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  In this article
 »  Abstract
 » Introduction
 » Mechanism of Action
 »  GnRH-A: Clinical...
 » Safety
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

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  Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 59  |  Issue : 5  |  Page : 142-159
 

Gonadotropin-releasing hormone agonists in prostate cancer: A comparative review of efficacy and safety


1 Department of Medical Oncology, Apollo Hospital, Chennai, Tamil Nadu, India
2 Department of Medical Oncology, Command Hospital Airforce, Bangalore, Karnataka, India
3 Department of Uro Oncology, Apollo Hospital, Hyderabad, Telangana, India
4 Department of Uro-oncology, RKM Seva Pratishthan, Kolkata, West Bengal, India
5 Department of Radiation Oncology, HCG Hospital, Bangalore, Karnataka, India
6 Medical Oncology and Hematology, Safdarjung Hospital & VMMC, New Delhi, India
7 Medical Oncologist, Hospital Ruby Hall Clinic, New Cancer Building, Pune, Maharashtra, India
8 Medical Affairs, AstraZeneca Pharma India Ltd, Manyatha Tech Park, Rachenahalli, Bangalore, Karnataka, India, Bangalore

Date of Submission14-Jan-2021
Date of Decision17-Jan-2021
Date of Acceptance11-Apr-2021
Date of Web Publication24-Mar-2022

Correspondence Address:
Ketaki Patil
Medical Affairs, AstraZeneca Pharma India Ltd, Manyatha Tech Park, Rachenahalli, Bangalore, Karnataka
Bangalore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_65_21

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 » Abstract 


Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.


Keywords: Androgen deprivation therapy, gonadotropin-releasing hormone agonist, goserelin, leuprorelin, prostate cancer
Key Message Goserelin is the most investigated GnRH-A among all GnRH-A
All GnRH-A share similar survival benefits in locally advanced or metastatic prostate cancer
Goserelin is associated with better long-term testosterone and PSA suppression
Goserelin is the most convenient GnRH-A for administration because of its unique delivery system and and dose scheduling facilitating optimum physician contact


How to cite this article:
Raja T, Sud R, Addla S, Sarkar KK, Sridhar P S, Talreja V, Jain M, Patil K. Gonadotropin-releasing hormone agonists in prostate cancer: A comparative review of efficacy and safety. Indian J Cancer 2022;59, Suppl S1:142-59

How to cite this URL:
Raja T, Sud R, Addla S, Sarkar KK, Sridhar P S, Talreja V, Jain M, Patil K. Gonadotropin-releasing hormone agonists in prostate cancer: A comparative review of efficacy and safety. Indian J Cancer [serial online] 2022 [cited 2022 May 22];59, Suppl S1:142-59. Available from: https://www.indianjcancer.com/text.asp?2022/59/5/142/340530





 » Introduction Top


Prostate cancer (PCa) is the second most prevalent malignancy in men globally, accounting for 1,276,106 new cases and 3.8% of cancer deaths in men in 2018.[1],[2] The incidence of PCa varies widely across the world, ranging from 4.4 per 100,000 persons in India to 118.2 per 100,000 persons in the United States.[3] Androgen deprivation therapy (ADT) forms the backbone of PCa management.[4],[5] ADT acts by downregulating the circulating testosterone levels (T levels)[5],[6],[7],[8] and has shown to significantly shrink prostate volume, improve urodynamic parameters, and relieve lower urinary tract symptoms in patients with PCa.[9] Currently available modalities of ADT include surgical castration through bilateral orchiectomy and chemical castration using gonadotropin-releasing hormone agonist (s) (GnRH-A), GnRH antagonists, antiandrogen therapy, and estrogen therapy. GnRH-A have yielded better testosterone and consequently prostate-specific antigen (PSA) suppression leading to them being the most widely used agents as ADT.[5],[8],[10] GnRH-A have shown to produce and maintain reversible and similar castration effects as bilateral orchiectomy, offering a more readily acceptable alternative with a lower psychological impact in the treatment of advanced PCa.[11],[12]


