Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :805
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (544 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 » Mechanism of Action
 »  Dosing and Admin...
 »  Pharmacokinetic ...
 »  Guideline Recomm...
 »  Efficacy Evaluat...
 »  Adjuvant or neoa...
 »  Safety: Gosereli...
 »  Clinical Implica...
 » Conclusion
 »  Combined androge...
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed421    
    Printed0    
    Emailed0    
    PDF Downloaded75    
    Comments [Add]    

Recommend this journal

 

  Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 59  |  Issue : 5  |  Page : 160-174
 

A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone–releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix)


1 Senior Consultant, Medical Oncology and Hematology, Max Cancer Centre, New Delhi, India
2 Consultant Medical Oncologist, Basavatarakam Indo-American Cancer Hospital & Research Institute, Hyderabad, India
3 Medical Director, Chief Genito Uro-Oncology, RCGI, Delhi, India
4 Department of Uro oncology, P D Hinduja National Hospital, Mahim, Mumbai, India
5 Professor & Radiation Oncologist, Tata Memorial Center, Mumbai, India
6 Medical Affairs, AstraZeneca Pharma India Ltd, Manyatha Tech Park, Rachenahalli, Bangalore, India

Date of Submission30-Dec-2020
Date of Decision04-Apr-2021
Date of Acceptance22-Apr-2021
Date of Web Publication24-Mar-2022

Correspondence Address:
Ketaki Patil
Medical Affairs, AstraZeneca Pharma India Ltd, Manyatha Tech Park, Rachenahalli, Bangalore
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_1415_20

Rights and Permissions

 » Abstract 


Luteinizing hormone–releasing hormone agonist (LHRH-A), goserelin, and antagonist, degarelix, are both indicated for the treatment of advanced prostate cancer (PCa); however, large comparative trials evaluating their efficacy and safety are lacking. In this review, we assessed the available evidence for both the drugs. Although degarelix achieves an early rapid decline in testosterone (T) and prostate-specific antigen (PSA) levels, median T and PSA levels, in addition to prostate volume and International Prostate Symptom Scores, become comparable with goserelin over the remaining treatment period. Degarelix causes no initial flare, therefore it is recommended in patients with spinal metastases or ureteric obstruction. Goserelin achieves lower PSA, improved time to progression, and better survival outcomes when administered adjunctively to radiotherapy compared with radiotherapy alone, with significant results even over long-term follow-up. The evidence supporting adjuvant degarelix use is limited. Goserelin has better injection site safety, single-step delivery, and an efficient administration schedule compared with degarelix, which has significantly higher injection site reactions and less efficient administration mechanism. There is conflicting evidence about the risk of cardiovascular disease (CVD), and caution is required when using LHRH-A in patients with preexisting CVD. There is considerable long-term evidence for goserelin in patients with advanced PCa, with degarelix being a more recent option. The available comparative evidence of goserelin versus degarelix has several inherent limitations related to study design, sample size, conduct, and statistical analyses, and hence warrants robust prospective trials and long-term follow-up.


Keywords: Advanced prostate cancer, degarelix, goserelin, LHRH-A
Key Message The short-term and long-term clinical benefits, safety and tolerability of goserelin are well established in a broad spectrum of PCa population. Though LHRH antagonists such as degarelix offer additional advantages in patients with advanced PCa with spinal metastasis and ureteric obstruction, their superiority over LHRH-A for clinical outcomes have not been proven. Also, the wider use of degarelix is restricted by monthly dosing and risk of injection site reactions. Hence, goserelin can be the drug of choice in PCa with a large evidence base.


How to cite this article:
Bahl A, Rajappa S, Rawal S, Bakshi G, Murthy V, Patil K. A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone–releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix). Indian J Cancer 2022;59, Suppl S1:160-74

How to cite this URL:
Bahl A, Rajappa S, Rawal S, Bakshi G, Murthy V, Patil K. A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone–releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix). Indian J Cancer [serial online] 2022 [cited 2022 May 22];59, Suppl S1:160-74. Available from: https://www.indianjcancer.com/text.asp?2022/59/5/160/340521





 » Introduction Top


Prostate cancer (PCa) is the second most common type of cancer in men with 1,276,106 new cases and 358,989 deaths reported worldwide in 2018.[1] Global incidences of PCa have increased 3.7-fold from 1990 to 2015.[2] In general, PCa has an excellent prognosis, with 100% 5-year survival rate in localized PCa.[3] However, the prognosis is worse in African American men, those with advanced-stage cancer, and those aged between 75 and 84 years.[4]

Depending on the stage of PCa, treatment options include surgery, radiotherapy (RT), and medical therapy.[5] Androgen deprivation therapy (ADT) by medical or surgical castration remains the standard mode of treatment in advanced PCa for the past five decades.[6],[7] As androgens such as testosterone (T) stimulate malignant prostate cell growth, inhibition of the androgen signaling pathway by luteinizing hormone–releasing hormone agonists (LHRH-A) or luteinizing hormone–releasing hormone (LHRH) antagonists can reduce T to castrate levels (<20 ng/dL) in PCa.[6],[7],[8],[9] Goserelin and leuprorelin are the most commonly used LHRH-A in patients with nonmetastatic disease or recurrent PCa after attempted curative treatment.[10] Degarelix, a third-generation LHRH antagonist is an alternate ADT option in recent times.[11],[12]

Currently, the European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of both goserelin and degarelix as possible options for ADT in PCa.[6],[7] Although clinical trials have compared the effects of goserelin and degarelix on prostate-specific antigen (PSA) and T levels, large comparative trials evaluating their effect on overall survival (OS) and/or progression-free survival (PFS) are lacking.[13] Furthermore, there has been conflicting evidence concerning the overall efficacy and safety, including cardiovascular (CV) safety. This review specifically aims to compare the efficacy and safety of goserelin and degarelix by reviewing data from randomized controlled trials (RCTs), meta-analyses, pooled analyses, and real-world evidence.


 » Mechanism of Action Top


The androgen signaling pathway involves the hypothalamic–pituitary–gonadal axis, and its inhibition by LHRH-A and LHRH antagonists [Figure 1]. Because PCa is largely hormone driven, the LHRH-A/antagonist-led centralized hormone suppression helps reduce circulating T levels.[14],[15]
Figure 1: Androgen signaling pathway and its inhibition by LHRH-A and antagonists. FSH: follicle-stimulating hormone, LH: luteinizing hormone: LHRH: luteinizing hormone–releasing hormone

Click here to view


Goserelin, an LHRH-A, binds and stimulates LHRH receptors, causing an initial transient surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, followed by downregulation of LHRH receptors on continuous, nonpulsatile exposure. Thus, LH, FSH, and T secretions are suppressed; castrate T levels are achieved within 2 to 4 weeks of treatment.[15],[16],[17]

Degarelix, an LHRH antagonist, directly inhibits LHRH receptors, leading to a rapid decrease in LH, FSH, and T levels (<72 hours), without causing an initial T surge or intermittent microsurges; this prevents the risk of flare in advanced PCa.[15],[16],[17],[18]

The standard castrate level currently considered by regulatory bodies and, therefore, by clinical trials is 50 ng/dL, although a revision to <20 ng/dL is being proposed because studies evaluating surgical castration observed a mean T level of 15 ng/dL.[6]


 » Dosing and Administration Top


Goserelin is available as 3.6 mg and 10.8 mg implants (depot formulation) in prefilled syringes for subcutaneous (SC) use and administered as 1- and 3-monthly injections, respectively. The implant helps in a gradual release of medicine over the intended period with the following advantages[19],[20],[21],[22]:

  • The syringe has a protective needle sleeve to prevent needlestick injury.
  • It is a convenient single-step delivery system with minimal administration time.
  • As goserelin is not a liquid injection, there is no need to displace air bubbles.


