Publication:
Impacto de las estatinas en pacientes con cáncer de próstata resistente a la castración en tratamiento con abiraterona

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2021-07
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Introducción y objetivos. El cáncer de próstata resistente a la castración (CPRC) tiene un carácter hormono-dependiente que permite tratamiento con acetato de abiraterona (AA), un inhibidor de la producción de andrógenos. Las estatinas son unos fármacos que bloquean la síntesis de colesterol, molécula precursora de hormonas sexuales. El tratamiento con estatinas parece impactar beneficiosamente en la supervivencia de pacientes con CPRC. El objetivo principal es determinar el efecto de las estatinas en supervivencia global en pacientes con CPRC pertenecientes a ensayos clínicos aleatorizados a un tratamiento con AA o placebo. Los objetivos secundarios son estimar el efecto de las estatinas en supervivencia libre de progresión radiográfica (RPFS) y tiempo hasta la progresión de PSA (TTPP) en los mismos pacientes. Metodología. Se lleva a cabo un estudio post hoc de los datos de los ensayos clínicos COU-AA-301 y COU-AA-302, ajustando distintos modelos de análisis de supervivencia. Resultados. En población por intención de tratar (ITT) en COU-AA-301 las estatinas redujeron el riesgo de muerte en un 18% (HR 0.82 IC95% [0.71;0.94], p-valor 0.005) y el riesgo de progresión radiográfica en un 19% (HR 0.0.81 IC95% [0.68;0.97], p-valor 0.02). En población por protocolo (PP) de COU-AA-301 y en COU-AA-302, estos hallazgos no se corroboran. Las estatinas no influyen en TTPP. En ningún modelo la interacción entre tratamiento y estatina era significativa. Conclusiones. Las estatinas reducen el riesgo de evento de muerte por cualquier causa y progresión radiográfica en COU-AA-301 población por ITT, pero no en COU-AA-301 población por PP ni en COU-AA-302.
Introduction and objectives. Castration-resistant prostate cancer (CRPC) has a hormone-dependent nature that allows treatment with abiraterone acetate (AA), an inhibitor of androgen production. Statins are drugs that block the synthesis of cholesterol, precursor of sex hormones. Statin therapy seems to have a beneficial impact on survival in patients with CRPC. The primary objective is to determine the effect of statins on overall survival (OS) in patients with CRPC in clinical trials randomised to treatment with AA or placebo. The secondary objectives are to estimate the effect of statins on radiographic progression-free survival (RPFS) and time to PSA progression (TTPP) in the same patients. Methodology. A post hoc study of the data from clinical trials COU-AA-301 and COU-AA-302 is carried out, fitting different survival analysis models. Results. In the intention-to-treat (ITT) population in COU-AA-301 statins reduced the risk of death by 18% (HR 0.82 CI95% [0.71;0.94], p-value 0.005) and the risk of radiographic progression by 19% (HR 0.81 CI95% [0.68;0.97], p-value 0.02). In the per protocol (PP) population of COU-AA-301 and in COU-AA-302, these findings are not corroborated. Statins do not influence TTPP. In no model the interaction between treatment and statin was significant. Conclusions. Statins reduce the risk of any cause death and radiographic progression in COU-AA-301 ITT population, but not in COU-AA-301 PP population nor in COU-AA-302.
