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Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses

Prostate Cancer and Prostatic Diseases volume 24, pages 244–252 (2021)Cite this article

Subjects

Abstract

Background

Abiraterone and enzalutamide may increase the risk of cardiovascular events in patients with castration-resistant prostate cancer (CRPC).

Methods

A comprehensive literature search was performed using a combination of keywords related to “abiraterone,” “enzalutamide,” “prostate cancer,” and “adverse events.” Phase II–IV randomized controlled trials (RCTs) on abiraterone or enzalutamide for patients with nonmetastatic or metastatic CRPC were included. Outcome measures included (1) any grade cardiac disorder, (2) severe grade cardiac disorder, (3) any grade hypertension, and (4) severe grade hypertension, as defined by the Common Terminology Criteria for Adverse Events. Pairwise meta-analysis and Bayesian network meta-analyses were performed to investigate the risk ratios (RRs) of abiraterone and enzalutamide. Surface under cumulative ranking curves (SUCRAs) and cumulative ranking probability plots based on the probability of developing cardiac disorders or hypertension were presented.

Results

A total of 7103 patients from seven RCTs were included. Upon pairwise meta-analysis, abiraterone was associated with increased risks of any grade (RR = 1.34, 95% confidence interval (CI) = 1.05–1.73) and severe grade cardiac disorders (RR = 1.71, 95% CI = 1.16–2.53); enzalutamide was associated with increased risks of any grade (RR = 2.66, 95% CI = 1.93–3.66) and severe grade hypertension (RR = 2.79, 95% CI = 1.86–4.18). Based on the SUCRA rankings, abiraterone had a higher probability of cardiac disorders (84.84% for any grade and 85.12% for severe grade) than enzalutamide (62.83% for any grade and 50.76% for severe grade); whereas enzalutamide had a higher probability of hypertension (99.43% for any grade and 89.71% for severe grade) than abiraterone (49.08% for any grade and 49.37% for severe grade).

Conclusions

Abiraterone and enzalutamide had different adverse effects on the cardiovascular system. We should take this into consideration when we are deciding on the choice of novel hormonal agents for patients with CRPC.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Huggins C, Clark PJ. Quantitative studies of prostatic secretion: Ii. The effect of castration and of estrogen injection on the normal and on the hyperplastic prostate glands of dogs. J Exp Med. 1940;72:747–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180–92.

    Article  CAS  PubMed  Google Scholar 

  4. Akaza H, Usami M, Hinotsu S, Ogawa O, Kagawa S, Kitamura T, et al. Characteristics of patients with prostate cancer who have initially been treated by hormone therapy in Japan: J-CaP surveillance. Jpn J Clin Oncol. 2004;34:329–36.

    Article  PubMed  Google Scholar 

  5. Cooperberg MR, Hinotsu S, Namiki M, Carroll PR, Akaza H. Trans-Pacific variation in outcomes for men treated with primary androgen-deprivation therapy (ADT) for prostate cancer. BJU Int. 2016;117:102–9.

    Article  CAS  PubMed  Google Scholar 

  6. Nuhn P, De Bono JS, Fizazi K, Freedland SJ, Grilli M, Kantoff PW, et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. Eur Urol. 2019;75:88–99.

    Article  PubMed  Google Scholar 

  7. Alpajaro SIR, Harris JAK, Evans CP. Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies. Prostate Cancer Prostatic Dis. 2019;22:16–23.

    Article  PubMed  Google Scholar 

  8. Lahcene H, Aprikian AG, Vanhuyse M, Hu J, Bladou F, Cury F, et al. Impact of the introduction of novel hormonal agents on metastatic castration-resistant prostate cancer treatment choice. J Oncol Pharm Pract. 2020;26:293–305.

    Article  PubMed  Google Scholar 

  9. Teoh JY, Ng CF. Cardiovascular risk after androgen deprivation therapy for prostate cancer: an Asian perspective. Int Urol Nephrol. 2016;48:1429–35.

    Article  CAS  PubMed  Google Scholar 

  10. Hotta Y, Kataoka T, Kimura K. Testosterone deficiency and endothelial dysfunction: nitric oxide, asymmetric dimethylarginine, and endothelial progenitor cells. Sex Med Rev. 2019;7:661–8.

    Article  PubMed  Google Scholar 

  11. Teoh JY, Chan SY, Chiu PK, Poon DM, Cheung HY, Hou SS, et al. Risk of cardiova scular thrombotic events after surgical castration versus gonadotropin-releasing hormone agonists in Chinese men with prostate cancer. Asian J Androl. 2015;17:493–6.

    CAS  PubMed  Google Scholar 

  12. Teoh JY, Chan SY, Chiu PK, Poon DM, Cheung HY, Hou SS, et al. Risk of acute myocardial infarction after androgen-deprivation therapy for prostate cancer in a Chinese population. BJU Int. 2015;116:382–7.

    Article  CAS  PubMed  Google Scholar 

  13. Teoh JY, Chiu PK, Chan SY, Poon DM, Cheung HY, Hou SS, et al. Risk of ischemic stroke after androgen deprivation therapy for prostate cancer in the Chinese population living in Hong Kong. Jpn J Clin Oncol. 2015;45:483–7.

    Article  PubMed  Google Scholar 

  14. Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382:2187–96.

    Article  CAS  PubMed  Google Scholar 

  15. Iacovelli R, Ciccarese C, Bria E, Romano M, Fantinel E, Bimbatti D, et al. The cardiovascular toxicity of abiraterone and enzalutamide in prostate cancer. Clin Genitourin Cancer. 2018;16:e645–53.

    Article  PubMed  Google Scholar 

  16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.