As a monthly depot formulation, degarelix requires reconstitution and administration as deep SC injection every 28 days with an initial dose of 240 mg (two injections of 120 mg) and a maintenance dose of 80 mg.[23],[24] The drawbacks include more frequent dose administration (monthly) due to lack of long-acting depot formulation, a longer time for injection reconstitution, and inconvenience of two injections during treatment initiation. A 3-monthly depot formulation of degarelix with 240 mg initiation dose and 360 mg/480 mg maintenance dose has been studied but is not marketed or used in routine practice in India or globally (unlicensed).[25]


 » Pharmacokinetic Profile Top


Goserelin is extensively metabolized before excretion.

Degarelix undergoes hydrolysis in the hepatobiliary system.[23] In mild and moderate hepatic impairment, degarelix exposure decreases by 10% and 18%, respectively, which does not require dose adjustment, but caution is required in severe hepatic dysfunction due to lack of data. However, monthly T monitoring is required in patients with hepatic impairment until medical castration is achieved because of reduced degarelix exposure.[23] Data on patients with moderate or severe renal impairment are limited and, therefore, degarelix should be used with caution in patients with creatinine clearance <50 mL/min.[23]


 » Guideline Recommendations for Androgen Deprivation Therapy Top


Androgen deprivation therapy is recommended as a leading systemic therapy for locally advanced and metastatic PCa (mPCa).[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] [Supplementary Table 1] summarizes some of the guideline recommendations for ADT in various stages of PCa.[29],[30],[31],[32],[33],[34],[35]



The European Association of Urology–European Association of Urology Section of Urological Research–E uropean Society for Radiotherapy and Oncology–International Society of Geriatric Oncology (EAU-ESUR-ESTRO-SIOG) guidelines on PCa consider the LHRH-A class as the main form of ADT, comparable with bilateral orchiectomy (BO), and states that the definitive superiority of degarelix over LHRH-A remains to be proven.[27] Most guidelines recommend antiandrogen (AA) therapy with LHRH-A in patients with overt metastases or those at risk of flare symptoms and acknowledge that LHRH antagonists are not associated with initial flare and do not require combination with AA.


 » Efficacy Evaluation: Goserelin Versus Degarelix Top


Head-to-head comparison

The efficacy of ADT with LHRH-A including goserelin has been well established in advanced PCa. Degarelix is a more recent therapeutic option. [Table 1] summarizes the RCTs with a head-to-head comparison of goserelin (± AA) with degarelix and enlists the reported study limitations.[36],[37],[38],[39],[40],[41]
Table 1: Efficacy of goserelin versus degarelix: Direct head-to-head comparison

Click here to view


Most RCTs compared the 1-monthly formulation of both drugs; Ozono et al.[37] and Tombal et al.[41] compared the 3-monthly formulations of degarelix (unlicensed dose) versus goserelin. Major direct comparison trials were open label, included patients at different stages of PCa, and were designed to prove that degarelix is noninferior to goserelin. Patients on degarelix showed a more rapid decline (Day 3) in T and PSA levels than those on goserelin, but a comparable reduction in PSA level, T suppression to castrate levels, and prostate volume reduction were seen thereafter for the remaining treatment period. In addition, more goserelin-treated individuals achieved a reduction in median T levels (100% vs. 95%) to < 0.2 ng/mL.[37] Furthermore, in contrast with some studies suggesting partial suppression of FSH by goserelin,[42],[43] Ozono et al.[37] showed similar suppression with degarelix and goserelin treatment (95.32% vs. 87.79%). The studies had inherent limitations in study design, conduct, and statistical analysis, and hence warrant further research for more robust comparative evidence [Table 1].

Meta-analysis and pooled analyses

Several systematic reviews and meta-analyses (SRMAs) and pooled analyses compared goserelin with degarelix and LHRH-A class (goserelin and leuprolide) with degarelix on diverse efficacy outcomes [Table 2].[11],[42],[43],[44],[45],[46],[47],[48],[49] The efficacy outcomes were overall comparable for goserelin and degarelix, with both treatments maintaining comparable castrate T levels till Day 364; however, Iversen et al.[45] showed lower median T levels with LHRH-A on Day 364. In addition, after an initial rapid reduction in T and PSA, there was no significant difference in PSA, prostate volume reduction, or T suppression after Day 28 between the two groups. Sciarra et al.[11] confirmed that most RCTs compared biochemical profiles of the two treatments, with limited information on oncological endpoints. Cui et al.[49] showed a larger decline in the International Prostate Symptom Score with degarelix but was comparable with LHRH-A for improvement in the quality of life related to urinary symptoms. Pooled analysis results by Klotz et al.[46] showed significant OS and PFS benefit, while Iversen et al.[45] showed a significant PSA-PFS gain with degarelix compared with LHRH-A [Table 2]. Heterogeneity was reported for most SRMA outcomes and may indicate bias.[11],[44],[49] Furthermore, pooled analyses are considered inferior because pooling ignores the individual study characteristics and assumes there are no differences between individual trials. Iversen et al.[45] reported differences between the groups in terms of patient numbers and baseline characteristics as a limitation of their pooled analysis, whereas Klotz et al.[46] suggested that individual studies had survival as a safety endpoint rather than a primary endpoint. Several limitations inherent in these analyses indicate the need for more robust comparative studies.
Table 2: Efficacy of LHRH-A (goserelin and leuprolide) versus degarelix: Meta-analysis and pooled analysis

Click here to view



 » Combined androgen blockade therapy: Goserelin versus degarelix Top


Combined androgen blockade (CAB) with AA therapy plus castration (medical or surgical) was theorized to be more effective because castration alone cannot eliminate androgens in the prostate gland.[50] However, several RCTs have shown conflicting evidence in this regard.[51],[52],[53],[54] Crawford et al.[51] reported longer PFS (16.5 vs. 13.9 months; P = 0.039) and an increase in the median OS (35.6 vs. 28.3 months; P = 0.035) in patients with untreated PCa (Stage D2) administered leuprolide and AA (n = 303) compared with patients receiving leuprolide alone (n = 300). However, other studies assessing goserelin + AA or goserelin alone (n = 373), BO ± AA (n = 1,387), or placebo after BO (n = 457) did not indicate a significant difference in the response rate, PFS, or OS.[52],[53],[54]

A retrospective study reported no significant difference between goserelin + AA and degarelix in terms of PSA-PFS (median PFS: 21 vs. 16 months, respectively) or the univariate PFS analysis (hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.41–1.36, P = 0.34) in Japanese participants with advanced PCa.[55] Kashiwabara and Suda[56] compared CAB therapy with LHRH-A (goserelin or leuprolide) versus degarelix in people with/without bone mPCa. The study demonstrated a significant difference in OS (P = 0.03) and PSA-PFS (P = 0.04) in patients with mPCa for degarelix; however, a comparable PSA-PFS and OS was shown in patients without mPCa. In addition to the retrospective design, this study was limited in terms of small sample size and a high risk of bias because of the differences in the number of population at risk at all time points.


