Drug Evaluation

*Author for correspondence: Tel.: +919 668 4615;

https://orcid.org/0000-0002-0836-8542

Department of Medicine & Surgery, Duke Cancer Institute, Duke University, Durham, NC 27710, USA

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David P Dearnaley

The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK

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Published Online:19 Aug 2021https://doi.org/10.2217/fon-2021-0575

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Abstract

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.

Lay abstract

The male sex hormone testosterone promotes the growth of prostate cancer cells. Some drug treatments for prostate cancer, such as gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists, work to reduce the production of testosterone. However, GnRH receptor agonists like leuprolide acetate can increase testosterone levels at first, before reducing it, and this temporary increase can cause side effects, such as bone pain. Drugs of this type have also been linked to a higher risk of heart attacks, strokes, and death. Relugolix works a different way; it is a GnRH receptor antagonist that reduces testosterone without an initial increase. A clinical study showed that relugolix reduced testosterone levels more quickly than leuprolide acetate, a commonly used injectable drug for the treatment of prostate cancer. After stopping treatment, levels of testosterone in the blood returned to normal faster in men who received relugolix than in men who received leuprolide acetate. Men who received relugolix had a lower incidence of heart attacks, strokes, and death compared with men who received leuprolide acetate. The US FDA approved relugolix as the first oral, once-daily GnRH receptor antagonist for the treatment of advanced prostate cancer, offering men a new treatment option.