 » Mechanism of Action Top


In a homeostatic state, the GnRH is released in a pulsatile manner by the hypothalamus and stimulates the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) through GnRH receptors, expressed on the membranes of the pituitary gonadotrophs. GnRH itself undergoes regulation by multiple neurotransmitters such as dopamine, serotonin, norepinephrine, and kisspeptin.[13] The LH stimulates receptors on Leydig cells in the testes to induce the production of T [Figure 1]. After binding, the receptor-GnRH complex, along with G protein αi activates phosphotyrosine phosphatase. This complex then dephosphorylates receptors of epidermal growth factor and stops the signaling pathways.[14] Thus, once optimal levels are reached, T exerts negative feedback and decreases the secretion of LH and subsequently GnRH.
Figure 1: Mechanism of Action of GnRH

Click here to view


When GnRH-A are administered to patients with PCa to achieve medical castration, they bind to and continuously stimulate the pituitary GnRH receptors. Chronic exposure to GnRH-A eventually results in desensitization of GnRH receptors making the pituitary gland refractory to further stimulation by GnRH, resulting in suppression of pituitary LH and FSH secretion and achieving castration level of T. A castrate T level is usually obtained in 2 to 4 weeks.[15],[16] The availability of long-acting synthetic GnRH-A in the 1980s revolutionized the hormonal treatment of PCa. Goserelin was the first approved GnRH-A in 1986 (UK: 1986, US: 1989), followed by leuprolide (1988), histrelin (2007), and triptorelin (2009).[17],[18],[19],[20],[21] Selection of GnRH-A for medical castration remains a challenge for the oncologists because of their similar efficacy profiles.

This narrative review discusses and compares the effectiveness of different GnRH-A in terms of T suppression, PSA suppression, response to treatment, and survival outcomes. The review also assesses the safety and ease of administration of various GnRH-A – goserelin, leuprorelin, triptorelin, buserelin – studied for early-stage, locally advanced, and metastatic PCa treatment in various scenarios; neoadjuvant/concomitant/adjuvant therapy, monotherapy or in combination with radiotherapy (RT), or as salvage therapy after RT. The findings of the review may be of value to oncologists to choose the appropriate GnRH-A agent for ADT in patients with PCa.

To synthesize existing evidences qualitatively, we performed a literature search using PubMed and citation lists of relevant publications. Subject heading and keywords used included combinations of terms such as “prostate cancer”; “androgen deprivation therapy”; “goserelin”; “leuprorelin”; “triptorelin”; “buserelin”; “histrelin”; “neo-adjuvant therapy”; “adjuvant therapy”; “orchiectomy”; “combined androgen blockade”; “T level”; “PSA,” “OS,” “DFS,” “PFS,” “MFS,” safety”; and “adverse events.”


 » GnRH-A: Clinical Outcomes Top


Historically, the castration level was defined as <50 ng/dL, but several studies have reported better survival outcomes with castration level <20 ng/mL.[22],[23],[24] However, the regulatory guidance still recommends T level <50 ng/dL to be the desired outcome for PCa management.[7]

In this review, we qualitatively compared various GnRH-A based on the suppression of the T levels, PSA levels, and survival outcomes across studies in various clinical settings [Table 1] and [Table 2].
Table 1: Effects of GnRH-A on Castration and PSA

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Table 2: Summary of survival outcomes with GnRH-A

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Effect on testosterone

Studies have demonstrated the suppression of T levels in patients administered varying dose formulations of each GnRH-A – goserelin, leuprorelin, and triptorelin (histrelin has only one sustained-release formulation available, no bioequivalence data are available for the two formulations of buserelin).[25],[26],[27],[28],[29] [Table 1][30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44] summarizes the clinical outcomes of GnRH-A with respect to the castration potential and PSA response.

Studies indicate that around 90% to 100% of individuals achieve T level ≤50 ng/dL in approximately 4 to 6 weeks,[33],[35],[37],[38],[39],[40],[41] with 100% patients on goserelin[33] and histrelin[41] achieving castration levels by 4 weeks. Shim et al.[42] in their review found comparable castration efficacy of goserelin, triptorelin, and leuprorelin (3-monthly formulations) with 98% to 100% individuals achieving T level ≤50 ng/dL and 90% to 93% achieving T level <20 ng/dL at 3 months of treatment, which was maintained even at 9 months (93%–100% patients with T level <20 ng/dL). The T level was maintained below the castration level over longer duration for >90% of the patients on triptorelin (11.25 mg; T level <20 ng/dL for 26 weeks), histrelin (50 mg; T level <50 ng/dL for 52 weeks), and triptorelin (22.5 mg; T level <20 ng/dL for 48 weeks) [Table 1].[38],[39],[41] Goserelin could maintain a more stringent castration level (T level <0.30 μg/L [<30 ng/dL]) for long term (13 and 26 weeks) in 100% and 98% patients, respectively.[33] Goserelin was also found to be effective in stringent T suppression in a review by Novara et al.,[45] with 96% patients attaining T <20 ng/dL compared with 87% to 92% of the patients achieving the same who were treated with the classical formulation of leuprorelin. In localized PCa, T suppression of ≤20 ng/dL was achieved in more than 85% patients on goserelin and triptorelin in around 6 weeks; more reduction in prostate volume was achieved with goserelin (36.8%) compared with triptorelin (30.7%) [Table 1].[43]