 » Adjuvant or neoadjuvant therapy: Goserelin versus degarelix Top


Although ADT has conventionally been used for palliation in patients with advanced PCa, evidence showing the benefit in combination with RT or surgery is growing. Neoadjuvant (NA) ADT before RT can reduce tumor bulk and potentiate RT action by apoptosis when given concomitantly.[39] In addition, NA ADT before radical prostatectomy (RP) can decrease the positive surgical margin rate, reduce tumor bulk (33.8%–54.9% >3 months of treatment), and downstage tumor grade.[57] There are no head-to-head comparison studies of goserelin and degarelix in the neoadjuvant or adjuvant (NA/A) setting. The individual studies of both molecules are presented in [Table 3]A and [Table 3]B.


Click here to view


Long-term efficacy of goserelin

The long-term efficacy of goserelin as NA/concurrent/adjuvant therapy to RT and as an alternative therapeutic option to BO is summarized in [Table 3]A.[58],[59],[60],[61],[62] The GETUG-AFU (Groupe d'Etude des Tumeurs Uro-Génitales) 16 trial reported a significantly higher (HR: 0.54, 95% CI: 0.43–0.68, P < 0.0001) 120 month PFS in the RT + goserelin group compared with RT alone in patients with rising PSA after RP over a 10-year follow-up.[58] Apart from their significant 10-year survival outcomes, the RTOG 85-31, RTOG 8610, and the EORTC (European Organisation for Research and Treatment of Cancer) trials showed clinical endpoint improvements at 5-year estimate time points with NA/A goserelin therapy.[59],[60],[61],[62] Additionally, several studies demonstrated lower PSA failure,[63],[64] improved time to progression,[65],[66],[67],[68],[69],[70],[71],[72] and better objective response rates compared with RT or BO.[66],[67],[68],[69],[70],[71],[72],[73],[74],[75] with NA/A goserelin in patients with localized, locally advanced, or mPCa.

The evidence evaluating degarelix as a NA/A therapy to RT or RP is limited [Table 3B.[76],[77] Moreover, the comparison between degarelix and goserelin outcomes in the NA/A setting may not be appropriate because of differences in endpoints evaluated (clinical vs. hormonal endpoints, respectively). The primary aim of Sayyid et al.[76] was to show the superiority of degarelix over LHRH-A + AA for intratumoral dihydrotestosterone (DHT) levels when administered as NA therapy to patients with PCa before RP. The NA treatment with degarelix was associated with significantly higher mean DHT levels than LHRH-A + AA (0.87 vs. 0.23, P < 0.01) despite comparable T levels, suggestive of increased risk of cellular proliferation, supported by increased tumor aggressiveness markers (Ki67 and AMACR). However, the significance of this result remained unexplained and needs further research. A randomized trial assessing the NA treatment with degarelix ± AA followed by RP for intermediate/high-risk PCa is underway.[78] As current evidence of NA use of LHRH analogs before surgery in PCa is limited, it is not used in current clinical practice.[79],[80],[81]

Long-term efficacy of degarelix

Freedland et al.[82] analyzed 17 controlled and uncontrolled trials evaluating the long-term efficacy of degarelix treatment in individuals with mPCa. The survival and PSA-PFS outcome at 36 months was 83% and 29%, respectively, for individuals with baseline PSA >50 to <200 ng/mL, and for those with PSA >200 ng/mL, survival and PSA-PFS outcome were 72% and 15%, respectively. Overall, 77% patients with mPCa and PSA >50 ng/mL were alive after a 36-month follow-up period with degarelix. However, this analysis involved uncontrolled data and awaits confirmation by a randomized approach. A real-world study from a German PCa patient registry evaluated the long-term efficacy of degarelix.[83] At 36 months, median survival was not reached; it demonstrated an OS (at 75th percentile value, where 25% patients reached an event) of 148.9 weeks and a median PSA-PFS of 141.4 weeks. Although degarelix caused a rapid and profound decline in T levels that continued to be <0.2 ng/mL at 24 months of follow-up (median level: 0.13 ng/mL), very few patients had data as T measurement was optional. Reduction in PSA level (≤4 ng/mL) was achieved in 65% patients at 12 months and in 71% patients by 24 months (lower than what was demonstrated in clinical trials). Patients who received prior hormonal therapy, followed by degarelix experienced a 58% higher mortality risk (HR: 1.58, 95% CI: 1.20–2.09). However, being a retrospective analysis from a registry with small patient numbers for some parameters and some patient groups, these results need to be interpreted with caution. A recent retrospective study analyzed survival in patients with PCa shifted from degarelix (changed group) to LHRH-A versus continuing on degarelix (continued group). Patient characteristics except for the duration of follow-up were comparable between the two groups. The reasons for the change in therapy were injection site induration and pain (n = 12), allergic reaction to degarelix (n = 1), and immediate decrease in PSA (n = 44). The 5-year OS (96.6% vs. 74.1%, P = 0.006) and cancer-specific survival (100% vs. 84.6%, P = 0.027) were significantly better in the changed group than in the continued group, respectively, indicating better outcomes with LHRH-A.[84] However, this was a small (108 patients) retrospective study, and the average time to castration-resistant PCa remained comparable between the two groups (changed: 43.3 months, continued: 35.2 months; P = 0.117). A literature review of degarelix studies revealed selection bias due to heterogeneous groups, low statistical quality, ad hoc analyses, and presentation of select favorable data and concluded that the overall evidence to support oncologic benefits was weak.[85]


 » Safety: Goserelin Versus Degarelix Top


Evidence suggests that both goserelin (3.6 and 10.8 mg) and degarelix have a similar acute and long-term safety profile.[17],[86],[87] The most common adverse events (AEs; hot flashes and weight increase) associated with goserelin are caused by a decrease in T levels, while injection site reactions (ISRs) form the most common AEs with degarelix.[17],[88] Intermittent androgen deprivation therapy may be an option to alleviate AEs in some patients with non-mPCa at modest risk of progression, if they had a good initial response to ADT (PSA <0.2 ng/mL).[10],[89],[90]

Injection site reactions

Klotz et al.[17] reported significantly higher ISR in the pooled degarelix groups (40%) versus the LHRH-A groups (<1%, P < 0.001). These reactions were mostly mild or moderate in severity and occurred chiefly after the first injection (33%) versus maintenance dose (4%) injections.

