The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer

PURPOSE: We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy. MATERIALS AND METHODS: In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed. RESULTS: No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated. CONCLUSIONS: Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.     

Gonadotropin‐releasing hormone: An update review of the antagonists versus agonists

Gonadotropin‐releasing hormone agonists and antagonists provide androgen‐deprivation therapy for prostate cancer. Unlike agonists, gonadotropin‐releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin‐releasing hormone receptors. There are two licensed gonadotropin‐releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well‐established, first‐line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate‐specific antigen, no risk for testosterone surge or clinical flare, and improved prostate‐specific antigen progression‐free survival, suggesting a delay in castration resistance. Other than minor injection‐site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first‐line androgen‐deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration‐resistant disease. In view of these clinical benefits and the lack of need for concomitant anti‐androgen treatment, gonadotropin‐releasing hormone antagonists might replace gonadotropin‐releasing hormone agonists as first‐line androgen‐deprivation therapy in the future.     

Management of advanced prostate cancer: can we improve on androgen deprivation therapy?

Gonadotrophin‐releasing hormone (GnRH) agonists are currently the mainstay in the management of advanced prostate cancer. Used either as monotherapy or combined with antiandrogens, GnRH agonists suppress serum testosterone levels and thus slow the growth of the tumour cells that depend on testosterone for growth. GnRH agonists have largely replaced orchidectomy in the management of advanced prostate cancer, because patients are reluctant to undergo surgical castration. However, can we do better in androgen‐deprivation therapy? There is some evidence to suggest that GnRH agonists do not achieve the level of testosterone suppression attained with orchidectomy, or as rapidly, factors which could be expected to affect overall survival. Together, these observations highlight the need to develop newer agents that can achieve rapid, profound and sustained testosterone suppression, equivalent to that with orchidectomy. Preliminary data for the GnRH blocker, degarelix, suggest that this new agent might overcome the shortcomings associated with GnRH agonists. Further clinical data are therefore awaited with much interest.     

New treatment paradigm for prostate cancer: abarelix initiation therapy for immediate testosterone suppression followed by a luteinizing hormone-releasing hormone agonist

Study Type – Therapy (prospective cohort) Level of Evidence 2a What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues.

OBJECTIVE

• ? To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin‐releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone‐releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer.

PATIENTS AND METHODS

• ? A multicentre, open‐label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate‐specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment.
• ? All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks
• ? The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy.
• ? PSA, LH and follicle‐stimulating hormone (FSH) levels were measured and adverse events were monitored.

RESULTS

• ? A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%).
• ? At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85–92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114–12) it was 93.3%.
• ? A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd ]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86.
• ? Mean (sd ) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase.
• ? Treatment‐related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases.

CONCLUSIONS

• ? Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated.
• ? This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen.
• ? Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.

     

地加瑞克和GnRH激动剂用于治疗进展型前列腺癌疗效及安全性的对比:Meta分析

目的 用Meta分析评价地加瑞克与GnRH激动剂治疗进展型前列腺癌的疗效和安全性.方法 通过计算机检索PubMed、Cochrane Library、Embase、中国生物医学文献服务系统、中国知网、VIP及万方数据库,对所纳入的研究运用Revman 5.3 软件进行Meta分析.结果 共纳入9篇文献,共3 818例患者,其中行地加瑞克治疗的患者2 625例,行GnRH激动剂治疗的患者1 193例.Meta分析结果显示,地加瑞克治疗与GnRH激动剂治疗两者在前列腺体积、国际前列腺症状评分、生活质量评分、前列腺特异性抗原、睾酮方面差异无统计学意义(P≥0.05);地加瑞克治疗的不良反应发生率明显比GnRH激动剂小(P<0.05).结论 地加瑞克在治疗进展型前列腺癌的疗效上与GnRH激动剂治疗差异无统计学意义,但在药物安全性上,地加瑞克比GnRH激动剂更具有优势.     

Gonadotropin-releasing hormone antagonist: A real advantage?

Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist that is approved for the treatment of prostate cancer. GnRH antagonists bind directly to and block GnRH receptors, without causing the initial testosterone surge associated with GnRH agonists. A pivotal phase III study indicated that degarelix induced significantly faster reduction of testosterone and prostate-specific antigen level than GnRH agonist does. In addition, its 5-year extension trial suggested that patients could be safely switched from GnRH agonist to degarelix treatment with sustained efficacy, as measured by biochemical markers. Possible benefits of GnRH antagonists over agonists were suggested especially in patients with advanced prostate cancer with metastatic and symptomatic disease. Moreover, the recent reports including pooled data analyses on degarelix suggest improved disease control, quality of life, and lower urinary tract symptoms and decreased risk of cardiovascular diseases when compared with GnRH agonists. However, interpretation of these reports should be conducted cautiously because of the potential biases involved. This article critically reviews the results of the clinical trials and subsequent analyses and evaluates the points and counterpoints of the conclusions.     

The efficacy and safety of degarelix: a 12‐month,comparative, randomized,open‐label,parallel‐group phase III study in patients with prostate cancer

OBJECTIVE

To evaluate the efficacy and safety of degarelix, a new gonadotrophin‐releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1‐year phase III trial involving patients with prostate cancer.

PATIENTS AND METHODS

In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate‐specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen‐deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator’s assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12‐month study. Both the intent‐to‐treat (ITT) and per protocol populations were analysed.

RESULTS

The primary endpoint of the trial was suppression of testosterone to ≤0.5 ng/mL at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were ≤0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (P < 0.001). The hormonal side‐effect profiles of the three treatment groups were similar to previously reported effects for androgen‐deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injection‐site reactions than with the i.m. leuprolide injection (40% vs <1%; P < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3% vs 9%. P < 0.01, respectively), arthralgia (4% vs 9%, P < 0.05, respectively) and chills (4% vs 0%, P < 0.01, respectively). There were no systemic allergic reactions.

CONCLUSIONS

Degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1‐year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for antiandrogen supplements to prevent the possibility of clinical ‘flare’.     

Testosterone Surge: Rationale for Gonadotropin-Releasing Hormone Blockers?

Gonadotropin-releasing hormone (GnRH) agonists currently form the mainstay of management of advanced prostate cancer. They effectively suppress serum testosterone levels, which in turn inhibits tumor growth. However, the initial response to GnRH agonists is a transient increase in the serum testosterone levels. Known as a testosterone surge, this can lead to a worsening of symptoms and can adversely affect survival. Therefore, much interest exists in the development of a new class of drugs-GnRH antagonists-which produce immediate suppression of luteinizing hormone and testosterone without a testosterone surge. The most promising GnRH antagonist to date is degarelix.     

Luteinizing hormone‐releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors?

Luteinizing hormone‐releasing hormone (LHRH) agonists and antagonists are commonly used androgen deprivation therapies prescribed for patients with advanced prostate cancer (PCa). Both types of agent target the receptor for LHRH but differ in their mode of action: agonists, via pituitary LRHR receptors (LHRH‐Rs), cause an initial surge in luteinizing hormone (LH), follicle‐stimulating hormone (FSH) and, subsequently, testosterone. Continued overstimulation of LHRH‐R down‐regulates the production of LH and leads to castrate levels of testosterone. LHRH antagonists, however, block LHRH‐R signalling causing a rapid and sustained inhibition of testosterone, LH and FSH. The discovery and validation of the presence of functional LHRH‐R in the prostate has led to much work investigating the role of LHRH signalling in the normal prostate as well as in the treatment of PCa with LHRH agonists and antagonists. In this review we discuss the expression and function of LHRH‐R, as well as LH/human chorionic gonadotropin receptors and FSH receptors and relate this to the differential clinical responses to agonists and antagonists used in the hormonal manipulation of PCa.     