Graphical abstract

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
MedlineGoogle Scholar
2. 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. 68(6), 394–424 (2018).
MedlineGoogle Scholar
3. Pishgar F, Ebrahimi H, Saeedi Moghaddam S, Fitzmaurice C, Amini E. Global, regional and national burden of prostate cancer, 1990 to 2015: results from the global burden of disease study 2015. J. Urol. 199(5), 1224–1232 (2018).
MedlineGoogle Scholar
4. National Comprehensive Cancer Network. National Comprehensive Cancer Network, Prostate Cancer (version 2.2020). https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf • Provides the recommended treatment protocols for prostate cancer.
Google Scholar
5. Huggins C, Hodges CV. Studies on prostate cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. J. Urol. 168, 9–12 (1941).
Google Scholar
6. Ulloa-Aguirre A, Timossi C. Biochemical and functional aspects of gonadotrophin-releasing hormone and gonadotrophins. Reprod Biomed Online 1(2), 48–62 (2000).
Medline CASGoogle Scholar
7. Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 61(1 Suppl. 2), 32–38 (2003).
MedlineGoogle Scholar
8. Waxman J. Hormonal aspects of prostatic cancer: a review. J. R. Soc. Med. 78(2), 129–135 (1985).
Medline CASGoogle Scholar
9. Byar DP. Treatment of prostatic cancer: studies by the Veterans Administration cooperative urological research group. Bull NY Acad. Med. 48(5), 751–766 (1972).
Medline CASGoogle Scholar
10. Dearnaley DP. Cancer of the prostate. BMJ 308(6931), 780–784 (1994).
Medline CASGoogle Scholar
11. Mcleod DG. Antiandrogenic drugs. Cancer 71, 1046–1049 (1993).
Medline CASGoogle Scholar
12. Mcleod DG. Tolerability of nonsteroidal antiandrogens in the treatment of advanced prostate cancer. Oncologist 2(1), 18–27 (1997).
Medline CASGoogle Scholar
13. Bennett CL, Tosteson TD, Schmitt B, Weinberg PD, Ernstoff MS, Ross SD. Maximum androgen-blockade with medical or surgical castration in advanced prostate cancer: a meta-analysis of nine published randomized controlled trials and 4128 patients using flutamide. Prostate Cancer Prostatic Dis. 2(1), 4–8 (1999).
Medline CASGoogle Scholar
14. Van Poppel H, Abrahamsson PA. Considerations for the use of gonadotropin-releasing hormone agonists and antagonists in patients with prostate cancer. Int. J. Urol. 27(10), 830–837 (2020).
Medline CASGoogle Scholar
15. Rosario DJ, Davey P, Green J et al. The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. World J. Urol. 34(12), 1601–1609 (2016).
Medline CASGoogle Scholar
16. Clayton RN. Gonadotropin-releasing hormone modulation of its own pituitary receptors: evidence for biphasic regulation. Endocrinology 111(1), 152–161 (1982).
Medline CASGoogle Scholar
17. Heber D, Dodson R, Stoskopf C, Peterson M, Swerdloff RS. Pituitary desensitization and the regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors following chronic administration of a superactive GnRH analog and testosterone. Life Sci. 30(26), 2301–2308 (1982).
Medline CASGoogle Scholar
18. Yamanaka H, Makino T, Kumasaka F, Shida K. [Clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LHRH ethylamide against prostatic cancer]. Hinyokika Kiyo 30(4), 545–560 (1984).
Medline CASGoogle Scholar
19. Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br. J. Urol. 67(5), 502–508 (1991).
Medline CASGoogle Scholar
20. Iversen P, Suciu S, Sylvester R, Christensen I, Denis L. Zoladex and flutamide versus orchiectomy in the treatment of advanced prostatic cancer. A combined analysis of two European studies, EORTC 30853 and DAPROCA 86. Cancer 66(Suppl. 5), 1067–1073 (1990).
Medline CASGoogle Scholar
21. Bubley GJ. Is the flare phenomenon clinically significant? Urology 58(1 Suppl. 2), 5–9 (2001).
Medline CASGoogle Scholar
22. Kirschenbaum A. Management of hormonal treatment effects. Cancer 75, 1983–1986 (1995).
Google Scholar
23. Smith MR, Lee H, Mcgovern F et al. Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer 112(10), 2188–2194 (2008).
Medline CASGoogle Scholar
24. Levine GN, D'amico AV, Berger P et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation 121(6), 833–840 (2010).
MedlineGoogle Scholar
25. US FDA. FDA drug and safety communication (2010). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-ongoing-safety-review-gnrh-agonists-and-notification
Google Scholar
26. Bolla M, Maingon P, Carrie C et al. Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: results of EORTC trial 22991. J. Clin. Oncol. 34(15), 1748–1756 (2016).
Medline CASGoogle Scholar
27. Bolla M, Van Tienhoven G, Warde P et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 11(11), 1066–1073 (2010).
Medline CASGoogle Scholar
28. Lawton CaF, Lin X, Hanks GE et al. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG oncology RTOG 9202. Int. J. Radiat. Oncol. Biol. Phys. 98(2), 296–303 (2017).
Medline CASGoogle Scholar
29. Jones CU, Hunt D, Mcgowan DG et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N. Engl. J. Med. 365(2), 107–118 (2011).
Medline CASGoogle Scholar