A head-to-head comparison of goserelin and degarelix reported that only degarelix treatment group had any ISR (pain: 14%, erythema: 4%, swelling: 4%).[40] In another head-to-head, Phase 2 study, patients received either 3-monthly degarelix or 3-monthly goserelin. The degarelix arm had a higher number of ISR than the goserelin arm (erythema: 81 [69.2%] vs. 1 [0.9%], induration: 77 [65.8%] vs. 1 [0.9%], pain: 88 [75.2%] vs. 7 [6.0%], pruritus: 17 [14.5%] vs. 1 [0.9%], swelling: 26 [22.2%] vs. 1 [0.9%], warmth: 7 [6.0%] vs. 0 [0.0%]).[37] Higher ISR in this study was attributed to higher maintenance dose and injection volume and more number of injection sites required for degarelix.

In an SRMA, incidences of ISR were significantly higher in patients receiving degarelix than in those receiving goserelin + AA (odds ratio [OR]: 92.47, 95% CI: 19.30–443.20, P < 0.00001).[54] Similar results for ISR were also reported by several other SRMAs.[11],[44],[47],[54]

Thus, individual studies, head-to-head comparative studies, and meta-analyses demonstrate a higher incidence of ISR with degarelix versus goserelin.

Metabolic safety

Although new-onset diabetes and raised lipid levels have been associated with LHRH-A, a recent study comparing LHRH-A (leuprolide) versus degarelix demonstrated no difference in body weight, abdominal circumference, lipid profiles, glycosylated hemoglobin, (HbA1c), or subcutaneous and visceral fat areas.[91],[92] This study concluded that lipid and glucose metabolism did not differ between the two arms. However, this was a single-center study in a limited number of patients (n = 100), with 6 months follow-up. Additionally, the EAU-ESUR-ESTRO-SIOG guidelines suggest decreased insulin sensitivity and an increase in lipids after LHRH-A initiation and recommend fasting plasma glucose, HbA1c, blood lipid levels, serum vitamin D, and calcium testing in addition to lifestyle modification (e.g., diet, exercise, smoking cessation, etc.).[27]

Cardiac safety

Metabolic abnormalities such as increased body weight, reduced insulin sensitivity, dyslipidemia, and activation of Th1 phenotype are proposed mechanisms by which ADT may increase the risk of CV events.[93] Degarelix is said to reduce FSH more than LHRH-A (90% vs. 50%) and, therefore, associated with lower CV risk, but the mechanism by which this difference is achieved is not yet understood.[93]

A retrospective analysis of the RTOG 85-31 study assessed the relationship between LHRH-A and CV mortality. With a median follow-up of 8.1 years, the authors found no differences in CV mortality between the treatment arms (8.4% vs. 11.4%, P = 0.17).[94] A subanalysis of the RTOG 92-02 trial evaluated the relationship between duration of LHRH-A therapy and CV mortality in 1,554 men with locally advanced PCa treated with 4 versus 24 months of adjuvant goserelin and RT. They concluded that a longer duration of adjuvant LHRH-A therapy did not appear to increase CV mortality (mortality rate = 4.8% vs. 5.9%, P = 0.16).[95] A recent SRMA including 8 RCTs (six involved goserelin) comparing short-term (6 months or less) and long-term ADT treatment (3 years to lifelong) groups versus control reported a similar finding for CV death (short-term, risk ratio [RR]: 1.00, 95% CI: 0.73–1.37; P = 0.99, long-term, RR: 0.91, 95% CI: 0.75–1.10, P = 0.34).[96]

However, a pooled analysis of three RCTs suggested that when patients with preexisting CVD received an LHRH antagonist, they had a significantly lower risk of subsequent CV events compared with those receiving an LHRH-A (HR: 0.44, 95% CI: 0.26–0.74; P = 0.002).[97] The authors, however, cautioned that this being a post hoc analysis was to be interpreted as purely hypothesis generating. Contrarily, a pooled analysis reported higher CV events (10.5 events/100 person-years) after 1 year of degarelix treatment initiation compared with baseline (5.3 events/100 person-years, P = 0.0013) in a subset of 498 men with baseline CVD.[98] A more recent analysis from a Scottish registry in a large cohort of men (n = 20,216) with newly diagnosed PCa reported an increase in CV events with both LHRH-A (adjusted HR: 1.3, 95% CI: 1.2–1.4) and degarelix (adjusted HR: 1.5, 95% CI: 1.2–1.9) compared with untreated patients.[99] A recent study conducted in Chinese patients randomized to receive either degarelix (240/80 mg, n = 142) or goserelin (3.6 mg, n = 141) for 12 months revealed serious cardiac AEs in both, degarelix (3.5%, n = 5) and goserelin (1.4%, n = 2) arms.[36]

ADT-induced T decline is associated with an increased QTc interval. Secondary analysis of a 12-month study in patients with PCa (n = 610) comparing degarelix (240/80 or 160 mg) versus leuprolide (7.5 mg) found no difference in pooled degarelix or leuprolide treatment groups for percentage mean change of QTcF (Day 3: 0.612 vs. 0.0132 or until trial end: 3.21 vs. 3.45).[100] In an SRMA, treatment-related severe CV side effects (prolonged QT, angina pectoris, atrial fibrillation, cardiac failure, and myocardial ischemia) were reported in 1.6% and 3.6% (OR: 0.55, 95% CI: 0.26–1.14; P > 0.1) patients in the degarelix (n = 952) and LHRH-A (n = 548) arms, respectively.[11] These comparable nonsignificant results suggest that the CV events associated with both agents result from hypogonadism rather than a direct drug effect.

Although conflicting evidence exists for a definite and quantifiable link between ADT and CV effects, a joint scientific statement published by the American Heart Association, American Cancer Society, and American Urological Association suggested a possible association between ADT and risk of CV events.[101] Subsequently, the U.S. Food and Drug Administration and Health Canada revised the LHRH-A label to include the possible risks of CVD and diabetes.[102] The European Medicines Agency also did a similar label change for both LHRH-A and LHRH antagonists.[103] Hence, patient counseling and education to effectively address modifiable CV risk factors should be incorporated in the management of patients with PCa and CV risk factors.


