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UROSCAN |
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| Year : 2020 | Volume
: 36
| Issue : 4 | Page : 327-328 |
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Relugolix – The novel oral androgen deprivation therapy for prostate cancer
Rahul Jena
Department of Urology and Renal Transplant, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| Date of Submission | 23-Jun-2020 |
| Date of Acceptance | 06-Aug-2020 |
| Date of Web Publication | 1-Oct-2020 |
Correspondence Address:
Dr. Rahul Jena
Department of Urology and Renal Transplant, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/iju.IJU_362_20
How to cite this article:
Jena R. Relugolix – The novel oral androgen deprivation therapy for prostate cancer. Indian J Urol 2020;36:327-8 |
 Summary | |  |
The HERO trial was a Phase 3, randomized, controlled, multicenter, open-label trial, comparing the relugolix, anoral Luteinizing hormone-releasing hormone (LHRH) antagonist, with injectable leuprolide acetate in advanced prostate cancer.[1] From April 2017 to October 2018, 934 patients, without any history of recent major adverse cardiovascular event (MACE), with either biochemical or clinical relapse after local curative treatment, newly diagnosed castrate-naïve metastatic disease or locally advanced histologically confirmed adenocarcinoma of prostate, not amenable to local curative treatment were selected. Subjects underwent 2:1 randomization to receive either relugolix (120 mg once daily after a single oral loading dose of 360 mg) or leuprolide acetate (22.5 mg by injection every 3 months) for 48 weeks, after stratification according to age, presence or absence of metastatic disease, and geographic region,. The primary endpoint was the sustained castration rate from day 29 to week 48. The secondary endpoints included noninferiority of relugolix to leuprolide with respect to sustained castration rate, cumulative probability of testosterone suppression to <50 ng/dl on day 4 and day 15, the percentage of patients with a prostate-specific antigen response (>50% decrease) at days 15 and 29, the profound castration rate (testosterone suppression to <20 ng/dl) on day 15, and the follicle-stimulating hormone (FSH) level at the end of week 24. At a median follow-up of 52 weeks, 96.7% (95% confidence interval [CI], 94.9–97.9) of men on relugolix maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6–91.8) of men on leuprolide. The sustained castration rate in the relugolix group was actually superior because the lower boundary of the 95% CI for the between-group difference was above zero (P < 0.001). Relugolix was superior to leuprolide with respect to the other secondary endpoints also (P < 0.001). Testosterone suppression was faster in the relugolix group and was unaccompanied by the testosterone surge seen in the leuprolide group, along with faster recovery of testosterone levels at 90 days on discontinuation. Among all the patients, the incidence of MACEs was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24–0.88), i.e., a 54% less risk, though there was higher incidence of diarrhea in the relugolix arm (12.2% vs. 6.8%).
| Commentary | | |
When compared with LHRH agonists, LHRH anatogonists avoid acute FSH, luteinizing hormone, and testosterone surge and the need for antiandrogen coadministration, along with a better cardiovascular risk profile. However, their popularity has been plagued by issues such as a higher incidence of histamine-mediated side effects, local injection site reactions, and the need for frequent administration.[2],[3] Being peptide drugs, their low aqueous solubility and need for parenteral administration make the development of an oral agent desirable and had been the subject of many clinical trials.
Relugolix is the second oral LHRH antagonist to be approved for manipulation of the GnRH axis, after elagolix [Table 1]. The HERO trial is the first phase III clinical trial evaluating its use in prostate cancer and confirms the results of an earlier phase II trial comparing relugolix with degarelix, along with radiotherapy.[4] A few points that are immediately evident are that relugolix is noninferior to leuprolide when it comes to sustained castration and the time taken to achieve castration levels of testosterone. Superiority of relugolix was seen in the other secondary endpoints including greater FSH suppression. This finding is particularly beneficial for men with severe bone pains and impending cord compression. The superior recovery of testosterone levels on discontinuation will be useful for patients being planned for intermittent androgen deprivation therapy (ADT) or those requiring ADT along with curative radiotherapy. Discontinuation of therapy is also easier for patients facing debilitating side effects of ADT that hamper quality of life. | Table 1: Agents used for manipulation of the gonadotropin-releasing hormone pathway
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However, a few findings merit critical appraisal. Although 90% of the men in this trial had cardiovascular risk factors, and there was a 54% less risk of MACE in the relugolix group, this study was not powered to detect differences in MACE. The results of the PRONOUNCE trial may shed more light on the cardiovascular safety of LHRH antagonist versus analogs.[5] Relugolix is an oral agent, and though in the study, the adherence to treatment was 99%, compliance to an oral regimen in the real-life setting is likely to be lower and needs to studied. Structurally, it is a nonpeptide N-phenylurea derivative, and food decreases its absorption by 50%. Hence, it is to be taken on an empty stomach. The plasma protein binding is approximately 70%, and since it is a substrate for P-glycoprotein, it may interact with inducers or inhibitors of P-glycoprotein such as amiodarone, nifedipine, verapamil, diltiazem, proton pump inhibitors, and antiepileptics, which are commonly used in the elderly population.[6] Furthermore, since P-glycoprotein is one of the molecules involved in drug resistance in cancers, mutations in this may contribute to the development of castration resistance and this aspect needs to be studied in future trials. Similar to other agents of its class, hot flashes, bone loss, and fatigue with altered bowel habits continue to accompany the use of relugolix. Finally, factors such as availability and cost will be important in its use and acceptance by practitioners and patients alike.
Financial support and sponsorship: Nil.
Conflicts of interest: There are no conflicts of interest.
| References | | |
| 1. | 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.  |
| 2. | Van Poppel H, Klotz L. Gonadotropin-releasing hormone: An update review of the antagonists versus agonists. Int J Urol 2012;19:594-601. |
| 3. | 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. |
| 4. | Dearnaley DP, Saltzstein DR, Sylvester JE, Karsh L, Mehlhaff BA, Pieczonka C, 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 2 trial. Eur Urol 2020;78(2):184-192. |
| 5. | Melloni C, Slovin SF, Blemings A, Goodman SG, Evans CP, Nilsson J, et al. Cardiovascular safety of degarelix versus leuprolide for advanced prostate cancer: The PRONOUNCE trial study design. JACC: CardioOncology 2020;2:70-81. |
| 6. | Barra F, Seca M, Della LC, Giampaolino P, Ferrero S. Relugolix for the treatment of uterine fibroids. Drugs of today (Barcelona, Spain: 1998). 2019 Aug; 55(8):503-12. |
[Table 1]
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An Efficient UPLC-MS/MS Method Established to Detect Relugolix Concentration in Rat Plasma |
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| Liying Xing, Ya-nan Liu, Hongye Yao, Tingting Wang, Fuchen Xie, Shunbin Luo, Pingping Luo, Shengling Tang | | Frontiers in Pharmacology. 2022; 13 | | [Pubmed] | [DOI] | |
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