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[1] R. L. Siegel, K. D. Miller, H. E. Fuchs, and A. Jemal, “Cancer Statistics, 2021,” CA. Cancer J. Clin., vol. 71, no. 1, pp. 7–33, 2021, doi: 10.3322/caac.21654. [2] “Cancer.” https://www.who.int/health-topics/cancer#tab=tab_1 (accessed Feb. 15, 2021). [3] G. Wang, D. Zhao, D. J. Spring, and R. A. Depinho, “Genetics and biology of prostate cancer,” Genes Dev., vol. 32, no. 17–18, pp. 1105–1140, 2018, doi: 10.1101/gad.315739.118. [4] L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-Tieulent, and A. Jemal, “Global cancer statistics, 2012.,” CA. Cancer J. Clin., vol. 65, no. 2, pp. 87–108, Mar. 2015, doi: 10.3322/caac.21262. [5] N. J. Sathianathen et al., “Abiraterone acetate in combination with androgen deprivation therapy compared to androgen deprivation therapy only for metastatic hormone-sensitive prostate cancer,” Cochrane Database Syst. Rev., no. 12, 2020, doi: 10.1002/14651858.CD013245.pub2. [6] A. Lopomo and F. Coppedè, “Epigenetic signatures in the diagnosis and prognosis of cancer,” in Epigenetic Mechanisms in Cancer, Elsevier Science & Tecnhology, 2017, pp. 321–322. [7] H. I. Scher, P. T. Scardino, and M. J. Zefelsky, “Cancer of Prostate,” in DeVita, Hellman, and Rosenberg’s Cancer : Principles & Practice of Oncology, 2015, pp. 932–975. [8] C. H. Pernar, E. M. Ebot, K. M. Wilson, and L. A. Mucci, “The Epidemiology of Prostate Cancer,” Cold Spring Harb. Perspect. Med., vol. 8, no. 12, pp. 1–18, 2018, doi: 10.1101/cshperspect.a030361. [9] R. J. MacInnis and D. R. English, “Body size and composition and prostate cancer risk: Systematic review and meta-regression analysis,” Cancer Causes Control, vol. 17, no. 8, pp. 989–1003, 2006, doi: 10.1007/s10552-006-0049-z. [10] M. M. Siddiqui et al., “Vasectomy and risk of aggressive prostate cancer: A 24-year follow-up study,” J. Clin. Oncol., vol. 32, no. 27, pp. 3033–3038, 2014, doi: 10.1200/JCO.2013.54.8446. [11] L. C. Harshman et al., “The impact of statin use on the efficacy of abiraterone acetate in patients with castration-resistant prostate cancer,” Prostate, vol. 77, no. 13, pp. 1303–1311, May 2017, doi: 10.1002/pros.23390. [12] F. C. Hamdy et al., “10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer.,” N. Engl. J. Med., vol. 375, no. 15, pp. 1415–1424, Oct. 2016, doi: 10.1056/NEJMoa1606220. [13] C. Huggins, R. E. Stevens Jr., and C. V Hodges, “Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland,” Arch. Surg., vol. 43, no. 2, pp. 209–223, Aug. 1941, doi: 10.1001/archsurg.1941.01210140043004. [14] N. D. James et al., “Survival with Newly Diagnosed Metastatic Prostate Cancer in the ‘Docetaxel Era’: Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019).,” Eur. Urol., vol. 67, no. 6, pp. 1028–1038, Jun. 2015, doi: 10.1016/j.eururo.2014.09.032. [15] F. Saad and S. J. Hotte, “Guidelines for the management of castrate-resistant prostate cancer,” J. Can. Urol. Assoc., vol. 4, no. 6, pp. 380–384, 2010, doi: 10.5489/cuaj.10167. [16] D. Tilki, E. M. Schaeffer, and C. P. Evans, “Understanding Mechanisms of Resistance in Metastatic Castration-resistant Prostate Cancer: The Role of the Androgen Receptor.,” Eur. Urol. Focus, vol. 2, no. 5, pp. 499–505, Dec. 2016, doi: 10.1016/j.euf.2016.11.013. [17] J. S. de Bono et al., “Abiraterone and increased survival in metastatic prostate cancer.,” N. Engl. J. Med., vol. 364, no. 21, pp. 1995–2005, May 2011, doi: 10.1056/NEJMoa1014618. [18] Janssen-Cilag, “Ficha técnica o resumen de las características del producto ZYTIGA,” Agencia Eur. Medicam., pp. 1–33, 2014, [Online]. Available: ec.europa.eu/health/documents/community.../anx_130850_es.pdf. [19] E. M. Agency, “Zytiga : EPAR - Product Information,” 2011. 52 https://www.ema.europa.eu/en/documents/product-information/zytiga-epar-product-information_en.pdf (accessed Feb. 19, 2021). [20] National Center for Biotechnology Information, “PubChem Compound Summary for CID 132971, Abiraterone,” 2021. https://pubchem.ncbi.nlm.nih.gov/compound/Abiraterone (accessed May 26, 2021). [21] National Center for Biotechnology Information, “PubChem Compound Summary for CID 9821849, Abiraterone acetate.” https://pubchem.ncbi.nlm.nih.gov/compound/Abiraterone-acetate (accessed May 26, 2021). [22] C. Gómez Martín, A. Díaz Serrano, and I. Otero Blas, “Fármacos antineoplásicos,” in Velázquez: Farmacología Básica y Clínica, 19a Ed., Editorial Panamericana, 2017, pp. 909–929. [23] H. S. Soifer et al., “Direct regulation of androgen receptor activity by potent CYP17 inhibitors in prostate cancer cells,” J. Biol. Chem., vol. 287, no. 6, pp. 3777–3787, 2012, doi: 10.1074/jbc.M111.261933. [24] K. Fizazi 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., vol. 13, no. 10, pp. 983–992, 2012, doi: 10.1016/S1470-2045(12)70379-0. [25] M. J. Morris et al., “Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results,” J. Clin. Oncol., vol. 33, no. 12, pp. 1356–1363, 2015, doi: 10.1200/JCO.2014.55.3875. [26] J. Tamargo Menéndez, R. Caballero Collado, and E. Delpón Mosquera, “Fármacos hipolipemiantes,” in Velázquez: Farmacología Básica y Clínica, 19a Ed., Editorial Panamericana, 2017, pp. 445–453. [27] H. Yang et al., “The effect of statins on advanced prostate cancer patients with androgen deprivation therapy or abiraterone/enzalutamide: A systematic review and meta-analysis,” J. Clin. Pharm. Ther., vol. 45, no. 3, pp. 488–495, 2020, doi: 10.1111/jcpt.13092. [28] L. M. Blanco-Colio, J. L. Martín-Ventura, A. Gómez-Hernández, and J. Egido, “Propiedades anti-inflamatorias e inmunomoduladoras de las estatinas,” Nefrologia, vol. 24, no. SUPPL.1, pp. 48–49, 2004. [29] J. H. Ruiz, “Diferentes Estatinas, distintas interacciones,” Boletín Atención Farm. Comunitaria, vol. 19, no. 10, pp. 61–62, 2005. [30] M. Schachter, “Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update,” Fundam. Clin. Pharmacol., vol. 19, no. 1, pp. 117–125, 2005, doi: 10.1111/j.1472-8206.2004.00299.x. [31] A. Hoque, H. Chen, and X. C. Xu, “Statin induces apoptosis and cell growth arrest in prostate cancer cells,” Cancer Epidemiol. Biomarkers Prev., vol. 17, no. 1, pp. 88–94, 2008, doi: 10.1158/1055-9965.EPI-07-0531. [32] S. F. Nielsen, B. G. Nordestgaard, and S. E. Bojesen, “Statin Use and Reduced Cancer-Related Mortality,” N. Engl. J. Med., vol. 367, no. 19, pp. 1792–1802, 2012, doi: 10.1056/nejmoa1201735. [33] Y. Furuya, Y. Sekine, H. Kato, Y. Miyazawa, H. Koike, and K. Suzuki, “Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins,” Prostate Int., vol. 4, no. 2, pp. 56–60, 2016, doi: 10.1016/j.prnil.2016.02.003. [34] C. A. Heinlein and C. Chang, “Androgen receptor in prostate cancer.,” Endocr. Rev., vol. 25, no. 2, pp. 276–308, Apr. 2004, doi: 10.1210/er.2002-0032. [35] F. Labrie et al., “Is dehydroepiandrosterone a hormone?,” J. Endocrinol., vol. 187, no. 2, pp. 169–196, Nov. 2005, doi: 10.1677/joe.1.06264. [36] J. A. Gordon et al., “Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study.,” Oncotarget, vol. 9, no. 28, pp. 19861–19873, Apr. 2018, doi: 10.18632/oncotarget.24888. 