In a long-term (4.7 years) study by Wilke et al.[44] in locally advanced or recurrent PCa, goserelin (n = 78 [68.4%]) was more effective than leuprorelin (intramuscular formulation: n = 44 [56.4%]; suspension concentrate formulation: n = 62 [64.5%]) and triptorelin (n = 19 [63.3%]) in achieving T level <50 ng/dL, whereas buserelin could achieve this castration level in the maximum percentage (76.7%) but comparatively in a fewer number of patients (n = 33; P = 0.003). In locally advanced or metastatic PCa, treatment with goserelin resulted in a significant reduction in mean ± SD T levels from 14.1 ± 8.34 nmol/L (~406 ng/dL; baseline) to ≤2 nmol/L (≤57.68 ng/dL) at 4 weeks (P < 0.001), which was maintained at castration level till 12 weeks.[32]

In a multicenter randomized controlled trial (RCT), goserelin 3.6 mg every 28 days was as effective as orchiectomy in reaching castrate level for T to orchiectomy in 4 weeks. The authors thus concluded that goserelin could be an effective alternative to orchiectomy.[11] Recently, triptorelin (24-week depot injection) has also been observed to be effective in achieving a lower castration levels compared with orchiectomy in individuals with advanced PCa.[38]

A recent systematic review and meta-analysis (SRMA) evaluating head-to-head comparison studies of GnRH-A by Bolton and Lynch[46] reported comparable efficacy of all GnRH-A for suppression and maintenance of T level, which is consistent with our finding.

T escape, a single-serum T level rising above the castrate level at any point while under GnRH-A therapy, is a frequent phenomenon with GnRH-A treatment. Buserelin displayed comparatively more individuals with incidences of T escape (n = 16/72, 22.2%)[40] over goserelin (n = 7/59, 11.8%; n = 3/43, 6.9%)[33],[35] and leuprorelin (n = 8/151, 5.3%).[37]

Effect on prostate-specific antigen

[Table 1] shows that the PSA level of ≤4 ng/mL was achieved by 78.4% to 90% patients receiving GnRH-A[32],[33],[37],[39],[41]; the highest percentage of the patients achieved the desired PSA levels with goserelin[33] and the lowest with histrelin.[41] As an adjuvant treatment with RT in a salvage setting, goserelin successfully downregulated the rising PSA concentration within 3 months (interquartile range [IQR]: 2.3–7.6) compared with the population on RT alone (9.4 months, IQR: 7.3–17.5) [Table 1].[30] Denham et al.[31] further demonstrated the benefit of long-term neoadjuvant treatment with goserelin: A lower rate of PSA progression was observed with 6-month therapy (52.8%) compared with 3-month therapy (60.4%).

Triptorelin resulted in 64.2% PSA reduction by Week 4 and 96% by Week 26 [Table 1].[39] Crawford et al.[12] reported a decline in PSA of >90% or to the level of <4 ng/mL in 81% of patients on triptorelin, whereas it was 51% to 95% of patients on leuprorelin.

We observed the maximum benefit with goserelin in terms of a decrease in PSA. In 2018, Bolton and Lynch[46] also reported similar findings in their review.

