|Year : 2022 | Volume
| 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)
Ankur Bahl1, Senthil Rajappa2, Sudhir Rawal3, Ganesh Bakshi4, Vedang Murthy5, Ketaki Patil6
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 Submission||30-Dec-2020|
|Date of Decision||04-Apr-2021|
|Date of Acceptance||22-Apr-2021|
|Date of Web Publication||24-Mar-2022|
Medical Affairs, AstraZeneca Pharma India Ltd, Manyatha Tech Park, Rachenahalli, Bangalore
Source of Support: None, Conflict of Interest: None
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|| |
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. Global incidences of PCa have increased 3.7-fold from 1990 to 2015. In general, PCa has an excellent prognosis, with 100% 5-year survival rate in localized PCa. However, the prognosis is worse in African American men, those with advanced-stage cancer, and those aged between 75 and 84 years.
Depending on the stage of PCa, treatment options include surgery, radiotherapy (RT), and medical therapy. Androgen deprivation therapy (ADT) by medical or surgical castration remains the standard mode of treatment in advanced PCa for the past five decades., 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.,,, Goserelin and leuprorelin are the most commonly used LHRH-A in patients with nonmetastatic disease or recurrent PCa after attempted curative treatment. Degarelix, a third-generation LHRH antagonist is an alternate ADT option in recent times.,
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., 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. 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|| |
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.,
|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|
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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.,,
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.,,,
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.
| » Dosing and Administration|| |
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,,,:
- 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., 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).
| » Pharmacokinetic Profile|| |
Goserelin is extensively metabolized before excretion.
Degarelix undergoes hydrolysis in the hepatobiliary system. 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. 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.
| » Guideline Recommendations for Androgen Deprivation Therapy|| |
Androgen deprivation therapy is recommended as a leading systemic therapy for locally advanced and metastatic PCa (mPCa).,,,,,,,,, [Supplementary Table 1] summarizes some of the guideline recommendations for ADT in various stages of PCa.,,,,,,
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. 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|| |
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.,,,,,
|Table 1: Efficacy of goserelin versus degarelix: Direct head-to-head comparison|
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Most RCTs compared the 1-monthly formulation of both drugs; Ozono et al. and Tombal et al. 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. Furthermore, in contrast with some studies suggesting partial suppression of FSH by goserelin,, Ozono et al. 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].,,,,,,,, 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. 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. confirmed that most RCTs compared biochemical profiles of the two treatments, with limited information on oncological endpoints. Cui et al. 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. showed significant OS and PFS benefit, while Iversen et al. 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.,, 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. reported differences between the groups in terms of patient numbers and baseline characteristics as a limitation of their pooled analysis, whereas Klotz et al. 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|
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| » Combined androgen blockade therapy: Goserelin versus degarelix|| |
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. However, several RCTs have shown conflicting evidence in this regard.,,, Crawford et al. 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.,,
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. Kashiwabara and Suda 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|| |
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. 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. 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.
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.,,,, 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. 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.,,, Additionally, several studies demonstrated lower PSA failure,, improved time to progression,,,,,,,, and better objective response rates compared with RT or BO.,,,,,,,,, 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., 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. 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. As current evidence of NA use of LHRH analogs before surgery in PCa is limited, it is not used in current clinical practice.,,
Long-term efficacy of degarelix
Freedland et al. 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. 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. 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.
| » Safety: Goserelin Versus Degarelix|| |
Evidence suggests that both goserelin (3.6 and 10.8 mg) and degarelix have a similar acute and long-term safety profile.,, 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., 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).,,
Injection site reactions
Klotz et al. 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%). 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%]). 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). Similar results for ISR were also reported by several other SRMAs.,,,
Thus, individual studies, head-to-head comparative studies, and meta-analyses demonstrate a higher incidence of ISR with degarelix versus goserelin.
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., 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.).
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. 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.
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). 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). 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).
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). 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. 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. 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.
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). 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. 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. 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. The European Medicines Agency also did a similar label change for both LHRH-A and LHRH antagonists. 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|| |
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. 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. 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. Alternatively, goserelin can be combined with AA in the initial days of treatment to suppress the flare phenomenon.,,,, 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.,,
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|| |
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.
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.
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[Table 1], [Table 2], [Table 3]