A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer

PURPOSE: We compared the endocrinological and biochemical efficacy of abarelix depot, a gonadotropin-releasing hormone antagonist, with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal antiandrogen. MATERIALS AND METHODS: A total of 255 patients were randomized to receive open label 100 mg. abarelix depot or 7.5 mg. leuprolide acetate intramuscularly injection on days 1, 29, 57, 85, 113 and 141 for 24 weeks. Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg. bicalutamide daily. Patients could continue treatment with study drug for an additional 28 weeks. The efficacy end points were the comparative rates of avoidance of testosterone surge (greater than 10% increase) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels (50 ng./dl. or less) on day 8. Patients were monitored for adverse events and laboratory abnormalities. RESULTS: Abarelix was more effective in avoidance of testosterone surge (p <0.001) and the rapidity of reduction of testosterone to castrate levels on day 8 (p <0.001) than combination therapy. No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone. No unusual or unexpected adverse events were reported. CONCLUSIONS: Abarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone.     

Cost-effectiveness analysis of degarelix for advanced hormone-dependent prostate cancer

Study Type – Therapy (cost‐effectiveness analysis) Level of Evidence 2b What's known on the subject? and What does the study add? The European Medicines Evaluation Agency recognised that the principal advantage of degarelix is the avoidance of the transient rise in testosterone. This paper compares the cost‐effectiveness of degarelix with the most common treatment in the UK (LHRHa plus short‐term anti‐androgen) for the management of prostate cancer, focusing on the costs and clinical consequences that might be associated by the avoidance of the transient rise in testosterone. Our analysis suggests that, at the current UK list price, degarelix would not represent good value for money for the NHS.

OBJECTIVE

• ? To evaluate the cost‐effectiveness of degarelix vs luteinizing hormone‐releasing hormone analogue (triptorelin) plus short‐term antiandrogen treatment for advanced prostate cancer.

METHODS

• ? We developed a decision analytic model based on a clinical trial and literature review. The two interventions evaluated were: (i) monthly injection of degarelix and (ii) 3‐monthly triptorelin therapy plus short‐term flutamide, cyproterone or bicalutamide treatment.
• ? The model consisted of a decision tree monitoring a hypothetical cohort of patients aged 70 years from the start of hormonal treatment to the end of the first month, and a Markov model monitoring patients from the end of month 1 for a time horizon of 10 years (i.e. when 96% of patients are assumed to have died).
• ? The base‐case analysis assumed patients present with asymptomatic metastatic prostate cancer. Costs and outcomes were collected over the model time horizon. Outcome measures were quality‐adjusted life years (QALYs), lifetime costs and incremental cost‐effectiveness ratios.
• ? Sensitivity analyses (one‐way and multi‐way) and probabilistic sensitivity analyses were conducted to explore the uncertainties around the assumptions.

RESULTS

• ? In the base‐case analysis, the incremental cost‐effectiveness ratio (ICER) for degarelix vs triptorelin plus antiandrogen was £59 000 per QALY gained.
• ? The model was most sensitive to the rate of significant adverse events in the triptorelin plus antiandrogen group. The model was also sensitive to the assumed survival of patients with metastatic prostate cancer and the price of degarelix.
• ? The results of the probabilistic sensitivity analyses suggested that there was a low probability (9.6%) of degarelix being the most cost‐effective treatment option when a willingness‐to‐pay threshold of £30 000 per QALY gained is assumed.

CONCLUSION

• ? Degarelix is unlikely to be cost‐effective compared to triptorelin plus short‐term antiandrogen in the management of advanced prostate cancer with respect to the usual thresholds of cost‐effectiveness used in the UK: £20 000–30 000 per QALY gained (used by the National Institute for Health and Clinical Excellence).

