BACKGROUND: Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear. METHODS: We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist. RESULTS: Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease. CONCLUSIONS: Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Canada

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Wahringer Gurtel 18 20 1090 Vienna Austria

Department of Urology Dentistry and Pharmaceutical Sciences Okayama University Graduate School of Medicine Okayama Japan

Department of Urology Jagiellonian University Medical College Krakow Poland

Department of Urology La Croix Du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 Update: treatment of relapsing and metastatic prostate cancer. Eur Urol. 2021;79:263–282. doi: 10.1016/j.eururo.2020.09.046. PubMed DOI

Yanagisawa T, Rajwa P, Thibault C, et al. Androgen receptor signaling inhibitors in addition to docetaxel with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis. Eur Urol. 2022;82:584–598. doi: 10.1016/j.eururo.2022.08.002. PubMed DOI

Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2022;30(399):1695–1707. doi: 10.1016/S0140-6736(22)00367-1. PubMed DOI

Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022 doi: 10.1016/j.eururo.2022.03.004. PubMed DOI PMC

Schaeffer EM, Srinivas S, Adra N, et al. NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023. J Natl Compr Canc Netw. 2022;20:1288–1298. PubMed

Hoyle AP, Ali A, James ND, et al. Abiraterone in "high-" and "low-risk" metastatic hormone-sensitive prostate cancer. Eur Urol. 2019;76:719–728. doi: 10.1016/j.eururo.2019.08.006. PubMed DOI

Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;10(36):1080–1087. doi: 10.1200/JCO.2017.75.3657. PubMed DOI PMC

Hussain M, Tombal B, Saad F, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol. 2010;41(20):3595–3607. doi: 10.1200/JCO.23.00041. PubMed DOI

Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;21(6):e1000100. doi: 10.1371/journal.pmed.1000100. PubMed DOI PMC

Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;21(358):j4008. doi: 10.1136/bmj.j4008. PubMed DOI PMC

Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;18(343):d5928. doi: 10.1136/bmj.d5928. PubMed DOI PMC

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;20(373):737–746. doi: 10.1056/NEJMoa1503747. PubMed DOI PMC

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;6(327):557–560. doi: 10.1136/bmj.327.7414.557. PubMed DOI PMC

Shim SR, Kim SJ, Lee J, Rucker G. Network meta-analysis: application and practice using R software. Epidemiol Health. 2019;41:e2019013. doi: 10.4178/epih.e2019013. PubMed DOI PMC

van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta-analysis. Res Synth Methods. 2012;3:285–299. doi: 10.1002/jrsm.1054. PubMed DOI

Woods BS, Hawkins N, Scott DA. Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol. 2010;10(10):54. doi: 10.1186/1471-2288-10-54. PubMed DOI PMC

Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;1(30):1992–2003. doi: 10.1093/annonc/mdz396. PubMed DOI PMC

Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;11(381):121–131. doi: 10.1056/NEJMoa1903835. PubMed DOI

Davis ID, Martin AJ, Zielinski RR, et al. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC) J Clin Oncol. 2022;40:LBA5004–LBA. doi: 10.1200/JCO.2022.40.17_suppl.LBA5004. PubMed DOI PMC

Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;27(377):352–360. doi: 10.1056/NEJMoa1704174. PubMed DOI

Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20:686–700. doi: 10.1016/S1470-2045(19)30082-8. PubMed DOI

Gravis G, Boher JM, Joly F, et al. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016;70:256–262. doi: 10.1016/j.eururo.2015.11.005. PubMed DOI

Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149–158. doi: 10.1016/S1470-2045(12)70560-0. PubMed DOI

James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;27(377):338–351. doi: 10.1056/NEJMoa1702900. PubMed DOI PMC

James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;19(387):1163–1177. doi: 10.1016/S0140-6736(15)01037-5. PubMed DOI PMC

Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;10(37):2974–2986. doi: 10.1200/JCO.19.00799. PubMed DOI PMC

Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021;10(39):2294–2303. doi: 10.1200/JCO.20.03488. PubMed DOI

Dzimitrowicz HE, Armstrong AJ. Triplet therapy: entering the metaverse of metastatic hormone-sensitive prostate cancer treatment. Eur Urol. 2022;82:599–601. doi: 10.1016/j.eururo.2022.08.031. PubMed DOI

Vale CL, Fisher D, Godolphin P, et al. Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: meta-analysis of individual participant data from randomized trials. J Clin Oncol. 2022;40:5070. doi: 10.1200/JCO.2022.40.16_suppl.5070. DOI

Nelson PS. Molecular states underlying androgen receptor activation: a framework for therapeutics targeting androgen signaling in prostate cancer. J Clin Oncol. 2012;20(30):644–646. doi: 10.1200/JCO.2011.39.1300. PubMed DOI

Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;4(381):13–24. doi: 10.1056/NEJMoa1903307. PubMed DOI

Menges D, Yebyo HG, Sivec-Muniz S, et al. Treatments for metastatic hormone-sensitive prostate cancer: systematic review, network meta-analysis, and benefit-harm assessment. Eur Urol Oncol. 2022;5:605. doi: 10.1016/j.euo.2022.04.007. PubMed DOI

Yanagisawa T, Kimura T, Hata K, et al. Does castration status affect docetaxel-related adverse events? Identification of risk factors for docetaxel-related adverse events in metastatic prostate cancer. Prostate. 2022;82:1322–1330. doi: 10.1002/pros.24406. PubMed DOI

Warner EW, Van der Eecken K, Murtha AJ, et al. Multiregion sampling of de novo metastatic prostate cancer reveals complex polyclonality and augments clinical genotyping. Nat Cancer. 2024;5:1–7. doi: 10.1038/s43018-023-00692-y. PubMed DOI

Lim B, Lee W, Kyung YS, et al. Biopsy-detected Gleason grade 5 tumor is an additional prognostic factor in metastatic hormone-sensitive prostate cancer. J Cancer Res Clin Oncol. 2022;148:727–734. doi: 10.1007/s00432-021-03642-2. PubMed DOI

Rajwa P, Pradere B, Gandaglia G, van den Bergh RCN, Tsaur I, Shim SR, et al. Intensification of systemic therapy in addition to definitive local treatment in nonmetastatic unfavourable prostate cancer: a systematic review and meta-analysis. Eur Urol. 2022;82(1):82–96. doi: 10.1016/j.eururo.2022.03.031. PubMed DOI

An Updated Systematic Review and Network Meta-Analysis of First-Line Triplet vs. Doublet Therapies for Metastatic Hormone-Sensitive Prostate Cancer