30. D'amico AV, Manola J, Loffredo M, Renshaw AA, Dellacroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 292(7), 821–827 (2004).
MedlineGoogle Scholar
31. Shelley MD, Kumar S, Coles B, Wilt T, Staffurth J, Mason MD. Adjuvant hormone therapy for localised and locally advanced prostate carcinoma: a systematic review and meta-analysis of randomised trials. Cancer Treat. Rev. 35(7), 540–546 (2009).
Medline CASGoogle Scholar
32. Bria E, Cuppone F, Giannarelli D et al. Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?: meta-analysis of randomized trials. Cancer 115(15), 3446–3456 (2009).
MedlineGoogle Scholar
33. Denham JW, Steigler A, Lamb DS et al. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol 12(5), 451–459 (2011).
Medline CASGoogle Scholar
34. Nejat RJ, Rashid HH, Bagiella E, Katz AE, Benson MC. A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J. Urol. 164(6), 1891–1894 (2000).
Medline CASGoogle Scholar
35. Pickles T, Agranovich A, Berthelet E et al. Testosterone recovery following prolonged adjuvant androgen ablation for prostate carcinoma. Cancer 94(2), 362–367 (2002).
Medline CASGoogle Scholar
36. Huirne JA, Lambalk CB. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 358(9295), 1793–1803 (2001).
Medline CASGoogle Scholar
37. Kato Y, Shigehara K, Kawaguchi S, Izumi K, Kadono Y, Mizokami A. Recovery of serum testosterone following neoadjuvant androgen deprivation therapy in Japanese prostate cancer patients treated with low-dose rate brachytherapy. Aging Male 23(5), 1210–1216 (2020).
MedlineGoogle Scholar
38. New treatment for advanced prostate cancer. FDA Consum. 38(2), 4 (2004).
Google Scholar
39. Tomera K, Gleason D, Gittelman M et al. The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J. Urol. 165(5), 1585–1589 (2001).
Medline CASGoogle Scholar
40. Trachtenberg J, Gittleman M, Steidle C et al. A Phase III, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J. Urol. 167(4), 1670–1674 (2002).
Medline CASGoogle Scholar
41. Huhtaniemi I, White R, Mcardle CA, Persson BE. Will GnRH antagonists improve prostate cancer treatment? Trends Endocrinol. Metab. 20(1), 43–50 (2009).
Medline CASGoogle Scholar
42. Bagatell CJ, Conn PM, Bremner WJ. Single-dose administration of the gonadotropin-releasing hormone antagonist, Nal-Lys (antide) to healthy men. Fertil. Steril. 60(4), 680–685 (1993).
Medline CASGoogle Scholar
43. Bagatell CJ, Rivier JE, Bremner WJ. Dose effects of the gonadotropin-releasing hormone antagonist, Nal-Glu, combined with testosterone enanthate on gonadotropin levels in normal men. Fertil. Steril. 64(1), 139–145 (1995).
Medline CASGoogle Scholar
44. Firmagon. Degarelix. Full prescribing information. 1–18 (2015). www.accessdata.fda.gov/drugsatfda_docs/label/2015/022201s009lbl.pdf
Google Scholar
45. Koechling W, Hjortkjaer R, Tankó LB. Degarelix, a novel GnRH antagonist, causes minimal histamine release compared with cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples. Br. J. Clin. Pharmacol. 70(4), 580–587 (2010).
Medline CASGoogle Scholar
46. Sun Y, Xie L, Xu T et al. Efficacy and safety of degarelix in patients with prostate cancer: results from a Phase III study in China. Asian J. Urol. 7(3), 301–308 (2020).
MedlineGoogle Scholar
47. Broqua P, Riviere PJ, Conn PM, Rivier JE, Aubert ML, Junien JL. Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix. J. Pharmacol. Exp. Ther. 301(1), 95–102 (2002).
Medline CASGoogle Scholar
48. Klotz L. Pharmacokinetic and pharmacodynamic profile of degarelix for prostate cancer. Expert Opin. Drug Metab. Toxicol. 11(11), 1795–1802 (2015).
Medline CASGoogle Scholar
49. 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. 102(11), 1531–1538 (2008).
Medline CASGoogle Scholar
50. Ferring Pharmaceuticals A/S. Firmagon (degarelix for injection) summary of product characteristics. (2018). https://www.ema.europa.eu/en/documents/product-information/firmagon-epar-product-information_en.pdf
Google Scholar
51. Frokjaer S, Otzen DE. Protein drug stability: a formulation challenge. Nat Rev. Drug Discov. 4(4), 298–306 (2005).
Medline CASGoogle Scholar
52. Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N. Engl. J. Med. 324(2), 93–103 (1991).
Medline CASGoogle Scholar
53. Meani D, Solarić M, Visapää H, Rosén RM, Janknegt R, Soče M. Practical differences between luteinizing hormone-releasing hormone agonists in prostate cancer: perspectives across the spectrum of care. Ther. Adv. Urol. 10(2), 51–63 (2018).
Medline CASGoogle Scholar
54. Berteau C, Filipe-Santos O, Wang T, Rojas HE, Granger C, Schwarzenbach F. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Med. Devices (Auckl.) 8, 473–484 (2015).
MedlineGoogle Scholar
55. Montgomery BS, Borwell JP, Higgins DM. Does needle size matter? Patient experience of luteinising hormone-releasing hormone analogue injection. Prostate Cancer Prostatic Dis 8(1), 66–68 (2005).
Medline CASGoogle Scholar
56. Lafeuille MH, 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. 20(5), 477–484 (2014).
MedlineGoogle Scholar