     

An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer

PURPOSE: The administration of gonadotropin hormone-releasing hormone agonists is well established for treating metastatic prostate cancer. In an ongoing study we evaluated the effect of a long acting implant that releases the gonadotropin hormone-releasing hormone agonist histrelin ([ImBzl]D-His6,Pro9-Net) in 15 patients with disseminated prostate cancer. MATERIALS AND METHODS: The 2.6 cm. implant releasing 60 microg. histrelin daily is inserted subcutaneously into the upper arm using local anesthesia. Of the patients 8 received 1 and the remainder received 2 implants. Treatment with the antiandrogen flutamide or cyproterone acetate began 2 weeks before implant insertion and continued for up to 12 weeks. Testosterone, luteinizing hormone (LH) and prostate specific antigen were determined monthly, and a metastatic evaluation was performed every 6 months. RESULTS: LH and testosterone increased after flutamide administration and decreased after implant insertion. By day 28 LH and testosterone were completely suppressed. LH and testosterone decreased immediately after cyproterone acetate administration. Prostate specific antigen began to decrease during antiandrogen therapy and decreased further after implant insertion. One patient requested implant removal after 1 year for personal reasons and 1 died of an unrelated cause 18 months after insertion. Escape was demonstrated in 4 cases at 5, 10, 12 and 19 months, although LH and testosterone remained suppressed. Duration of treatment in the remaining 9 patients was between 21 and 30 months. LH and testosterone remained completely suppressed and prostate specific antigen levels were in the normal range. The clinical and biochemical response was identical in those who received 1 or 2 implants. At 12 months 8 patients were challenged at intermittent intervals for up to 24 months with a bolus of 100 microg. gonadotropin hormone-releasing hormone followed by 2 weeks of flutamide. The response was compared with that in untreated controls recently diagnosed with prostate cancer. Unlike controls there was complete LH suppression in the 8 challenged patients. CONCLUSIONS: A histrelin implant suppresses LH and testosterone in prostate cancer for up to 30 months. This finding represents a significant improvement over existing preparations, which must be administered at 1 to 3-month intervals.     

Hormone therapy in prostate cancer: LHRH antagonists versus LHRH analogues

GnRH agonists have a proven and well-established role in the management of prostate cancer. Further adaptations of the amino-acid sequence led to the development of antagonists with potential therapeutic uses, including a possible role in prostate cancer patients. Treatment of prostate cancer with GnRH agonists results in an initial flare of symptoms that may be prevented by co-administration of a steroidal or non-steroidal antiandrogen. However, this can be associated with additional adverse effects. Clinical studies have shown that GnRH antagonists produce a rapid decline in testosterone but without the disease flare. However these short-term effects have yet to be proven to lead to long-term survival benefits. There have been some reports that antagonists may be associated with adverse effects due to histamine release leading to severe allergic reactions. GnRH agonists are currently available in a range of depot formulations, allowing treatment to be tailored to the patient's needs. At present, the antagonists are only available as on-month depot formulations, which may limit their clinical use. Abarelix should be given intramuscularly. It is the first GnRH antagonist which is approved by the FDA for patients with advanced prostate cancer who should be treated under a risk management program. In Europe, abarelix has not been registered yet.     

The hypothalamic–pituitary–gonadal axis and prostate cancer: implications for androgen deprivation therapy

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) may play important roles in prostate cancer (PCa) progression. Specifically, LH expression in PCa tissues has been associated with metastatic disease with a poor prognosis, while FSH has been shown to stimulate prostate cell growth in hormone-refractory PCa cell lines. Gonadotropin-realizing hormone (GnRH) analogues are common agents used for achieving androgen deprivation in the treatment for PCa. GnRH analogues include LH-releasing hormone (LHRH) agonists and GnRH antagonists, both of which exhibit distinct mechanisms of action that may be crucial in terms of their overall clinical efficacy. LHRH agonists are typically used as the primary therapy for most patients and function via a negative-feedback mechanism. This mechanism involves an initial surge in testosterone levels, which may worsen clinical symptoms of PCa. GnRH antagonists provide rapid and consistent hormonal suppression without the initial surge in testosterone levels associated with LHRH agonists, thus representing an important therapeutic alternative for patients with PCa. The concentrations of testosterone and dihydrotestosterone are significantly reduced after treatment with both LHRH agonists and GnRH antagonists. This reduction in testosterone concentrations to castrate levels results in significant, rapid, and consistent reductions in prostatic-specific antigen, a key biomarker for PCa. Evidence suggests that careful maintenance of testosterone levels during androgen deprivation therapy provides a clinical benefit to patients with PCa, emphasizing the need for constant monitoring of testosterone concentrations throughout the course of therapy.     