Prognostic significance of T levels and PSA levels

T levels have been shown to predict survival in PCa. ADT (GnRH-A, GnRH antagonist, or antiandrogen) use in men with low baseline T levels was found to be associated with a significantly higher risk of overall mortality compared with men with normal and high T levels (P < 0.01).[47] Perachino et al.[48] in their retrospective analysis of 129 patients with newly diagnosed bone metastasis treated with goserelin reported that higher T levels at 6 months increased the risk of death by 1.33 times (95% confidence interval [CI] 1.053–1.687). T levels >1.7 nmol/L (>50 ng/dL) and >1.1 nmol/L (>30 ng/dL) are considered as predictors of progression to castration-resistant PCa.[49],[50] T surges, seen in 2% to 13% patients treated with GnRH-A, can lead to clinical deterioration and can adversely affect survival.[51],[52] Several studies have also shown PSA as a strong prognostic factor of PCa progression and survival. In the EORTC (European Organisation for Research and Treatment of Cancer) 30892 study, a PSA response defined as a decrease to ≤1 ng/mL and to between 1 and 10 ng/mL was associated with a hazard ratio (HR) of 0.30 and 0.61 for OS, respectively, compared with the nonresponders (PSA >10 ng/mL).[53] There is a significant correlation between PSA response and disease progression, time to progression, and OS.[54],[55],[56],[57] A recent study from the Surveillance, Epidemiology, and End Results (SEER) database found that PCa patients with a PSA level <4 ng/mL have more favorable tumor characteristics at diagnosis and receive more benefit from active treatment.[58] Thus, T and PSA levels may influence clinical outcomes in patients with PCa.

Clinical response and survival outcomes

[Table 2][30],[31],[35],[36],[40],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69] presents survival outcomes and clinical response of various GnRH-A in different treatment settings.

GnRH-A as a neo-adjuvant therapy

In neoadjuvant settings to RT, goserelin, because of its ability to downregulate the PSA in a short duration, was associated with higher 10-year OS (OS rate: 42.6%–86%) over RT alone (33.8%–85%); also, a higher proportion of individuals reported no biochemical/clinical progression (80% vs. 62%) as well as metastasis-free survival (MFS; 51%–75% vs. 30.2%–69%) compared with RT alone in population with T1–4N0–4 disease [Table 2].[30],[59],[60],[61],[65] Greater benefits were also observed with long-term treatment with neoadjuvant goserelin (6-month NADT [Neoadjuvant androgen deprivation therapy]) over its short-term treatment (3-month NADT; local progression rate: 13.3% vs. 15.7%; death rate: 11.4% vs. 18.9%).[31]

GnRH-A as an adjuvant therapy

Goserelin (10-year OS: 87%) and triptorelin (8-year OS: 84.6%) demonstrated OS rates of >80% in the adjuvant setting to radical prostatectomy (RP) [[Table 2], data on leuprorelin not available],[62],[63] whereas the 8-year disease-free survival (DFS) rate was 88.5% in patients with T3b-T4 with triptorelin[63] and 10-year DFS was 72% with goserelin in patients with cT1–3N0 disease[62] [Table 2].[63] Moreover, goserelin when used adjuvant to RT showed improved absolute survival rate (49% vs. 39%) and DFS rate (37% vs. 23%) over RT alone [[Table 2], data on leuprorelin and triptorelin not available].[68] Additionally, long-term treatment with goserelin (neoadjuvant, concurrent, and adjuvant treatment to RT) provided even better survival and clinical outcomes than the short-term therapy (only neoadjuvant and concurrent treatment to RT; P < 0.05) in localized/locally advanced PCa [Table 2].[66],[67]

GnRH-A versus orchiectomy

Compared with orchiectomy, triptorelin, goserelin, as well as buserelin [Table 2] demonstrated better clinical and survival outcomes in patients with T0–4NxM1 disease.[40],[64] However, these outcomes were not evaluated uniformly for each of these GnRH-A. Soloway et al.[11] documented better objective response with goserelin compared with orchiectomy [Table 1]. The clinical outcomes for comparison of GnRH-A with orchiectomy are not well documented in case of other commonly used GnRH-A, leuprorelin, and triptorelin.

GnRH-A as combined androgen blockade

Denis et al.[64] demonstrated that compared with bilateral orchiectomy, maximal androgen blockade with goserelin acetate (3.6 mg SC once every 4 weeks) and flutamide (250 mg 3 × daily) had significantly better results for the duration of survival (P = 0.04), time to death due to malignant disease (P = 0.008), time to first progression (P = 0.009), and PFS (P = 0.02) in patients with metastatic PCa.

