Addressing the risk and management of cardiometabolic complications in prostate cancer patients on androgen deprivation therapy and androgen receptor axis-targeted therapy: consensus statements from the Hong Kong Urological Association and the Hong Kong Society of Uro-Oncology.

Background: Androgen deprivation therapy (ADT) is the foundational treatment for metastatic prostate cancer (PCa). Androgen receptor (AR) axis-targeted therapies are a new standard of care for advanced PCa. Although these agents have significantly improved patient survival, the suppression of testosterone is associated with an increased risk of cardiometabolic syndrome. This highlights the urgency of multidisciplinary efforts to address the cardiometabolic risk of anticancer treatment in men with PCa. Methods: Two professional organizations invited five urologists, five clinical oncologists, and two cardiologists to form a consensus panel. They reviewed the relevant literature obtained by searching PubMed for the publication period from April 2013 to April 2023, to address three discussion areas: (i) baseline assessment and screening for risk factors in PCa patients before the initiation of ADT and AR axis-targeted therapies; (ii) follow-up and management of cardiometabolic complications; and (iii) selection of ADT agents among high-risk patients. The panel convened four meetings to discuss and draft consensus statements using a modified Delphi method. Each drafted statement was anonymously voted on by every panelist. Results: The panel reached a consensus on 18 statements based on recent evidence and expert insights. Conclusion: These consensus statements serve as a practical recommendation for clinicians in Hong Kong, and possibly the Asia-Pacific region, in the management of cardiometabolic toxicities of ADT or AR axis-targeted therapies in men with PCa.

Testosterone bounce predicts favorable prognoses for prostate cancer patients treated with degarelix.

BACKGROUND: To clarify the clinical roles of changes in testosterone (T) levels with a cut-off level of 20 ng/dL as predictive factors for prostate cancer patients treated with degarelix acetate. METHODS: A total of 120 prostate cancer patients who received hormone therapies with gonadotropin-releasing hormone antagonist degarelix acetate were retrospectively analyzed. The predictive values of nadir T levels, max T levels, T bounce, and other clinical factors were evaluated for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). T bounce was defined as satisfying both nadir serum T levels of <20 ng/dL and max serum T levels of ≥20 ng/dL during hormone therapies. RESULTS: In 120 prostate cancer patients, 16 (13%) patients did not achieve nadir T < 20 ng/dL, and 76 (63%) patients had max T ≥ 20 ng/dL. The median times to nadir T and max T are 108 and 312 days, respectively. T bounce was shown in 60 (50%) patients and is associated with favorable prognoses both for OS (p = 0.0019) and CSS (p = 0.0013) but not for PFS (p = 0.92). While in the subgroup analyses of the patients with the progression of the first-line hormone therapies, T bounce predicts favorable OS (p = 0.0015) and CSS (p = 0.0013) after biochemical recurrence. CONCLUSIONS: The present study revealed that T bounce with cut-off levels of 20 ng/dL is a promising biomarker that predicts OS and CSS for prostate cancer patients treated with degarelix acetate.

Investigation of the GnRH antagonist degarelix isomerization in biological matrices.

One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long-acting GnRH antagonist degarelix in various biologic media by the tailor-made HPLC method, which allows precise determination of 5-Aph(Hyd)-degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.

A multicenter, retrospective observational study investigating baseline characteristics and clinical outcomes in patients with hormone-sensitive prostate cancer treated with primary androgen deprivation therapy.

OBJECTIVE: This multicenter, retrospective, observational study investigated baseline characteristics and clinical outcomes in patients with hormone-sensitive prostate cancer who received primary androgen deprivation therapy, using Japan Study Group of Prostate Cancer registry data. METHODS: Among patients in the Japan Study Group of Prostate Cancer registry, those who initiated primary androgen deprivation therapy and were aged 20 years or older were enrolled in this study. The primary endpoint was time to disease progression, defined as time from primary androgen deprivation therapy initiation to either prostate-specific antigen or clinical progression. Secondary endpoints included prostate-specific antigen progression-free survival, prostate-specific antigen response (90% or greater reduction from baseline) and distribution of second-line treatment. RESULTS: Of the 2494 patients (goserelin, n = 564; leuprorelin, n = 1148; surgical castration, n = 161; degarelix, n = 621), those who received degarelix had higher prostate-specific antigen levels and Gleason scores and were at a more advanced clinical stage than those receiving goserelin or leuprorelin. The median time to disease progression (identical to the prostate-specific antigen progression-free survival result) was not reached for goserelin and leuprorelin, 52.7 months for surgical castration and 54.0 months for degarelix. Although baseline prostate-specific antigen values in the degarelix cohort were higher than those of the leuprorelin or goserelin cohorts, prostate-specific antigen responses were not different among the three cohorts. Regarding second-line treatment, the largest patient group received degarelix followed by leuprorelin (n = 195). CONCLUSIONS: This study clarified patient characteristics and long-term effectiveness of primary androgen deprivation therapy in real-world clinical practice. Japanese urologists appear to select appropriate primary androgen deprivation therapy based on patient background and tumour characteristics, with degarelix largely reserved for higher risk patients.