53 [37] G. Di Lorenzo et al., “Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate.,” Eur. Urol. Focus, vol. 4, no. 6, pp. 874–879, Dec. 2018, doi: 10.1016/j.euf.2017.03.015. [38] J. S. Ross et al., “Overview and experience of the YODA project with clinical trial data sharing after 5 years,” Sci. Data, vol. 5, pp. 1–14, 2018, doi: 10.1038/sdata.2018.268. [39] “The YODA project.” https://yoda.yale.edu/ (accessed Apr. 13, 2021). [40] C. I. Matthews and B. C. Shilling, Validating Clinical Trial Data Reporting with SAS ®. Cary, NC: SAS Institute Inc., 2008. [41] European Medicines Agency (EMA), “EMA/CHMP/ICH/135/1995. Guideline Good Clinical Practice E6(R2) Step 5,” 1 December 2016, 2016. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf. [42] D. Wang and A. Bakhai, Clinical Trials: a practical guide to design, analysis and reporting. Remedica, 2006. [43] ClinicalTrials.gov [Internet], “Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy,” National Library of Medicine (US), 2013. https://clinicaltrials.gov/ct2/show/results/NCT00638690?term=NCT00638690&draw=2&rank=1 (accessed Feb. 04, 2021). [44] ClinicalTrials.gov [Internet], “Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer,” National Library of Medicine (US), 2015. https://clinicaltrials.gov/ct2/show/results/NCT00887198?term=NCT00887198&draw=2&rank=1 (accessed Feb. 04, 2021). [45] D. G. Kleinbaum and M. Klein, Survival analysis. A self-learning text, 3rd Editio. Springer, 2012. [46] M. Buyse and P. Piedbois, “On the relationship between response to treatment and survival time,” Stat. Med., vol. 15, no. 24, pp. 2797–2812, 1996, doi: 10.1002/(SICI)1097-0258(19961230)15:24<2797::AID-SIM290>3.0.CO;2-V. [47] M. J. Bradburn, T. G. Clark, S. B. Love, and D. G. Altman, “Survival analysis part II: multivariate data analysis--an introduction to concepts and methods.,” Br. J. Cancer, vol. 89, no. 3, pp. 431–436, Aug. 2003, doi: 10.1038/sj.bjc.6601119. [48] T. G. Clark, M. J. Bradburn, S. B. Love, and D. G. Altman, “Survival analysis part I: basic concepts and first analyses.,” Br. J. Cancer, vol. 89, no. 2, pp. 232–238, Jul. 2003, doi: 10.1038/sj.bjc.6601118. [49] T. M. Therneau and P. M. Grambsch, Modeling Survival Data: Extending the Cox Model. Springer Science + Business Media , LLC, 2000. [50] P. M. Grambsch and T. M. Therneau, “Proportional Hazards Tests and Diagnostics Based on Weighted Residuals,” Biometrika, vol. 81, no. 3, pp. 515–526, Jun. 1994, doi: 10.2307/2337123. [51] T. M. Therneau, C. Crowson, and E. Atkinson, “Using Time Dependent Covariates and Time Dependent Coefficients in the Cox Model,” 2021. [52] NIH, “Impact of Atorvastatin on Prostate Cancer Progression During ADT (ESTO2),” ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04026230?term=statin&recrs=abdf&cond=Prostate+Cancer&draw=2&rank=2 (accessed Jun. 15, 2021). [53] NIH, “Trial of Acetylsalicylic Acid and Atorvastatin in Patients With Castrate-resistant Prostate Cancer (PEACE-4),” ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03819101?term=statin&recrs=abdf&cond=Prostate+Cancer&draw=2&rank=3 (accessed Jun. 15, 2021).