A recent meta-analysis on combined androgen blockade (CAB) therapy for advanced PCa mostly included studies on GnRH-A (goserelin, leuprorelin, and buserelin) as CAB therapy and few on orchiectomy as CAB therapy. The results demonstrated significantly higher OS (HR 0.90; 95% CI 0.84–0.97; P = 0.003) and PFS (HR 0.89; 95% CI 0.80–1.00; P = 0.04) when these agents were used as CAB therapy compared with when they were used as monotherapy.[70] A systematic review by Bolton and Lynch[46] in localized/locally advanced/metastatic PCa patients demonstrated that the CAB therapy with goserelin and leuprorelin had comparable OS and PFS outcomes, whereas the survival rate for triptorelin CAB therapy was found to be higher than that of leuprorelin.

Some SRMAs either compared the GnRH-A head-to-head or evaluated them for their efficacy in different treatment settings. Tosco et al.[71] in their SRMA on localized/locally advanced PCa found that when used in neoadjuvant, concurrent, or adjuvant setting to RT, goserelin and leuprorelin showed greater survival rates over the comparators such as RT alone and salvage ADT treatment; goserelin was further associated with greater DFS or MFS. Similarly, another SRMA evaluated RT and androgen suppression therapy combinations for PCa with a high risk of recurrence/metastasis. Studies involving comparison of the goserelin + RT combination with RT alone showed that the combination resulted in 28% reduction of the risk of death (OS: HR 0.72, 95% CI 0.60–0.87, P = 0.0008) and 47% absolute reduction in disease recurrence (DFS: HR 0.53, 95% CI 0.43–0.65, P < 0.00001).[72]


 » Safety Top


The most common adverse events (AEs) associated with GnRH-A are hot flushes, fatigue, sexual dysfunction, decreased erections, general pain, testicular atrophy, joint disorder, osteoporosis, and metabolic alterations, which can be attributed to T suppression.[28],[33],[37],[39],[40],[73],[74],[75],[76] The frequency and severity of the AEs were comparable for all GnRH-A and were mild-to-moderate in nature.

Several observational studies have reported an association of GnRH-A with a high risk of cardiovascular disease (CVD),[77],[78],[79],[80],[81],[82],[83],[84] decrease in bone mineral density (BMD),[85],[86] and T surges,[9],[87],[88] which appear to be a class effect of these agents.

Cardiovascular risk

Increased risk of diabetes and cardiovascular (CV) events has been reported with GnRH-A. These risks are observed for all ADTs and may be attributed to the effect of ADTs on the CV system, such as the development and progression of atherosclerotic plaques and their effect on plaque growth, rupture, and thrombosis.[77] The CV risk is mainly driven by the modification of CV risk factors such as hyperinsulinemia, dyslipidemia, and changes in body composition with increased fat and decreased lean mass by ADT.[78] The association of these risks with GnRH-A has been documented; and although scarce, the evidence suggests that they may be comparable in all types of ADT.[79],[80] In an observational study (RTOG [Radiation Therapy Oncology Group] protocol 85-31) in the United States in 37,443 men diagnosed with local or regional PCa, treatment with GnRH-A was associated with significantly higher risks of incident diabetes (adjusted HR [aHR] 1.28, 95% CI 1.19–1.38), incident coronary heart disease (aHR 1.19, 95% CI 1.10–1.28), myocardial infarction (aHR 1.28, 95% CI 1.08–1.52), sudden cardiac death (aHR 1.35, 95% CI 1.18–1.54), and stroke (aHR 1.22, 95% CI 1.10–1.36) compared with non-GnRH-A treatment.[81] Moreover, in a Phase III study, leuprorelin and goserelin used as a monotherapy or in combination with bicalutamide were associated with an increase in the QT interval.[82] In a recent Phase III trial for patients with advanced PCa, the incidence of major adverse CV events was lower in the relugolix (GnRH-Aantagonist) group compared with leuprolide (GnRH-A) group (2.9% vs. 6.2%; HR 0.46; 95% CI, 0.24–0.88; P value not reported).[83] Similarly, in an Italian real-world study, the CV events were significantly lower in patients treated with GnRH antagonist compared with those treated with GnRH-A (HR 0.76, 95% CI 0.60–0.95, P = 0.018).[84] The ongoing PRONOUNCE (Patients With Advanced Prostate Cancer and Cardiovascular Disease) trial comparing major adverse CV outcomes in patients treated with GnRH-A (leuprolide) and antagonist (degarelix) may provide additional evidence regarding the difference in CV risk with both classes of drugs.[89]

