BACKGROUND: Androgen-receptor pathway inhibitors (ARPIs) have dramatically changed the management of advanced/metastatic prostate cancer (PCa). However, their cardiovascular toxicity remains to be clarified. OBJECTIVE: To analyze and compare the risks of cardiovascular events secondary to treatment of PCa patients with different ARPIs. METHODS: In August 2023, we queried PubMed, Scopus, and Web of Science databases to identify randomized controlled studies (RCTs) that analyze PCa patients treated with abiraterone, apalutamide, darolutamide, and enzalutamide. The primary outcomes of interest were the incidence of cardiac disorder, heart failure, ischemic heart disease (IHD), atrial fibrillation (AF), and hypertension. Network meta-analyses (NMAs) were conducted to compare the differential outcomes of each ARPI plus androgen deprivation therapy (ADT) compared to standard of care (SOC). RESULTS: Overall, 26 RCTs were included. ARPIs were associated with an increased risk of cardiac disorders (RR: 1.74, 95% CI: 1.13-2.68, p = 0.01), heart failure (RR: 2.49, 95% CI: 1.05-5.91, p = 0.04), AF (RR: 2.15, 95% CI: 1.14-4.07, p = 0.02), and hypertension (RR: 2.06, 95% CI: 1.67-2.54, p < 0.01) at grade ≥3. Based on NMAs, abiraterone increased the risk of grade ≥3 cardiac disorder (RR:2.40, 95% CI: 1.42-4.06) and hypertension (RR:2.19, 95% CI: 1.77-2.70). Enzalutamide was associated with the increase of grade ≥3 AF(RR: 3.17, 95% CI: 1.05-9.58) and hypertension (RR:2.30, 95% CI: 1.82-2.92). CONCLUSIONS: The addition of ARPIs to ADT increases the risk of cardiac disorders, including IHD and AF, as well as hypertension. Each ARPI exhibits a distinct cardiovascular event profile. Selecting patients carefully and vigilant monitoring for cardiovascular issues is imperative for those undergoing ARPI + ADT treatment.

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

Department of Urology 2nd Faculty of Medicine Charles University Prague Czechia

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology La Croix du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Semmelweis University Budapest Hungary

Department of Urology Shariati Hospital Tehran University of Medical Science Tehran Iran

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

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Medicine Urology Department Tabriz University of Medical Sciences Tabriz Iran

Unit of Urology Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Vita Salute San Raffaele University Milan Italy

Erratum v

Prostate Cancer Prostatic Dis. 2024 Oct 7. doi: 10.1038/s41391-024-00902-3. PubMed

Zobrazit více v PubMed

Yanagisawa T, Rajwa P, Thibault C, Gandaglia G, Mori K, Kawada T, 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;82:584–98. PubMed

Mori K, Mostafaei H, Pradere B, Motlagh RS, Quhal F, Laukhtina E, et al. Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Int J Clin Oncol. 2020;25:1892–1900. PubMed PMC

Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022;40:1616–22. PubMed PMC

Sweeney CJ, Martin AJ, Stockler MR, Begbie S, Cheung L, Chi KN, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24:323–34. PubMed

Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, 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. PubMed

James ND, Clarke NW, Cook A, Ali A, Hoyle AP, Attard G, et al. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476). Int J Cancer. 2022;151:422–34. PubMed PMC

Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, 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;39:2294–303. PubMed

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;82:82–96. PubMed

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97. PubMed

Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020;383:1040–9. PubMed

Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–92. PubMed

Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152–60. PubMed

Armstrong AJ, Lin P, Tombal B, Saad F, Higano CS, Joshua AM, et al. Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol. 2020;78:347–57. PubMed

Sternberg CN, Fizazi K, Saad F, Shore ND, De Giorgi U, Penson DF, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382:2197–206. PubMed

Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021;79:150–8. PubMed

Abufaraj M, Iwata T, Kimura S, Haddad A, Al-Ani H, Abusubaih L, et al. Differential Impact of Gonadotropin-releasing Hormone Antagonist Versus Agonist on Clinical Safety and Oncologic Outcomes on Patients with Metastatic Prostate Cancer: A Meta-analysis of Randomized Controlled Trials. Eur Urol. 2021;79:44–53. PubMed

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, 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;6:e1000100. PubMed PMC

Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, 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;358:j4008. PubMed PMC

Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Health. 2015;13:147–53.

Astellas. Astellas Internal Report: AFFIRM Study Clinical Report.

Pharmaceutical J Zytiga Appropriate Use Guide, 2023.

Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj. 2011;343:d5928. PubMed PMC

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

van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta-analysis. Res Synth Methods. 2012;3:285–99. PubMed

Khalaf DJ, Annala M, Taavitsainen S, Finch DL, Oja C, Vergidis J, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20:1730–9. PubMed

Pu YS, Ahn H, Han W, Huang SP, Wu HC, Ma L, et al. Enzalutamide in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Asian Multiregional, Randomized Study. Adv Ther. 2022;39:2641–56. PubMed PMC

Shore ND, Chowdhury S, Villers A, Klotz L, Robert Siemens D, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): A randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17:153–63. PubMed

Sun Y, Zou Q, Sun Z, Li C, Du C, Chen Z, et al. Abiraterone acetate for metastatic castration-resistant prostate cancer after docetaxel failure: A randomized, double-blind, placebo-controlled phase 3 bridging study. Int J Urol. 2016;23:404–11. PubMed

Ye D, Huang Y, Zhou F, Xie K, Matveev V, Li C, et al. A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol. 2017;4:75–85. PubMed PMC

Ternov KK, Sønksen J, Fode M, Lindberg H, Kistorp C, Bisbjerg R, et al. Fatigue, health-related quality-of-life and metabolic changes in men treated with enzalutamide or abiraterone acetate plus prednisone for metastatic castration-resistant prostate cancer: A randomised clinical trial (HEAT). Eur J Cancer. 2022;171:75–84. PubMed

Izumi K, Shima T, Mita K, Kato Y, Kamiyama M, Inoue S, et al. Enzalutamide Versus Abiraterone plus Prednisolone Before Chemotherapy for Castration-resistant Prostate Cancer: A Multicenter Randomized Controlled Trial. Eu Uro Op Sci. 2022;41:16–23.

Penson DF, Armstrong AJ, Concepcion RS, Agarwal N, Olsson CA, Karsh LI, et al. Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial. Prostate Cancer Prostatic Dis. 2022;25:363–5. PubMed

Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Fléchon A, 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 × 2 factorial design. Lancet. 2022;399:1695–707. PubMed

Attard G, Murphy L, Clarke NW, Sachdeva A, Jones C, Hoyle A, et al. Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Lancet Oncol. 2023;24:443–56. PubMed

Maluf FC, Schutz FA, Cronemberger EH, Luz MDA, Martins SPS, Muniz DQB, et al. A phase 2 randomized clinical trial of abiraterone plus ADT, apalutamide, or abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels (LACOG 0415). Eur J Cancer. 2021;158:63–71. PubMed

Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N. Engl J Med. 2023;389:1453–65. PubMed

Autio KA, Antonarakis ES, Mayer TM, Shevrin DH, Stein MN, Vaishampayan UN, et al. Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy. Eu Uro Op Sci. 2021;34:70–78.

Spetsieris N, Boukovala M, Alafis I, Davis J, Zurita A, Wang X, et al. Abiraterone acetate plus prednisone in non-metastatic biochemically recurrent castration-naïve prostate cancer. Eur J Cancer. 2021;157:259–67. PubMed

Liu JM, Lin CC, Chen MF, Liu KL, Lin CF, Chen TH, et al. Risk of major adverse cardiovascular events among second-line hormonal therapy for metastatic castration-resistant prostate cancer: A real-world evidence study. Prostate. 2021;81:194–201. PubMed

Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J Steroid Biochem Mol Biol. 2011;125:23–31. PubMed

Kokubo Y, Matsumoto C. Hypertension Is a Risk Factor for Several Types of Heart Disease: Review of Prospective Studies. Adv Exp Med. Biol. 2017;956:419–26. PubMed

Bretagne M, Lebrun-Vignes B, Pariente A, Shaffer CM, Malouf GG, Dureau P, et al. Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study. Arch Cardiovasc Dis. 2020;113:9–21. PubMed

Liu Y, Zhang HM, Jiang Y, Wen Z, Bao EH, Huang J et al. Cardiovascular Adverse Events Associated With New-Generation Androgen Receptor Pathway Inhibitors (ARPI) for Prostate Cancer: A Disproportionality Analysis Based on the FDA Adverse Event Reporting System (FAERS). Clin Genitourin Cancer. 2023;21:594–601.e2.

Conover MM, Weaver J, Fan B, Leitz G, Richarz U, Li Q, et al. Cardiovascular outcomes among patients with castration-resistant prostate cancer: A comparative safety study using US administrative claims data. Prostate. 2023;83:729–39. PubMed

Hussain M, Tombal B, Saad F, Fizazi K, Sternberg CN, Crawford ED, 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. 2023;41:3595–607. PubMed

Haresh KP, Vjaters E, Castellano D, Olmos D, Shore ND, Nevalaita L et al. A randomized, controlled, phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus ADT alone in metastatic hormone-sensitive prostate cancer (ARANOTE). J Clin Oncol. 2022;40:TPS200.

Hu JR, Duncan MS, Morgans AK, Brown JD, Meijers WC, Freiberg MS, et al. Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses. Arterioscler Thromb Vasc Biol. 2020;40:e55–e64. PubMed PMC

Iversen P. The third analysis of the bicalutamide Early Prostate Cancer programme. BJU Int. 2006;97:438–9. PubMed

Mladěnka P, Applová L, Patočka J, Costa VM, Remiao F, Pourová J, et al. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev. 2018;38:1332–403. PubMed PMC

Shimoyama M, Murata Y, Sumi KI, Hamazoe R, Komuro I. Docetaxel induced cardiotoxicity. Heart. 2001;86:219. PubMed PMC

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