Efficacy of Degarelix in the Neoadjuvant Setting in Managing Locally Advanced Prostate Cancer.

Background Prostate cancer holds a substantial presence in the global cancer landscape, and a considerable proportion of diagnoses occur at late stages, particularly in India. Management of locally advanced prostate cancer necessitates a multimodal treatment strategy. A critical part of this strategy is neoadjuvant androgen deprivation therapy, typically administered via luteinizing hormone-releasing hormone (LHRH) analogs. This study explores the potential of an alternative approach: neoadjuvant therapy with degarelix, an LHRH antagonist, and its impact on perioperative and postoperative outcomes in patients undergoing radical prostatectomy for locally advanced or high-risk prostate cancer. Methodology We conducted a retrospective, non-randomized clinical study at Apollo Hospitals in Chennai, India. Patients diagnosed with locally advanced or high-risk prostate cancer who underwent radical prostatectomy were included. Participants were patients treated with neoadjuvant degarelix and subsequent radical prostatectomy between March 2020 and June 2022. We excluded patients receiving radical radiotherapy, those switching from LHRH agonists to antagonists, and those contraindicated for androgen deprivation therapy due to existing comorbidities. For comparison, we selected a group from the institutional database who received conventional treatment (i.e., without neoadjuvant therapy). Results The study compared two groups, each with 32 patients. The groups had no significant difference in total operative duration and console times. The postoperative pathological assessment showed significantly lower margin positivity rates and notable pathological downstaging in the group receiving neoadjuvant degarelix compared to the control group. The incidence of node positivity, prostate-specific antigen levels at three months postoperative, and number of pads used per day at one month did not differ significantly between the two groups. Conclusions Our study suggests that neoadjuvant degarelix could notably enhance patient outcomes in locally advanced prostate cancer management. The benefits include improved symptom control, significant reductions in margin positivity rates, and facilitated surgical procedures. Neoadjuvant degarelix therapy could potentially enhance the feasibility of the surgical intervention in locally advanced prostate cancer management, thus suggesting a promising pathway for improved patient care.

Comparison of Quality of Life and Injection Site Reactions After Switching from Degarelix 80 mg to 480 mg in Advanced Prostate Cancer: A Prospective Trial.

BACKGROUND/AIM: Degarelix has been widely used for prostate cancer; however, injection site reactions (ISRs) can be a clinical issue. We assessed differences in ISR intensity and patient quality of life (QOL) between degarelix 80 mg and 480 mg, a three-month formulation launched in 2020 in Japan. PATIENTS AND METHODS: We prospectively analyzed 25 patients with advanced prostate cancer. ISR intensity and patient QOL were evaluated before and after switching from degarelix 80 mg to 480 mg. A visual analogue scale (VAS) and faces rating scale (FRS) were applied to assess the ISRs. We applied a rating format from the M. D. Anderson Symptom Inventory (MDASI) to assess patient QOL. RESULTS: For degarelix 80 mg and a first dose of 480 mg, the incidence rate of ISRs was 84% and 92%, respectively (p=0.083). ISR pain on the third day after injection scored by VAS was 2.7±2.8 and 5.2±2.7, respectively (p<0.001). Other ISR findings such as redness, induration, swelling, warmth, and itching were significantly worse for degarelix 480 mg than for 80 mg. In the category of patient QOL, interference with activities of daily living such as general activity was significantly worse after degarelix 480 mg (p=0.003). However, 80% of patients were able to continue degarelix 480 mg during the nine months of follow-up. CONCLUSION: Degarelix 480 mg seems to exacerbate pain and other ISR findings, and to reduce patient QOL, compared with degarelix 80 mg. Optimal management of ISRs is essential to maintain patient QOL when using degarelix 480 mg.

Degarelix vs. leuprorelin for the treatment of prostate cancer in China: A cost-utility analysis.