 » Clinical Implications Top


Goserelin has been effectively used for more than three decades, alone or in combination with other therapies in patients with localized, advanced, and mPCa. Similar to other agents of its class, goserelin is associated with an initial T flare, which is potentially detrimental in people with spinal metastases with signs or symptoms of spinal cord compression or ureteric obstruction. The NICE (National Institute for Health and Care Excellence) degarelix appraisal reports that in such cases, degarelix be provided as an initial treatment option as it is not associated with flare or symptom worsening, but specifies that LHRH antagonists should otherwise not be used as first-line ADT because of reasons such as the following: studies had insufficient duration to determine OS, inadequate justification of efficacy equivalence with LHRH-A, pooled data-based reduced cardiovascular AEs, or extrapolated data on PSA progression.[104] A rapid achievement of castrate T levels enables degarelix to be used in aggressive PCa at risk of progression, and where immediate symptom relief is required, especially for patients who decline BO. The early sharp drop in T levels, however, has not translated into improved survival.[105] In clinical practice, degarelix can be used to ensure rapid T suppression without a flare followed by a switch to a more tolerable and easy to administer LHRH-A.[84] Alternatively, goserelin can be combined with AA in the initial days of treatment to suppress the flare phenomenon.[51],[106],[107],[108],[109] Overall, the wider use of degarelix is restricted by the lack of a dose that lasts more than a month and the higher frequency and severity of ISR. Goserelin has fewer ISR than degarelix that may be due to the inbuilt implant device safety system. The drug administration procedure of goserelin (ready-to-use depot) is quick and hassle-free, whereas degarelix requires a vial system for reconstitution. Lower administration frequency, acquisition cost, and use of resources are additional advantages offered by goserelin, reducing the labor time for health care professionals, with resultant cost savings.[110],[111],[112]

The cardiac safety of goserelin and degarelix is comparable. However, caution and monitoring may be required in patients with preexisting CV/metabolic disorders, when on LHRH-A; in patients with symptoms of spinal cord compression, ureteric obstruction, or preexisting CVD, degarelix should be preferred.


 » Conclusion Top


Goserelin is a widely used LHRH-A, with a large evidence base, established short-term and long-term clinical efficacy, and survival benefits in a broad spectrum of PCa population in the NA/A setting. Goserelin also has a unique and safe implant delivery system ensuring minimal ISR. LHRH antagonists such as degarelix do offer the advantage of lower flare and rapid T suppression in patients with advanced PCa with spinal metastasis or ureteric obstruction but have not proven superiority over LHRH-A for clinical or oncological endpoints. Furthermore, degarelix use faces challenges such as high ISR and an inconvenient monthly formulation. Evidence regarding CV safety has so far shown comparable results for LHRH-A and degarelix and may need further evaluation.

Acknowledgments

The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Dr. Anita Bhat and Mr. Rahul Nikam, from Covance Scientific Services & Solutions Pvt. Ltd. in accordance with the GPP3 guidelines (http://www. ismpp.org/gpp3).

Financial support and sponsorship

AstraZeneca Pharma India Ltd.

Conflicts of interest

Ketaki Patil was an employee of AstraZeneca Pharma India Ltd.



 
 » References Top

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.  Back to cited text no. 1
    
2.
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 2018;199:1224-32.  Back to cited text no. 2
    
3.
American Cancer Society. Survival Rates for Prostate Cancer. Available from: https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/survival-rates.html. [Last accessed on 2020 Jan 02].  Back to cited text no. 3
    
4.
Cancer Stat Facts: Prostate Cancer. Available from: https://seer.cancer.gov/statfacts/html/prost.html. [Last accessed on 2020 Jan 02].  Back to cited text no. 4
    
5.
Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intentupdate 2013. Eur Urol 2014;65:124-37.  Back to cited text no. 5
    
6.
Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65:467-79.  Back to cited text no. 6
    
7.
Mohler JL, Antonarakis ES, Armstrong AJ, D'Amico AV, Davis BJ, Dorff T, et al. Prostate cancer, Version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2019;17:479-505.  Back to cited text no. 7
    
8.
Crawford ED, Phillips JM. Six-month gonadotropin releasing hormone (GnRH) agonist depots provide efficacy, safety, convenience, and comfort. Cancer Manag Res 2011;3:201-9.  Back to cited text no. 8
    
9.
Anderson J, Abrahamsson PA, Crawford D, Miller K, Tombal B. Management of advanced prostate cancer: Can we improve on androgen deprivation therapy? BJU Int 2008;101:1497-501.  Back to cited text no. 9
    
10.
Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur Urol 2017;71:618-29.  Back to cited text no. 10
    
11.
Sciarra A, Fasulo A, Ciardi A, Petrangeli E, Gentilucci A, Maggi M, et al. A meta-analysis and systematic review of randomized controlled trials with degarelix versus gonadotropin-releasing hormone agonists for advanced prostate cancer. Medicine (Baltimore) 2016;95:e3845.  Back to cited text no. 11
    
12.
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 2010;70:580-7.  Back to cited text no. 12
    
13.
Salciccia S, Gentilucci A, Cattarino S, Sciarra A. GNRH-agonist or antagonist in the treatment of prostate cancer: A comparison based on oncological results. Urologia 2016;83:173–8.  Back to cited text no. 13
    
14.
Lepor H, Shore ND. LHRH agonists for the treatment of prostate cancer: 2012. Rev Urol 2012;14:1-12.  Back to cited text no. 14
    
15.
Crawford ED, Heidenreich A, Lawrentschuk N, Tombal B, Pompeo AC, Mendoza-Valdes A, et al. Androgen-targeted therapy in men with prostate cancer: Evolving practice and future considerations. Prostate Cancer Prostatic Dis 2019;22:24-38.  Back to cited text no. 15
    
16.
Visapaa H. Switching from an LHRH antagonist to an LHRH agonist: A case report of 10 Finnish patients with advanced prostate cancer. Oncol Ther 2017;5:119-23.  Back to cited text no. 16
    
17.
Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, 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;102:1531-8.  Back to cited text no. 17
    
18.
Princivalle M, Broqua P, White R, Meyer J, Mayer G, Elliott L, et al. Rapid suppression of plasma testosterone levels and tumor growth in the dunning rat model treated with degarelix, a new gonadotropin-releasing hormone antagonist. J Pharmacol Exp Ther 2007;320:1113-8.  Back to cited text no. 18
    
19.
Goserelin acetate. Zoladex® 3.6 mg implant SafeSystem™. Consumer Medicine Information. 2017. p. 1-3. Available from: http://www.guildlink.com.au/gc/ws/astra/cmi.cfm?product=apczolad10517. [Last accessed on 2020 Jan 02].  Back to cited text no. 19
    
20.
Zoladex® (goserelin). Zoladex administration and product information. AstraZeneca. AstraZeneca Medicines. 2018 Available from: https://medicines.astrazeneca.co.uk/home/oncology/zoladex/administration.html. [Last accessed on 2020 Jan 02].  Back to cited text no. 20
    
21.
Zoladex® (goserelin acetate implant) 3.6 mg. Production Information. 2019 Available from: https://documents.tersera.com/zoladex-us/3.6mg_MagnumPI.pdf. [Last accessed on 2020 Jan 02].  Back to cited text no. 21
    