Effect on bone mineral density

Long-term treatment with ADT is shown to be associated with pathologic or nonpathologic fracture compared with shorter ADT.[85],[86] In an analysis of prospective 12-month data from 65 men receiving initial and long-term GnRH-A treatment, the mean BMD of the total hip decreased by 1.9% at 12 months. The mean lean body mass decreased by 2.0%, and the mean fat mass increased by 6.6% (all P < 0.001).[86]

T flare-up

The GnRH-A mimics the physiological response of the upregulation of LH and FSH by binding to the GnRH receptors. This leads to a transitory increase in the circulating levels of testosterone, also known as a flare-up.[9] Flare-up is often manifested as an exacerbation of pain, an increase in uremia, and development of neurologic sequelae, and it may rarely be fatal.[87] In a recent Korean real-world study in 292 men with a mean follow-up of 12.8 months where leuprolide was frequently used GnRH-A, the breakthrough rate was 6.6%; dyslipidemia worsened after 4 weeks of hormone treatment and the mean BMD T-score was significantly lowered.[88] Flare-ups due to GnRH-A are usually managed by prescribing antiandrogens during the initial few days of therapy.[9]

All GnRH-A share a similar safety profile, and most AEs could be attributed to the class effect. The risk assessment for comorbidities and possible AEs is essential when considering GnRH-A for the management of PCa.

Dosing and acceptability of GnRH-A

GnRH-A are available in a wide range of sustained-release formulations with the dosing intervals of 1, 2, 3, 4, 6, and 12 months to provide stable effect for a long duration with reduced number of injections and better treatment adherence [Table 3].[90],[91],[92],[93],[94],[95],[96],[97]
Table 3: Summary of Formulations Parameters of GnRH-A

Click here to view


The formulations and methods of drug administration substantially affect clinical decisions and practice, and patient satisfaction. The subcutaneous (SC) or intramuscular (IM) administration procedure is similar for all GnRH-A, except for histrelin, which requires anesthesia and incision. [Table 3] describes the formulations and doses of all GnRH-A. Although buserelin is available as an intranasal formulation, the SC administration of 2-monthly and 3-monthly formulations is widely used.

Because of their ready-to-use and single-step administration process, formulations of goserelin, leuprorelin, and buserelin significantly reduce the administration time and labor for health care professionals, posing an advantage over other formulations that require reconstitution.[98],[99] A unique device characteristic seen with goserelin formulation is the SafeSystem® syringe, which has a needle sleeve that locks in place following the administration of the implant. This mechanism provides a safer alternative for the administration of the drug by preventing needlestick injuries.[90],[91]

Histrelin has a 12-month implant formulation;[97] leuprorelin and triptorelin have formulations lasting maximum of up to 6 months,[92],[93],[94],[95] whereas goserelin and buserelin have formulations that last up to 3 months.[90],[91],[96] Although lower dosing frequency offers convenience and adherence to the treatment, studies have considered 3-monthly formulation as an optimum dosing interval because of the opportunity to have face-to-face connection between the health care providers and the patient, and their caregivers contributing positively to the patient's coping strategies and quality of life.[100],[101]

In a recent review, leuprorelin and goserelin proved to be better with respect to overall clinical parameters such as efficacy, safety, tolerability, and ease of administration.[102]


 » Conclusion Top


All GnRH-A appear to be comparable in terms of efficacy, safety, and convenience of use. As demonstrated in the studies, GnRH-A as a single agent can achieve T suppression (T level ≤50 ng/dL) in >90% patients in approximately 4 weeks and can maintain this level throughout the treatment duration. Evidence indicating the efficacy and safety of goserelin has been the most investigated GnRH-A in all settings. It has demonstrated efficacy as an alternative to surgical castration by showing comparable survival benefits. As an adjuvant treatment to RT, and RP as a neoadjuvant treatment prior to RT, goserelin has shown improved DFS and OS. Comparatively long-term PSA suppression has also been observed with goserelin. Goserelin also has an edge over other GnRH-A because of ease of administration and lesser chances of needlestick injury. The safety profile of all GnRH-A is comparable, and the risks may be attributable to class effect. The incidences of T escape are lower with goserelin and leuprolide than with buserelin. Despite extensive research data on individual products and three decades of effective global clinical use, there is no novel data to allow conclusive comparisons, and hence the choice of agents remains a challenge. Patients' age, stage of the disease, assessment of CV risk factors, and the need for symptomatic relief should be considered before choosing an appropriate GnRH-A as ADT for the effective management of PCa.

Acknowledgments

The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Neelam Joglekar 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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