    Article  PubMed  Google Scholar 

  17. Chen HL, Hao SY, Tsai HY. Cardiovascular risk of abiraterone and enzalutamide among castration-resistant prostate cancer patients—a systematic review and Bayesian network meta-analysis. Available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=140807. Accessed 7 March 2020.

  18. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed 7 March 2020.

  19. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 2011: [updated March 2011]. The Cochrane Collaboration, 2011. Available at http://www.cochrane-handbook.org. Accessed 27 March 2020.

  20.  Deeks JJ, Higgins JP. Statistical algorithms in Review Manager 5. Statistical Methods Group of The Cochrane Collaboration. Available at https://training.cochrane.org/handbook/statistical-methods-revman5. Accessed 20 March 2020.

  21. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.

  22. Spiegelhalter DJ, Thomas A, Best NG, Lunn D. WinBUGS version 1.4.3 user manual. Cambridge: MRC Biostatistics Unit; 2003.

  23. Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Mak. 2013;33:607–17.

    Article  Google Scholar 

  24. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71.

    Article  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151–4.

    Article  CAS  PubMed  Google Scholar 

  27. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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-naive patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol. 2017;4:75–85.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pagliarulo V, Bracarda S, Eisenberger MA, Mottet N, Schroder FH, Sternberg CN, et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol. 2012;61:11–25.

    Article  CAS  PubMed  Google Scholar 

  33. Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK, Nilsson J. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565–73.

    Article  CAS  PubMed  Google Scholar 

  34. Bell KJ, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of incidental prostate cancer: a systematic review of autopsy studies. Int J Cancer. 2015;137:1749–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li H, Hodgson E, Watson L, Shukla A, Nelson JJ. Comorbidities and concomitant medication use in men with prostate cancer or high levels of PSA compared to matched controls: a GPRD analysis. J Cancer Epidemiol. 2012;2012:291704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23:3105–24.

    Article  CAS  PubMed  Google Scholar 

  37. Li T, Puhan MA, Vedula SS, Singh S, Dickersin K. Ad hoc network meta-analysis methods meeting working G. Network meta-analysis-highly attractive but more methodological research is needed. BMC Med. 2011;9:79.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Vale CL, Fisher DJ, White IR, Carpenter JR, Burdett S, Clarke NW, et al. What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis. Ann Oncol. 2018;29:1249–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xiong T, Turner RM, Wei Y, Neal DE, Lyratzopoulos G, Higgins JP. Comparative efficacy and safety of treatments for localised prostate cancer: an application of network meta-analysis. BMJ Open. 2014;4:e004285.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yin L, Hu Q. CYP17 inhibitors−abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nat Rev Urol. 2014;11:32–42.

    Article  CAS  PubMed  Google Scholar 

  41. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol. 2013;189:S34–42.

    Article  CAS  PubMed  Google Scholar 

  42. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009;30:23–32.

    Article  CAS  PubMed  Google Scholar 

  43. Dai CF, Xie X, Yang YN, Li XM, Zheng YY, Fu ZY, et al. Relationship between CYP17A1 genetic polymorphism and coronary artery disease in a Chinese Han population. Lipids Health Dis. 2015;14:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Lu S, Zhong J, Zhang Y, Huang K, Wu M, Zhou Y, et al. CYP17A1 polymorphisms are linked to the risk of coronary heart disease in a case-control study. J Cardiovasc Pharmacol. 2019;74:98–104.

    Article  CAS  PubMed  Google Scholar 

  45. Linder S, van der Poel HG, Bergman AM, Zwart W, Prekovic S. Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond. Endocr Relat Cancer. 2018;26:R31–52.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. van Soest RJ, van Royen ME, de Morree ES, Moll JM, Teubel W, Wiemer EA, et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer. 2013;49:3821–30.

    Article  PubMed  CAS  Google Scholar 

  48. Torres-Estay V, Carreno DV, San Francisco IF, Sotomayor P, Godoy AS, Smith GJ. Androgen receptor in human endothelial cells. J Endocrinol. 2015;224:R131–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cai JJ, Wen J, Jiang WH, Lin J, Hong Y, Zhu YS. Androgen actions on endothelium functions and cardiovascular diseases. J Geriatr Cardiol. 2016;13:183–96.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by grants from the Kaohsiung Municipal Ta-Tung Hospital (KMTTH 107-018).

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Authors and Affiliations

  1. Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

    Hsiang Ying Lee & Yung-Shun Juan

  2. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Hsiang Ying Lee

  3. Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Hsiang Ying Lee & Yung-Shun Juan

  4. Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

    Hsiao-Ling Chen, Shao-Yuan Hao, Hsin-Yi Tsai, Wei-Hsuan Huang & Hsiu-Mei Chang

  5. S.H. Ho Urology Centre, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

    Jeremy Yuen-Chun Teoh

  6. Division of Infectious Diseases, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

    Tun-Chieh Chen

  7. Center for Evidence-based Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Hao-Min Cheng

  8. Institute of Public Health, National Yang-Ming University Hospital, Taipei, Taiwan

    Hao-Min Cheng

  9. Department of Medicine, National Yang-Ming University, Taipei, Taiwan

    Hao-Min Cheng

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HYL: protocol development and manuscript writing; HLC: protocol development, data analysis, and paper writing; JYCT: data interpretation and paper writing TCC: protocol/project development; SYH and HYT: data extraction; WHH and YSJ: data interpretation; HM Cheng and HM Chang: project development and paper writing.

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Correspondence to Hao-Min Cheng or Hsiu-Mei Chang.

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Lee, H.Y., Chen, HL., Teoh, J.YC. et al. Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses. Prostate Cancer Prostatic Dis 24, 244–252 (2021). https://doi.org/10.1038/s41391-020-00275-3

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