22.
Zoladex® (goserelin acetate implant) 10.8 mg. Production Information. 2019 Available from: https://documents.tersera.com/zoladex-us/10.8mg_MagnumPI.pdf. [Last accessed on 2020 Jan 02].  Back to cited text no. 22
    
23.
FIRMAGON® [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2020. Available from: http://www.ferringusa.com/wp-content/uploads/2020/02/Firmagon-USPI-25feb2020.pdf. [Last accessed on 2020 Jan 02].  Back to cited text no. 23
    
24.
FIRMAGON® (degarelix for injection) 120mg/80 mg. 2020 Available from: https://firmagon.com/hcp/dosing-and-administration/. [Las accessed on 2020 Jan 02].  Back to cited text no. 24
    
25.
Ozono S, Tsukamoto T, Naito S, Ohashi Y, Ueda T, Nishiyama T, et al. Efficacy and safety of a 3-month dosing regimen of degarelix in Japanese patients with prostate cancer: A phase II maintenance-dose-finding study. Jpn J Clin Oncol 2017;47:438-46.  Back to cited text no. 25
    
26.
US FDA. Zoladex prescription information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019726s059,020578s037lbl.pdf. [Last accessed on 2020 Jan 09].  Back to cited text no. 26
    
27.
EAU-ESTRO-ESUR -SIOG Guidelines on Prostate Cancer. Prostate Cancer-Update March 2018: Approved by European Association of Urology. p. 1-145.  Back to cited text no. 27
    
28.
Sanda MG, Chen RC, Crispino T, Freedland S, Nelson MD, Reston J, et al. Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Risk 2017;6:27.  Back to cited text no. 28
    
29.
Bhatia N, Santos M, Jones LW, Beckman JA, Penson DF, Morgans AK, et al. Cardiovascular effects of androgen deprivation therapy for the treatment of prostate cancer: ABCDE steps to reduce cardiovascular disease in patients with prostate cancer. Circulation 2016;133:537-41.  Back to cited text no. 29
    
30.
Connolly RM, Carducci MA, Antonarakis ES. Use of androgen deprivation therapy in prostate cancer: Indications and prevalence. Asian J Androl 2012;14:177-86.  Back to cited text no. 30
    
31.
Prostate Cancer-Version 4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) (2019). National Comprehensive Cancer Network®. p. 1-166.  Back to cited text no. 31
    
32.
Prostate cancer: Diagnosis and management (NG131) NICE guideline. National Institute for Health and Care Excellence. 2019. p. 1-51.  Back to cited text no. 32
    
33.
Prostate Cancer guideline- Summary of Changes 2019. European Association of Urology. Available from: https://uroweb.org/guideline/prostate-cancer/?type=summary-of-changes. [Last accessed on 2020 Jan 09].  Back to cited text no. 33
    
34.
Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline (2017). American Urological Association 2017. Available from: https://www.auanet.org/guidelines/prostate-cancer-clinically-localized-guideline. [Lastaccessed on 2020 Jan 09].  Back to cited text no. 34
    
35.
Parker C, Gillessen S, Heidenreich A, Horwich A; ESMO Guideline Committee. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Approved by the ESMO Guidelines Committee. Ann Oncol 2015;26(Suppl 5):v69–77.  Back to cited text no. 35
    
36.
Sun Y, Xie L, Xu T, Jakobsen JS, Han W, Sørensen PS, et al. Efficacy and safety of degarelix in patients with prostate cancer: Results from a phase III study in China. Asian J Urol 2020;7:301-8.  Back to cited text no. 36
    
37.
Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, et al. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: A phase III study. Cancer Sci 2018;109:1920-9.  Back to cited text no. 37
    
38.
Anderson J, Al-Ali G, Wirth M, Gual JB, Gomez Veiga F, Colli E, et al. Degarelix versus goserelin (+ antiandrogen flare protection) in the relief of lower urinary tract symptoms secondary to prostate cancer: Results from a phase IIIb study (NCT00831233). Urol Int 2013;90:321-8.  Back to cited text no. 38
    
39.
Mason M, Pijoan XM, Steidle C, Guerif S, Wiegel T, van der Meulen E, et al. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate-to high-risk prostate cancer: A randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide. Clin Oncol 2013;25:190-6.  Back to cited text no. 39
    
40.
Axcrona K, Aaltomaa S, da Silva CM, Ozen H, Damber JE, Tankó LB, et al. Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: Degarelix vs goserelin plus bicalutamide. BJU Int 2012;110:1721-8.  Back to cited text no. 40
    
41.
Tombal B, Tammela TL, Wolff JM, Payne H, Crawford ED, Shore N, et al. P109 Efficacy and safety of a 3-monthly depot formulation of degarelix compared with goserelin in prostate cancer. Eur Urol Suppl 2012;11:228.  Back to cited text no. 41
    
42.
Weckermann D, Harzmann R. Hormone therapy in prostate cancer: LHRH antagonists versus LHRH analogues. Eur Urol 2004;46:279-84.  Back to cited text no. 42
    
43.
Mahler C, Verhelst J, Chaban M, Denis L. Prolactin and pituitary gonadotropin values and responses to acute luteinizing hormone-releasing hormone (LHRH) challenge in patients having long-term treatment with a depot LHRH analogue. Cancer 1991;67:557-9.  Back to cited text no. 43
    
44.
Hosseini SA, Rajabi F, Sari AA, Ayati M, Heidari S, Ghamary F. Degarelix for the treatment of advanced prostate cancer compared with GnRH-Agonists: A systematic review and meta-analysis. Med J Islam Repub Iran 2016;30:317.  Back to cited text no. 44
    
45.
Iversen P, Damber JE, Malmberg A, Persson BE, Klotz L. Degarelix monotherapy compared with luteinizing hormone-releasing hormone (LHRH) agonists plus anti-androgen flare protection in advanced prostate cancer: An analysis of two randomized controlled trials. Ther Adv Urol 2016;8:75-82.  Back to cited text no. 45
    
46.
Klotz L, Miller K, Crawford ED, Shore N, Tombal B, Karup C, et al. Disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists. Eur Urol 2014;66:1101-8.  Back to cited text no. 46
    
47.
Fang C, Wu CL, Liu SS, Ge L, Bai JL. Efficacy, safety, and dose comparison of degarelix for the treatment of prostate cancer: A systematic review and meta-analysis. World J Metaanal 2016;4:69-76.  Back to cited text no. 47
    
48.
Mason M, Richaud P, Bosnyak Z, Malmberg A, Neijber A. Degarelix versus goserelin plus bicalutamide in the short-term relief of lower urinary tract symptoms in prostate cancer patients: Results of a pooled analysis. LUTS: Low Urin Tract Symptoms 2015;9:82-8.  Back to cited text no. 48
    