57. Fallara G, Lissbrant IF, Styrke J, Montorsi F, Garmo H, Stattin P. Observational study on time on treatment with abiraterone and enzalutamide. PLoS ONE 15(12), e0244462 (2020).
Medline CASGoogle Scholar
58. Zytiga. Abiraterone. Full prescribing information (2020). www.accessdata.fda.gov/drugsatfda_docs/label/2020/202379s031s033lbl.pdf
Google Scholar
59. Xtandi. Enzalutamide. Full prescribing information (2021). www.accessdata.fda.gov/drugsatfda_docs/label/2021/213674s002lbl.pdf
Google Scholar
60. Morote J, Orsola A, Planas J et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J. Urol. 178(4 Pt 1), 1290–1295 (2007).
Medline CASGoogle Scholar
61. Klotz L, O'callaghan C, Ding K et al. Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J. Clin. Oncol. 33(10), 1151–1156 (2015).
Medline CASGoogle Scholar
62. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int. 105(5), 648–651 (2010).
Medline CASGoogle Scholar
63. Wang Y, Dai B, Ye DW. Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients. Asian J. Androl. 19(2), 178–183 (2017).
Medline CASGoogle Scholar
64. Mottet N, Bellmunt J, Briers E et al. EAU - ESTRO - SIOG guidelines on prostate cancer (2016). https://uroweb.org/wp-content/uploads/EAU-Guidelines-Prostate-Cancer-2016.pdf
Google Scholar
65. Nguyen PL, Alibhai SM, Basaria S et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur. Urol. 67(5), 825–836 (2015).
Medline CASGoogle Scholar
66. Tsumura H, Satoh T, Ishiyama H et al. Recovery of serum testosterone following neoadjuvant and adjuvant androgen deprivation therapy in men treated with prostate brachytherapy. World J. Radiol. 7(12), 494–500 (2015).
MedlineGoogle Scholar
67. Driver JA, Djoussé L, Logroscino G, Gaziano JM, Kurth T. Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study. BMJ 337, doi: https://doi.org/10.1136/bmj.a2467 (2008) (Epub ahead of print).
MedlineGoogle Scholar
68. Zaorsky NG, Churilla TM, Egleston BL et al. Causes of death among cancer patients. Ann. Oncol. 28(2), 400–407 (2017).
Medline CASGoogle Scholar
69. Tsai HK, D'amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J. Natl Cancer Inst. 99(20), 1516–1524 (2007).
MedlineGoogle Scholar
70. D'amico AV, Denham JW, Crook J et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J. Clin. Oncol. 25(17), 2420–2425 (2007).
MedlineGoogle Scholar
71. Haque R, Ulcickasyood M, Xu X et al. Cardiovascular disease risk and androgen deprivation therapy in patients with localised prostate cancer: a prospective cohort study. Br. J. Cancer 117(8), 1233–1240 (2017).
Medline CASGoogle Scholar
72. Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating NL, Van Hemelrijck M. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur. Urol. 68(3), 386–396 (2015).
MedlineGoogle Scholar
73. O'farrell S, Garmo H, Holmberg L, Adolfsson J, Stattin P, Van Hemelrijck M. Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. J. Clin. Oncol. 33(11), 1243–1251 (2015).
MedlineGoogle Scholar
74. 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. 65(3), 565–573 (2014). • Discusses gonadotropin-releasing hormone (GnRH) antagonists versus agonists and their impact on cardiovascular disease (CVD).
Medline CASGoogle Scholar
75. 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. 202(6), 1199–1208 (2019). • Provides further evidence on the different impacts of GnRH agonists versus antagonists on CVD.
MedlineGoogle Scholar
76. Margel D, Ber Y, Peer A et al. Cardiac biomarkers in patients with prostate cancer and cardiovascular disease receiving gonadotrophin releasing hormone agonist vs antagonist. Prostate Cancer Prostatic Dis. 24(1), 177–185 (2020). • Provides further evidence on the different impacts of GnRH agonists versus antagonists on CVD.
Google Scholar
77. Crawford ED, Schally AV, Pinthus JH et al. The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy. Urol. Oncol. 35(5), 183–191 (2017). • Provides details on the mechanism of follicle-stimulating hormone’s role in plaque rupture and bone issues.
Medline CASGoogle Scholar
78. Zareba P, Duivenvoorden W, Leong DP, Pinthus JH. Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism? Ther. Adv. Urol. 8(2), 118–129 (2016).
Medline CASGoogle Scholar
79. Tombal B, Miller K, Boccon-Gibod L et al. Additional analysis of the secondary end point of biochemical recurrence rate in a Phase III trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur. Urol. 57(5), 836–842 (2010).
Medline CASGoogle Scholar
80. Ammirati E, Moroni F, Magnoni M, Camici PG. The role of T and B cells in human atherosclerosis and atherothrombosis. Clin. Exp. Immunol. 179(2), 173–187 (2015).
Medline CASGoogle Scholar
81. 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. 54(14), 4998–5012 (2011).
Medline CASGoogle Scholar
82. Sasaki S, Cho N, Nara Y et al. Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J. Med. Chem. 46(1), 113–124 (2003).
Medline CASGoogle Scholar
83. 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. 723, 167–174 (2014).
Medline CASGoogle Scholar
