), while it did not reach statistical significance in within-trial approach (P = .14; Supplementary Figure 3, https://www.jurology.com). The Cochran's Q tests revealed no significant heterogeneity in this analysis. The Efficacy of DOC-based Doublet Therapy for mHSPC Only the CHAARTED trial provided the data on OS in mHSPC patients treated with DOC + ADT stratified by presence of visceral metastasis.12,33 Among 502 patients with high-volume disease, adding DOC to ADT significantly reduced the risk of overall mortality in patients with visceral metastasis (HR: 0.53, 95% CI: 0.30-0.92) and those without (HR: 0.65, 95% CI: 0.50-0.85). NMAs of the Efficacy of Combination Systemic Therapy for mHSPC OS Six different agents/regimens were included in this NMA (Supplementary Figure 5, A, https://www.jurology.com). DAR + DOC + ADT, DOC + ADT, and ABI +ADT combinations outperformed ADT alone in terms of OS in patients with visceral metastasis (Figure 3). Based on the SUCRA analysis of treatment rankings, among patients with visceral metastasis, DAR + DOC + ADT had the highest likelihood of providing the maximal OS benefit (90%), followed by DOC + ADT (76%), and ABI + ADT (63%; Table 2). Figure 3. Network meta-analysis for overall survival in metastatic hormone-sensitive prostate cancer patients with visceral metastasis. A, Forest plots. B, Surface under the cumulative ranking graph showing the treatment ranking for overall survival. ABI indicates abiraterone; ADT, androgen deprivation therapy; APA, apalutamide; CI, confidence interval; DAR, darolutamide; DOC, docetaxel; ENZ, enzalutamide; HR, hazard ratio. On the other hand, all combination regimens significantly reduced the risk of death in patients without visceral metastasis, when compared to ADT alone (Supplementary Figure 6, https://www.jurology.com). Based on the SUCRA analysis of treatment rankings, among patients without visceral metastasis, DAR + DOC + ADT (98%) had the highest likelihood of providing the maximal OS benefit (Table 2). We did not find any heterogeneity in all analyses. PFS Three different ARSI-based doublet regimens, ABI, enzalutamide (ENZ), or apalutamide with ADT, were included in this NMA (Supplementary Figure 5, B, https://www.jurology.com). ABI + ADT and ENZ + ADT combinations reduced the risk of disease progression in patients with visceral metastasis (Supplementary Figure 7, https://www.jurology.com). The SUCRA analysis of treatment rankings revealed that ABI + ADT (82%) had the highest likelihood of providing the maximal PFS benefit (Supplementary Table 2, https://www.jurology.com). On the other hand, all combination regimens significantly reduced the risk of disease progression in patients without visceral metastasis compared to ADT alone (Supplementary Figure 8, https://www.jurology.com). The SUCRA analysis of treatment rankings revealed that ENZ + ADT (91%) had the highest likelihood of providing the maximal PFS benefit in patients without visceral metastasis (Supplementary Table 2, https://www.jurology.com). We did not find any heterogeneity in all analyses. mCRPC Study Selection and Characteristics Table 1 shows the study demographics and oncologic outcomes of included studies of mCRPC. The PREVAIL and AFFIRM trials, which assessed the efficacy of ENZ + ADT in mCRPC patients, provided the data of HR for OS in patients with visceral metastasis.34,39 Only the COU-AA-301 trial, which assessed the efficacy of ABI + ADT in mCRPC patients, included the patients with visceral metastasis.35 In addition, the CARD, VISION, and PROfound trials provided OS data stratified by visceral metastasis status.36-38 However, the clinical settings and the control arms of these trials were different; therefore, we performed the meta-analysis of OS in the post-DOC setting only. Meta-analysis of the Efficacy of Combination Systemic Therapy in Post-DOC mCRPC Patients As shown in Figure 4, ARSI-based combination therapy significantly reduced the risk of overall