49.
Cui Y, Zong H, Yan H, Li N, Zhang Y. Degarelix versus goserelin plus bicalutamide therapy for lower urinary tract symptom relief, prostate volume reduction and quality of life improvement in men with prostate cancer: A systematic review and meta-analysis. Urol Int 2014;93:152-9.  Back to cited text no. 49
    
50.
Labrie F, Belanger A, Simard J, Labrie C, Dupont A. Combination therapy for prostate cancer. Endocrine and biologic basis of its choice as new standard first-line therapy. Cancer 1993;71:1059–67.  Back to cited text no. 50
    
51.
Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419–24.  Back to cited text no. 51
    
52.
Boccardo F, Pace M, Rubagotti A, Guarneri D, Decensi A, Oneto F, et al. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. The Italian Prostatic Cancer Project (PONCAP) Study Group. Eur J Cancer 1993;29A: 1088–93.  Back to cited text no. 52
    
53.
Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339:1036–42.  Back to cited text no. 53
    
54.
Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group. J Urol 1997;158:160–3.  Back to cited text no. 54
    
55.
Hashimoto T, Kanematsu A, Nojima M, Nagasawa S, Fukui K, Aihara K. Retrospective analysis of clinical efficacy of luteinizing hormone-releasing hormone antagonist as compared to agonists with combined anti-androgen blockade (CAB) in advanced prostate cancer. Clin Oncol 2018;3:1-54.  Back to cited text no. 55
    
56.
Kashiwabara T, Suda S. Usefulness of combined androgen blockade therapy with gonadotropin-releasing hormone antagonist for bone metastatic prostate cancer with pretreatment prostate-specific antigen level≥50 ng/mL. BMC Cancer 2018;18:1-11.  Back to cited text no. 56
    
57.
Labrie F, Cusan L, Gomez JL, Diamond P, Suburu R, Lemay M, et al. Downstaging by combination therapy with flutamide and an LHRH agonist before radical prostatectomy. Cancer Surv 1995;23:149-56.  Back to cited text no. 57
    
58.
Carrie C, Magné N, Provost PB, Sargos P, Latorzeff I, Lagrange JL, et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): A 112-month follow-up of a phase 3, randomised trial. Lancet Oncol 2019:20;1740-9.  Back to cited text no. 58
    
59.
Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, 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 2010;11:1066-73.  Back to cited text no. 59
    
60.
Roach M, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: Long-term results of RTOG 8610. J Clin Oncol 2008;26:585-91.  Back to cited text no. 60
    
61.
Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long-term results of phase III RTOG 85–31. Int J Radiat Oncol Biol Phys 2005;61:1285-90.  Back to cited text no. 61
    
62.
Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, et al. Maximal androgen blockade: Final analysis of EORTC phase III trial 30853. Eur Urol 1998;33:144-51.  Back to cited text no. 62
    
63.
Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: A phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497-504.  Back to cited text no. 63
    
64.
Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, Matthews J, 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 2011;12:451-9.  Back to cited text no. 64
    
65.
Lukkarinen O, Kontturi M. Comparison of a long-acting LHRH agonist and polyoestradiol phosphate in the treatment of advanced prostatic carcinoma. An open prospective, randomized multicentre study. Scand J Urol Nephrol 1994;28:171-8.  Back to cited text no. 65
    
66.
Iversen P. Zoladex plus Flutamide vs. orchidectomy for advanced prostatic cancer. Danish Prostatic Cancer Group (DAPROCA). Eur Urol 1990;18:41-4.  Back to cited text no. 66
    
67.
Iversen P, Rasmussen F, Klarskov P, Christensen IJ. Long-term results of Danish Prostatic Cancer Group trial 86. Goserelin acetate plus flutamide versus orchiectomy in advanced prostate cancer. Cancer 1993;72 (12 Suppl):3851-4.  Back to cited text no. 67
    
68.
Denis L, Smith PH, De Moura JC, Newling DW, Bono A, Keuppens F, et al. Orchidectomy vs. Zoladex plus flutamide in patients with metastatic prostate cancer. Eur Urol 1990;18:34-40.  Back to cited text no. 68
    
69.
Ryan PG, Peeling WB. UK trials of treatment for M1 prostatic cancer. The LH-RH analogue Zoladex vs. orchidectomy. Am J Clin Oncol 1988;11(Suppl 2):169-72.  Back to cited text no. 69
    
70.
Peeling WB. Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology 1989;33 (5 Suppl):45-52.  Back to cited text no. 70
    
71.
Parmar H, Edwards L, Phillips RH, Allen L, Lightman SL. Orchiectomy versus long-acting D-Trp-6-LHRH in advanced prostatic cancer. Br J Urol 1987;59:248-54.  Back to cited text no. 71
    
72.
Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 1991;67:502-8.  Back to cited text no. 72
    
73.
Emtage LA, George J, Boughton BJ, Trethowan C, Blackledge GR. Haemostatic changes during hormone manipulation in advanced prostate cancer: A comparison of DES 3 mg/day and goserelin 3.6 mg/month Eur J Cancer 1990;26:315-9.  Back to cited text no. 73
    
74.
Waymont B, Lynch TH, Dunn JA, Emtage LA, Arkell DG, Wallace DM, et al. Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol 1992;69:614-20.  Back to cited text no. 74
    
75.
Iversen P, Christensen MG, Friis E, Hornbøl P, Hvidt V, Iversen HG, et al. A phase III trial of Zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer 1990;66:1058-66.  Back to cited text no. 75
    
76.
Sayyid RK, Evans A, Hersey K, Maloni R, Hurtado-Coll A, Kulkarni G, et al. A phase II, randomized, open-label study of neoadjuvant degarelix versus LHRH agonist in prostate cancer patients prior to radical prostatectomy. Clin Cancer Res 2017;23:1974-80.  Back to cited text no. 76
    
77.
Montgomery RB, Russell KJ, Liao JJ, Ellis WJ, Cheng HH, Yu EY, et al. A phase II study of degarelix prior to radiation on prostatic tissue androgens. J Clin Oncol 2018;36:103. doi: 10.1200/JCO.2018.36.6_suppl. 103.  Back to cited text no. 77
    
78.
Tosco L, Laenen A, Gevaert T, Salmon I, Decaestecker C, Davicioni E, et al. Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebocontrolled trial. BMC Cancer 2018:18:354-63.  Back to cited text no. 78
    
79.
Hagiwara K, Koie T, Ohyama C, Yamamoto H, Imai A, Hatakeyama S, et al. Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: A single-center study. Int Urol Nephrol 2017;49:811-6.  Back to cited text no. 79
    
80.
Koie T, Mitsuzuka K, Yoneyama T, Narita S, Kawamura S, Kaiho Y, et al. Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: A propensity score-matched analysis. Int J Clin Oncol 2015;20:1018-25.  Back to cited text no. 80
    
81.
Koie T, Ohyama C, Yamamoto H, Hatakeyama S, Yoneyama T, Hashimoto Y, et al. Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: A prospective single-arm study. Prostate Cancer Prostatic Dis 2012;15:397-401.  Back to cited text no. 81
    