84. Maclean DB, Shi H, Faessel HM, Saad F. Medical castration using the investigational oral GnRH antagonist TAK-385 (relugolix): Phase I study in healthy males. J. Clin. Endocrinol. Metab. 100(12), 4579–4587 (2015).
Medline CASGoogle Scholar
85. Lepor H, Shore ND. LHRH agonists for the treatment of prostate cancer: 2012. Rev. Urol. 14(1–2), 1–12 (2012).
MedlineGoogle Scholar
86. Thway K, Strauss DC, Smith MJ, Fisher C. Foreign body granulomas induced by intramuscular leuprorelin acetate injection for prostate cancer: clinical mimics of soft tissue sarcoma. Case Rep. Oncol. Med. 2015, 947040 (2015).
MedlineGoogle Scholar
87. Kawai M, Ikoma N, Yamada A et al. A case of foreign body granuloma induced by subcutaneous injection of leuprorelin acetate clinical analysis for 335 cases in our hospital. Tokai J. Exp. Clin. Med. 39(3), 106–110 (2014).
MedlineGoogle Scholar
88. Koechling W. Effect of various GnRH antagonists on histamine release from human skin. Presented at: 8th International Symposium on GnRH Analogues in Cancer and Human Reproduction. Salzburg, Austria, (10–13 February 2005).
Google Scholar
89. 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 randomised, open-label, parallel-group Phase II trial. Eur. Urol. 78(2), 184–192 (2020). •• It is the Phase II clinical trial with relugolix showing effectiveness in treating men with advanced prostate cancer.
Medline CASGoogle Scholar
90. Shore ND, Saad F, Cookson MS et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N. Engl. J. Med. 382(23), 2187–2196 (2020). •• It is the Phase III clinical trial with relugolix for the treatment of advanced prostate cancer.
Medline CASGoogle Scholar
91. Myovant Sciences. Relugolix. Full prescribing information. 1–18 (2020). www.myovant.com/wp-content/uploads/2020/12/NDA-214621-Final-USPIandPI.pdf •• Contains the full prescribing information for relugolix.
Google Scholar
92. Shore ND, Chu F, Moul J et al. Polymer-delivered subcutaneous leuprolide acetate formulations achieve and maintain castrate concentrations of testosterone in four open-label studies in patients with advanced prostate cancer. BJU Int. 119(2), 239–244 (2017).
Medline CASGoogle Scholar
93. Spitz A, Gittelman M, Karsh LI et al. Intramuscular depot formulations of leuprolide acetate suppress testosterone levels below a 20 ng/dL threshold: a retrospective analysis of two Phase III studies. Res. Rep. Urol. 8, 159–164 (2016).
Medline CASGoogle Scholar
94. Kao CC, Chang YH, Wu T et al. Open, multi-center, Phase IV study to assess the efficacy and tolerability of triptorelin in Taiwanese patients with advanced prostate cancer. J. Chin. Med. Assoc. 75(6), 255–261 (2012).
Medline CASGoogle Scholar
95. Virgo KS, Rumble RB, De Wit R et al. Initial management of noncastrate advanced, recurrent, or metastatic prostate cancer: ASCO guideline update. J. Clin. Oncol. 39(11), 1274–1305 (2021).
Google Scholar
96. Hoare D, Skinner TA, Black A, Robert Siemens D. Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer. Can. Urol. Assoc. J. 9(3–4), 122–127 (2015).
MedlineGoogle Scholar
97. Ide H, Terado Y, Sakamaki K et al. Serum level of follicle-stimulating hormone is associated with extraprostatic extension of prostate cancer. Prostate Int. 1(3), 109–112 (2013).
MedlineGoogle Scholar
98. Rove KO, Crawford ED. Traditional androgen ablation approaches to advanced prostate cancer: new insights. Can. J. Urol. 21(1 Suppl. 2), 14–21 (2014).
MedlineGoogle Scholar
99. Atchia KS, Wallis CJD, Fleshner N, Toren P. Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: a systematic review and meta-analysis. Can. Urol. Assoc. J. 14(2), 36–41 (2020).
MedlineGoogle Scholar
100. Crawford ED, Schally AV. The role of FSH and LH in prostate cancer and cardiometabolic comorbidities. Can. J. Urol. 27(2), 10167–10173 (2020). • Presents the relationship between follicle-stimulating hormone and luteinizing hormone and cardiometabolic morbidities, which may explain the reduced incidence of major adverse cardiovascular event in patients receiving relugolix.
MedlineGoogle Scholar
101. Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373(8), 737–746 (2015).
Medline CASGoogle Scholar
102. Fizazi K, Tran N, Fein L et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 377(4), 352–360 (2017).
Medline CASGoogle Scholar
103. Scailteux LM, Lacroix C, Bergeron S et al. [Adverse drug reactions profiles for abiraterone and enzalutamide: a pharmacovigilance descriptive analysis]. Therapie doi:10.1016/j.therap.2020.12.012 (2020) (Epub ahead of print).
Google Scholar
104. Tahaineh L, Wazaify M. Difficulties in swallowing oral medications in Jordan. Int. J. Clin. Pharm. 39(2), 373–379 (2017).
MedlineGoogle Scholar
105. Smith D, Lovell J, Weller C et al. A systematic review of medication non-adherence in persons with dementia or cognitive impairment. PLoS ONE 12(2), e0170651 (2017).
MedlineGoogle Scholar
106. Jacobs JM, Pensak NA, Sporn NJ et al. Treatment satisfaction and adherence to oral chemotherapy in patients with cancer. J. Oncol. Pract. 13(5), e474–e485 (2017).
MedlineGoogle Scholar

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Received 7 May 2021

Accepted 3 August 2021

Published online 19 August 2021

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Financial & competing interest disclosure

DJ George reports receiving research grants from Astellas, AstraZeneca, BMS, Calithera, Exelixis, Janssen, Novartis, Pfizer and Sanofi; consultant and/or advisory board fees from Astellas, AstraZeneca, Bayer, BMS, Capio Biosciences, Constellation Pharmaceuticals, Exelixis, Flatiron, Janssen, Merck Sharp & Dohme, Michael J Hennessey Associates, Modra Pharmaceuticals B.V., Myovant Sciences, Physician Education Resource LLC, Pfizer, Propella TX, RevHealth LLC, and Sanofi; and speaker fees, honoraria, and/or reimbursement for travel accommodations from Bayer, EMD Serono, Exelixis, Ipsen, Michael J Hennessey Associates, Pfizer, Sanofi, UroGPO, and UroToday. He has also served as Senior Editor for the American Association for Cancer Research; as Co-Editor-in-Chief for Clinical Advances in Hematology & Oncology; on an Independent Data Monitoring Committee for Janssen; and on Steering Committees for AstraZeneca, BMS, Leidos Biomedical Research, Nektar Therapeutics, and Pfizer. DP Dearnaley declares personal fees through the Rewards to Discoverer’s Scheme from The Institute of Cancer Research which receives royalty income from abiraterone, support from Cancer Research UK Program Grants C33589/A19727 “Advances in Physics for Precision Radiotherapy,” and honoraria for advisory boards from Janssen. In addition, DP Dearnaley has a patent EP1933709B1 issued for a localization and stabilization device. This work is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing and editing support were provided by N Patocka, R Marwick, and WM Roberts, funded by Myovant Sciences GmbH in collaboration with Pfizer, through a contract to Stratenym Inc.

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Relugolix, an oral gonadotropin-releasing hormone antagonist for the treatment of prostate cancer

Abstract

Lay abstract

Graphical abstract

References