Reversibility of androgen deprivation therapy in patients with prostate cancer

PURPOSE: We determined the duration of testosterone suppression and recovery in patients with prostate cancer treated with a hydrogel implant releasing the gonadotropin releasing hormone (GnRH) agonist histrelin or treated with a depot GnRH agonist. MATERIALS AND METHODS: Luteinizing hormone (LH) and testosterone (T) responses were monitored in 3 groups. Group 1 comprised 7 patients treated with histrelin implant, which is inserted into the arm of the patient while under local anesthesia, and suppresses LH and testosterone. Following implant removal antiandrogens (flutamide or bicalutamide) were administered. Group 2 comprised 8 patients treated with long-term depot GnRH super agonists which were later withheld and patients were given bicalutamide. Group 3 consisted of 7 patients treated with bicalutamide. RESULTS: In group 1 LH and T were in the castration range while implants were in place. LH increased 1 to 6 weeks after implant removal followed by an increase in T. In 7 of 8 patients in group 2, LH, T and prostate specific antigen remained suppressed for 9 months. In 6 of 7 group 3 patients LH and T increased with a decrease in prostate specific antigen. CONCLUSIONS: Despite continuous prolonged T suppression for up to 3 years due to histrelin implant, LH and T increased rapidly following implant removal, indicating that suppression is reversible. In view of the 9-month suppression of LH and T after the last depot GnRH injection in 7 of 8 patients, it is possible to space GnRH agonist administration at longer intervals. However, T must be monitored to determine that suppression is maintained.     

Effects of long term GnRH analogue treatment on hormone levels and spermatogenesis in patients with carcinoma of the prostate

Summary The effects of long term GnRH treatment with the biodegradable depot formulation of ICI 118.630 on hormone levels and spermatogenesis were investigated in 18 males with advanced prostate cancer. Plasma levels of FSH, LH, testosterone, DHEA-S and SHBG were monitored at regular intervals. The drug suppressed FSH, LH and testosterone significantly and did not affect DHEA-S and SHBG plasma levels. Tissue specimens for histologic assessment and quantitative analysis of germinal cell types were obtained at secondary orchidectomy in 16 patients immediately following GnRH analogue treatment. Germinal cell maturation was arrested at the spermatogonial stage. In two patients discontinuing treatment histologic assessment of secundary orchidectomy specimens 9 and 10 months after the last GnRH analogue depot injection resulted in germinal cell maturation to late spermatides in part of the tubule cross sections. These results indicate that long term administration of the GnRH analoge fails to produce complete testicular sclerosis and spermatogenic arrest might be reversible.     

Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer

BACKGROUND: Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. OBJECTIVE: To determine the efficacy and safety of initial doses of 200mg or 240mg of degarelix and thereafter monthly subcutaneous maintenance doses of 80mg, 120mg, or 160mg of degarelix for the treatment of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: The 1-yr study was of open-label, randomised design and involved 187 patients (range: 52-93 yr, median: 72 yr) with histologically confirmed adenocarcinoma of the prostate and a baseline PSA >2ng/ml. RESULTS AND LIMITATIONS: At baseline, median serum testosterone was 4.13ng/ml (range: P25-P75, 3.37-5.19ng/ml) and PSA was 27.6ng/ml (range: P25-P75, 11.9-55.0ng/ml). On day 3, 88% and 92% of patients in the groups to whom 200-mg and 240-mg initial doses of degarelix were administered, respectively, had testosterone levels 相似文献   