82.
Freedland SJ, Sørensen PS, Persson BE. Overall survival of patients with metastatic prostate cancer starting androgen deprivation therapy with degarelix, a gonadotropin-releasing hormone antagonist. J Clin Oncol 2018;36:198. doi: 10.1200/JCO.2018.36.6_suppl. 198.  Back to cited text no. 82
    
83.
Geiges G, Harms T, Rodemer G, Eckert R, König F, Eichenauer R, et al. Degarelix therapy for prostate cancer in a real-world setting: Experience from the German IQUO (Association for Uro-Oncological Quality Assurance) Firmagon® registry. BMC Urol 2015;15:3-9.  Back to cited text no. 83
    
84.
Asakawa J, Iguchi T, Tamada S, Yasuda S, Ninomiya N, Kato M, et al. A change from gonadotropin releasing hormone antagonist to gonadotropin releasing hormone agonist therapy does not affect the oncological outcomes in hormone sensitive prostate cancer. Basic Clin Androl 2018;28:9.  Back to cited text no. 84
    
85.
Secin FP. Questionable oncologic benefits of degarelix. Urol Oncol 2016;10:423-6.  Back to cited text no. 85
    
86.
Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, et al. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: Interim results of a randomized study in Japanese patients. Jpn J Clin Oncol 2004;34:20-8.  Back to cited text no. 86
    
87.
Sarosdy MF, Schellhammer PF, Soloway MS, Vogelzang NJ, Crawford ED, Presti J, et al. Endocrine effects, efficacy and tolerability of a 10.8-mg depot formulation of goserelin acetate administered every 13 weeks to patients with advanced prostate cancer. BJU Int 1999;83:801-6.  Back to cited text no. 87
    
88.
Kumar RJ, Barqawi A, Crawford ED. Adverse events associated with hormonal therapy for prostate cancer. Rev Urol 2005;7(Suppl 5):S37-43.  Back to cited text no. 88
    
89.
Salonen AJ, Taari K, Ala-Opas M, Sankila A, Viitanen J, Lundstedt S, et al. Comparison of intermittent and continuous androgen deprivation and quality of life between patients with locally advanced and patients with metastatic prostate cancer: A post hoc analysis of the randomized FinnProstate Study VII. Scand J Urol 2014;48:513-22.  Back to cited text no. 89
    
90.
Hussain M, Tangen CM, Berry DL, Higano CS, Crawford DE, Liu G, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;368:1314-25.  Back to cited text no. 90
    
91.
Jhan JH, Yeh HC, Chang YH, Guu SJ, Wu WJ, Chou YH, et al. New-onset diabetes after androgen-deprivation therapy for prostate cancer: A nationwide propensity score-matched four-year longitudinal cohort study. J Diabetes Complications 2018;32:688-92.  Back to cited text no. 91
    
92.
Sawazaki H, Araki D, Kitamura Y, Yagi K. Metabolic changes with degarelix vs leuprolide plus bicalutamide in patients with prostate cancer: A randomized clinical study. World J Urol 2020;38:1465-71.  Back to cited text no. 92
    
93.
Melloni C, Roe MT. Androgen deprivation therapy and cardiovascular disease. Urol Oncol 2020;38:45-52.  Back to cited text no. 93
    
94.
Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol 2009;27:92-9.  Back to cited text no. 94
    
95.
Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM. Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: Analysis of RTOG 92-02. Eur Urol 2008;54:816-24.  Back to cited text no. 95
    
96.
Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: A meta-analysis of randomized trials. JAMA 2011;306:2359-66.  Back to cited text no. 96
    
97.
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.  Back to cited text no. 97
    
98.
Smith MR, Klotz L, van der Meulen E, Colli E, Tankó LB. Gonadotropin releasing hormone blockers and cardiovascular disease risk: Analysis of prospective clinical trials of degarelix. J Urol 2011;186:1835-42.  Back to cited text no. 98
    
99.
Caldwell CR, O'Sullivan JM, Jain S, Harbinson MT, Cook MB, Hicks BM, et al. The risk of cardiovascular disease in prostate cancer patients receiving androgen deprivation therapies. Epidemiology 2020;31:432-40.  Back to cited text no. 99
    
100.
Smith MR, Klotz L, Persson BE, Olesen TK, Wilde AA. Cardiovascular safety of degarelix: Results from a 12-month, comparative, randomized, open label, parallel group phase III trial in patients with prostate cancer. J Urol 2010;184:2313-9.  Back to cited text no. 100
    
101.
Levine GN, D'Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, 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 2010;121:833-40.  Back to cited text no. 101
    
102.
U.S. Food & Drug Administration. FDA drug safety communication: Update to ongoing safety review of gnrh agonists and notification to manufacturers of gnrh agonists to add new safety information to labeling regarding increased risk of diabetes and certain cardiovascular diseases. 2010. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm229986.htm. [Last accessed on 2020 Jan 09].  Back to cited text no. 102
    
103.
European Medicines Agency. Firmagon: Summary of product characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/firmagon-epar-product-information_en.pdf. [Last accessed on 2020 Jan 14].  Back to cited text no. 103
    
104.
Uttley L, Whyte S, Gomersall T, Ren S, Wong R, Chambers D, et al. Degarelix for treating advanced hormone-dependent prostate cancer: An evidence review group perspective of a NICE single technology appraisal. Pharmacoeconomics 2017;35:717-26.  Back to cited text no. 104
    
105.
Degarelix for treating advanced hormone dependent prostate cancer- Final appraisal determination. National Institute for Health and Care Excellence. 2014. p. 1-17.  Back to cited text no. 105
    
106.
Clinton TN, Woldu SL, Raj GV. Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer. Expert Opin Pharmacother 2017;18:825-32.  Back to cited text no. 106
    
107.
Kuhn JM, Billebaud T, Navratil H, Moulonguet A, Fiet J, Grise P, et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med 1989;321:413-8.  Back to cited text no. 107
    
108.
Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol 1990;144:934-41.  Back to cited text no. 108
    
109.
Labrie F, Dupont A, Belanger A, Lachance R. Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. J Urol 1987;138:804-6.  Back to cited text no. 109
    
110.
Merseburger AS, Björk T, Whitehouse J, Meani D. Treatment costs for advanced prostate cancer using luteinizing hormone-releasing hormone agonists: A solid biodegradable leuprorelin implant versus other formulations. J Comp Eff Res 2015;4:447-53.  Back to cited text no. 110
    
111.
Erdkamp F, Boone N, Janknegt R, Zambon V. GnRH agonists and antagonists in prostate cancer. GaBI J 2014;3:133-42.  Back to cited text no. 111
    
112.
Wex J, Sidhu M, Odeyemi I, Abou-Setta AM, Retsa P, Tombal B. Leuprolide acetate 1-, 3-and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: Evidence review and economic evaluation. Clinicoecon Outcomes Res 2013;5:257-69.  Back to cited text no. 112
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer | Privacy Notice
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow