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口服relugolix用于晚期前列腺癌的雄激素剥夺治疗
Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer


Neal D. Shore ... 肿瘤 • 2020.06.04
相关阅读
• 阿帕鲁胺治疗转移性去势敏感性前列腺癌 • 非转移性去势抵抗性前列腺癌患者经恩扎卢胺治疗的生存期

摘要


背景

注射用黄体生成素释放激素激动剂(如亮丙瑞林)是用于前列腺癌患者雄激素剥夺治疗的标准药物,但存在初期睾酮激增和疗效延迟的问题。口服促性腺激素释放激素拮抗剂relugolix与亮丙瑞林相比的疗效和安全性尚不明确。

 

方法

在这项3期试验中,我们以2∶1的比例将晚期前列腺癌患者随机分组,分别接受为期48周的relugolix(口服,每日1次,每次120 mg)或亮丙瑞林(每3个月注射1次)治疗。主要终点是将睾酮持续抑制至去势水平(<50 ng/dL)48周。次要终点包括在主要终点方面的非劣效性、第4日睾酮达到去势水平及第15日达到显著去势水平(<20 ng/dL)。我们在一个患者亚组中评估了睾酮恢复情况。

 

结果

共计622例患者接受了relugolix治疗,308例患者接受了亮丙瑞林治疗。在接受relugolix治疗的患者中,96.7%(95%置信区间[CI],94.9~97.9)将去势水平维持至48周,而在接受亮丙瑞林治疗的患者中,这一比例为88.8%(95% CI,84.6~91.8)。7.9个百分点(95% CI,4.1~11.8)的差异表明relugolix具有非劣效性和优效性(优效性P<0.001)。所有其他关键次要终点均表明relugolix优于亮丙瑞林(P<0.001)。在relugolix组和亮丙瑞林组中,第4日睾酮达到去势水平的患者百分比分别为56.0%和0。我们在包含184例患者的亚组中评估了睾酮恢复情况,结果表明在relugolix组和亮丙瑞林组中,治疗停止后90日时的平均睾酮水平分别为288.4 ng/dL和58.6 ng/dL。在全部患者中,relugolix组和亮丙瑞林组的主要心血管不良事件发生率分别为2.9%和6.2%(风险比,0.46;95% CI,0.24~0.88)。

 

结论

在这项对晚期前列腺癌患者进行的试验中,relugolix迅速且持续对睾酮水平产生抑制作用,效果优于亮丙瑞林,并且主要心血管不良事件风险比亮丙瑞林低54%(由Myovant Sciences资助,HERO在ClinicalTrials.gov注册号为NCT03085095)。





作者信息

Neal D. Shore, M.D., Fred Saad, M.D., Michael S. Cookson, M.D., M.M.H.C., Daniel J. George, M.D., Daniel R. Saltzstein, M.D., Ronald Tutrone, M.D., Hideyuki Akaza, M.D., Alberto Bossi, M.D., David F. van Veenhuyzen, M.B., Ch.B., M.Pharm.Med., Bryan Selby, M.S., Xiaolin Fan, Ph.D., Vicky Kang, M.D., Jackie Walling, M.B., Ch.B., Ph.D., and Bertrand Tombal, M.D., Ph.D. for the HERO Study Investigators*
From the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); the University of Montreal Hospital Center, Montreal (F.S.); the Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City (M.S.C.); the Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC (D.J.G.); Urology San Antonio, San Antonio, TX (D.R.S.); Chesapeake Urology, Towson, MD (R.T.); the Department of Strategic Investigation on Comprehensive Cancer Network, Interfaculty Initiative in Information Studies–Graduate School of Interdisciplinary Information Studies, University of Tokyo, Tokyo (H.A.); the Department of Radiation Oncology, Gustave Roussy Cancer Institute, Villejuif, France (A.B.); Myovant Sciences, Brisbane, CA (D.F.V., B.S., X.F., V.K., J.W.); and Service d’Urologie, Cliniques Universitaires Saint Luc, Brussels (B.T.). Address reprint requests to Dr. Shore at the Carolina Urologic Research Center, 823 82nd Pkwy., Suite B, Myrtle Beach, SC 29572, or at nshore@gsuro.com. *A full list of the HERO Study Investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Oh WK, Landrum MB, Lamont EB, McNeil BJ, Keating NL. Does oral antiandrogen use before leuteinizing hormone-releasing hormone therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Urology 2010;75:642-647.

2. Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogs. Annu Rev Med 1994;45:391-405.

3. Mcleod DG. Hormonal therapy: historical perspective to future directions. Urology 2003;61:Suppl 1:3-7.

4. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238-244.

5. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. II. Treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol 2017;71:630-642.

6. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prostate cancer 2019, version 4.2019. August 19, 2019 (https://www.nccn.org/patients/guidelines/content/PDF/prostate-patient.pdf. opens in new tab).

7. Ben-Josef E, Yang SY, Ji TH, et al. Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 1999;161:970-976.

8. Crawford ED, Tombal B, Keane T, et al. FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist. Scand J Urol 2018;52:349-357.

9. Suzuki H, Uemura H, Mizokami A, et al. Phase I trial of TAK-385 in hormone treatment-naïve Japanese patients with nonmetastatic prostate cancer. Cancer Med 2019;8:5891-5902.

10. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008;102:1531-1538.

11. Van Poppel H, Klotz L. Gonadotropin-releasing hormone: an update review of the antagonists versus agonists. Int J Urol 2012;19:594-601.

12. MacLean DB, Shi H, Faessel HM, Saad F. Medical castration using the investigational oral GnRH antagonist TAK-385 (relugolix): phase 1 study in healthy males. J Clin Endocrinol Metab 2015;100:4579-4587.

13. Dearnaley DP, Saltzstein DR, Sylvester JE, et al. The oral gonadotropin-releasing hormone receptor antagonist relugolix as neoadjuvant/adjuvant androgen deprivation therapy to external beam radiotherapy in patients with localised intermediate-risk prostate cancer: a randomized, open-label, parallel-group phase 2 trial. Eur Urol 2020 April 6 (Epub ahead of print).

14. Saad F, Bailen JL, Pieczonka CM, et al. Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts). J Clin Oncol 2016;34:Suppl:200-200. abstract.

15. Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34:1402-1418.

16. Food and Drug Administration. Non-inferiority clinical trials to establish effectiveness: guidance for industry. November 2016 (https://www.fda.gov/media/78504/download. opens in new tab).

17. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999;17:3461-3467.

18. Schally AV, Arimura A, Kastin AJ, et al. Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science 1971;173:1036-1038.

19. Crawford ED, Hou AH. The role of LHRH antagonists in the treatment of prostate cancer. Oncology (Williston Park) 2009;23:626-630.

20. Vis AN, van der Sluis TM, Al-Itejawi HHM, van Moorselaar RJA, Meuleman EJH. Risk of disease flare with LHRH agonist therapy in men with prostate cancer: myth or fact? Urol Oncol 2015;33:7-15.

21. Krakowsky Y, Morgentaler A. Risk of testosterone flare in the era of the saturation model: one more historical myth. Eur Urol Focus 2019;5:81-89.

22. Skinner DC, Albertson AJ, Navratil A, et al. Effects of gonadotrophin-releasing hormone outside the hypothalamic-pituitary-reproductive axis. J Neuroendocrinol 2009;21:282-292.

23. Miwa K, Hitaka T, Imada T, et al. Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem 2011;54:4998-5012.

24. Nakata D, Masaki T, Tanaka A, et al. Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice. Eur J Pharmacol 2014;723:167-174.

25. Siddiqui ZA, Krauss DJ. Adjuvant androgen deprivation therapy for prostate cancer treated with radiation therapy. Transl Androl Urol 2018;7:378-389.

26. Zietman AL, Prince EA, Nakfoor BM, Park JJ. Androgen deprivation and radiation therapy: sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 1997;38:1067-1070.

27. Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367:895-903.

28. Ritch C, Cookson M. Recent trends in the management of advanced prostate cancer. F1000Res 2018;7:1513-1513.

29. 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;65:565-573.

30. Margel D, Peer A, Ber Y, et al. Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and GnRH-antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. J Urol 2019;202:1199-1208

31. Knutsson A, Hsiung S, Celik S, et al. Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE(-/-) mice. Sci Rep 2016;6:26220-26220.

32. Hopmans SN, Duivenvoorden WCM, Werstuck GH, Klotz L, Pinthus JH. GnRH antagonist associates with less adiposity and reduced characteristics of metabolic syndrome and atherosclerosis compared with orchiectomy and GnRH agonist in a preclinical mouse model. Urol Oncol 2014;32:1126-1134.

33. Thomsen FB, Sandin F, Garmo H, et al. Gonadotropin-releasing hormone agonists, orchiectomy, and risk of cardiovascular disease: semi-ecologic, nationwide, population-based study. Eur Urol 2017;72:920-928.

34. Sturgeon KM, Deng L, Bluethmann SM, et al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J 2019;40:3889-3897.

35. Davis MK, Rajala JL, Tyldesley S, Pickles T, Virani SA. The prevalence of cardiac risk factors in men with localized prostate cancer undergoing androgen deprivation therapy in British Columbia, Canada. J Oncol 2015;2015:820403-820403.

36. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56(25):e50-e103.

37. Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010;102:39-46.

38. Leong DP, Fradet V, Shayegan B, et al. Cardiovascular risk in men with prostate cancer: insights from the RADICAL PC Study. J Urol 2020 January 3 (Epub ahead of print).

39. Behl AS, Ellis LA, Pilon D, Xiao Y, Lefebvre P. Medication adherence, treatment patterns, and dose reduction in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate or enzalutamide. Am Health Drug Benefits 2017;10:296-303.

40. Lafeuille M-H, Grittner AM, Lefebvre P, et al. Adherence patterns for abiraterone acetate and concomitant prednisone use in patients with prostate cancer. J Manag Care Spec Pharm 2014;20:477-484.

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