前列腺癌患者LH—RH缓释剂治疗后性激素及肿瘤标记物水平变化

对３２例采用ＬＨＲＨ缓释剂治疗的前列腺癌患者进行性激素水平及肿瘤标记物状态的对比研究，１６例为初诊经组织病理学诊断及治疗后获得可评价性资料病例。６例患者在ＬＨＲＨ缓释剂初次治疗后血浆睾酮一过性升高，５例３日达高峰，１例持续近１４日；５例患者出现一过性症状加重，２例表现为骨痛加重，３例排尿困难加重。Ｄ期患者的生存时间较切睾组长７～１４个月。１４例患者治疗前检查了前列腺特异抗原（ＰＳＡ），治疗后６例睾酮升高患者中４例同时ＰＳＡ出现轻微升高，ＰＳＡ对前列腺癌的诊断及预后判断均有重要意义。认为ＬＨＲＨ缓释剂与抗雄激素联合治疗可提高其安全性，减少在初次治疗后的一过性加重反应，相对延长生存时间。     

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

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used in patients with PCa as neo‐adjuvant hormone therapy to reduce prostate volume and down‐stage the disease before radiotherapy with curative intent. The present study showed that ADT with the gonadotropin hormone‐releasing hormone (GhRH) antagonist degarelix is non‐inferior to combined treatment with the LHRH agonist goserelin and bicalutamide in terms of reducing prostate volume during the treatment period of 3 months. Degarelix treatment evokes, however, significantly better relief of lower urinary tract symptoms in patients having moderate and severe voiding problems.

OBJECTIVE

• ? To assess the efficacy of monthly degarelix treatment for reduction of total prostate volume (TPV), relief of lower urinary tract symptoms (LUTS) and improvement of quality of life (QoL) in patients with prostate cancer (PCa) using monthly goserelin as active control.

METHODS

• ? This was a randomized, parallel‐arm, active‐controlled, open‐label, multicentre trial on 182 patients treated with either monthly degarelix (240/80 mg) or goserelin (3.6 mg) for 12 weeks.
• ? For flare protection, goserelin‐treated patients also received daily bicalutamide (50 mg) during the initial 28 days.
• ? Key trial variables monitored monthly were TPV (primary endpoint), serum testosterone, prostate‐specific antigen (PSA), the International Prostate Symptom Score (IPSS) and the Benign Prostate Hyperplasia Impact Index.

RESULTS

• ? In all, 175 patients completed the trial (96.1%).
• ? At week 12, changes in TPV for degarelix and goserelin were similar (?37.2% vs ?39.0%) and met the predefined non‐inferiority criterion.
• ? Decreases in IPSS were greater in degarelix than in goserelin‐treated patients, differences being statistically significant in patients with baseline IPSS > 13 (?6.7 ± 1.8 vs ?4.0 ± 1.0; P= 0.02).
• ? The number of patients with an IPSS change of ≥3 over baseline was also significantly higher in patients treated with degarelix (61.0 vs 44.3%, P= 0.02).
• ? Both treatments were safe and well tolerated.

CONCLUSIONS

• ? Medical castration reduces TPV and could also improve LUTS in patients with PCa.
• ? While the short‐term efficacy of degarelix and goserelin + bicalutamide was the same in terms of TPV reduction, degarelix showed superiority in LUTS relief in symptomatic patients, which could highlight the different actions of these drugs on extrapituitary gonadotrophin‐releasing hormone (GnRH) receptors in the bladder and/or the prostate.

     

Effect of epidural anesthesia on the function of hormonal regulation in the hypothalamic-pituitary-testicular axis

To evaluate the effects of epidural anesthesia on the hypothalamic-pituitary-testicular axis, we examined the concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T). The effects of epidural anesthesia on plasma levels of LH, FSH and T were investigated in 8 men aged from 64 to 87 years, suffering from untreated prostate cancer. There were no significant differences in plasma levels of LH, FSH or T between patients under epidural anesthesia and patients under no anesthesia. The effects of epidural anesthesia on plasma levels of LH, FSH and T after LH releasing hormone (LH-RH) administration were studied in 10 men between 65 and 84 years with diagnoses of untreated prostate cancer. Plasma LH and FSH levels increased significantly after LH-RH administration under epidural anesthesia or no anesthesia. Plasma LH and FSH were lower under epidural anesthesia than under no anesthesia. No change in plasma T level was observed after LH-RH administration under epidural anesthesia. We conclude that there is no effect of epidural anesthesia on the hypothalamic-pituitary-testicular axis.