Objective: To explore the cost-effectiveness of degarelix acetate for injection (degarelix) compared to leuprorelin in prostate cancer (Pca) castration treatment from Chinese healthcare system perspective. Methods: A Markov model, adapted from the one established in Finland was conducted for the cost-effectiveness analysis of degarelix and leuprorelin for Pca treatment. The main data were derived from global phase III clinical trials of degarelix (CS21), published study and expert surveys. Outcomes, utility and costs of prostate cancer patients were calculated on a 30-year time horizon. The CS21 study based population of intention-to-treat (ITT) population and three scenarios were modeled. Taking three times of the Gross domestic product (GDP) per capita (242,928 yuan, 2021) as the acceptable threshold for cost-effectiveness. One-way and probabilistic sensitivity analyses were performed on key parameters, including transition probabilities, costs, utility, and discount rate to test the robustness of the model. Results: Base case analysis for ITT population revealed that total costs of degarelix and leuprorelin were 566,226 yuan and 489,693 yuan, while the total quality-adjusted life years (QALYs) were 5.19 and 4.51 during the 30-year time horizon, resulting an incremental cost effectiveness ratio (ICER) of 112,674 yuan/QALY which was 1.39 times the GDP per capita, lower than willingness-to-pay level of three times the GDP per capita. The results for scenario analyses revealed that compared to leuprorelin, degarelix for Pca treatment in China was cost-effective. One-way sensitivity analysis showed that the model was most sensitive to price of 80 mg degarelix, utility of 1st-line therapy, hazard ratio of PSA recurrence, price of 3.75 mg leuprorelin, response rate of docetaxel per cycle, and discount rate of cost. In probabilistic sensitivity analysis, compared to leuprorelin, the probability of degarelix to be cost-effective was 53 and 81% for willingness-to-pay threshold of one and three times the GDP per capita. Conclusion: Compared to leuprorelin, degarelix for prostate cancer treatment is cost-effective. Moreover, scenario, one-way, and probabilistic sensitivity analyses revealed that the model was robust.

Effect of Degarelix Administration on Bone Health in Prostate Cancer Patients Without Bone Metastases. The Blade Study.

CONTEXT: As patients are now living with prostate cancer for longer, the long-term impact of hormonal treatment on bone health is an increasingly debated subject. OBJECTIVE: To characterize the changes in bone mineral density (BMD) and bone turnover markers after degarelix administration in prostate cancer patients without bone metastases. To explore the predictive role of body composition on treatment induced bone loss. METHODS: BMD and body composition (lean body mass, fat body mass, and appendicular mass index [ALMI]) were assessed by dual X-ray absorptiometry on study entry and after 12 months of degarelix therapy. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline, and 6 and 12 months. RESULTS: Twenty-nine patients entered the study. Degarelix administration was associated with a significant decrease in BMD after 12 months (2.4% reduction from baseline at lumbar spine). Serum CTX and ALP increased significantly (median increase from baseline 99% and 19.3%, respectively). An inverse correlation was observed between ALMI and CTX, but not ALP, at both baseline (Pearson r = -0.62, P < .0001) and month 12 (Pearson r = -0.41, P = .032). Moreover, a significant inverse correlation between changes in ALMI and CTX at 12 months (Pearson r = -0.43, P = .019) and a direct relationship between changes of ALMI and ALP (Pearson r = 0.44, P = .016) during degarelix therapy were observed. CONCLUSION: Degarelix administration is associated with a significant decrease in BMD and increase in bone turnover markers. ALMI is a promising predictor of bone loss in prostate cancer patients receiving androgen deprivation therapy, and ALMI changes during therapy are associated with bone turnover derangement favoring bone quality alterations.

Relugolix in the management of prostate cancer.

INTRODUCTION: Relugolix is the first oral gonadotrophin-releasing hormone (GnRH) receptor antagonist. Based on the phase III HERO trial results, relugolix received Food and Drug Administration approval for adult patients with advanced prostate cancer (PCa). AREAS COVERED: We provide an overview of the preclinical and clinical development of relugolix and its role in the current treatment landscape of PCa. EXPERT OPINION: Relugolix leads to rapid inhibition of testicular production of testosterone and its rapid recovery upon discontinuation. In the HERO trial, relugolix was associated with a superior cardiovascular safety profile compared to GnRH agonists. These attributes make relugolix a promising therapy for patients with preexisting cardiovascular comorbidities, those pursuing intermittent androgen deprivation therapy, and those who desire rapid testosterone recovery during 'off-treatment' periods. In the HERO trial, very few patients received concomitant enzalutamide (n = 17, 2.7%) or docetaxel (n < 10, 1.3%). Safety of relugolix has not been established in combination with many androgen-receptor-axis targeted therapies (e.g. abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan, which precludes its use in combination with these agents. In addition, being an oral drug, relugolix may also be associated with challenges of affordability, adherence, and compliance in this predominantly elderly population.

Impact of add-back FSH on human and mouse prostate following gonadotropin ablation by GnRH antagonist treatment.

Objective: During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins. Methods: The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1-5), and all with testosterone (weeks 4-5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured. Results: In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels. Conclusions: These data provide novel evidence for the direct effects of FSH on prostate size and gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.

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

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.

[Factors influencing the choice of androgen deprivation therapy for patients with hormone-sensitive prostate cancer : Results of the ProComD study]. / Einflussfaktoren bei der Wahl der Androgendeprivationstherapie für Patienten mit hormonsensitiven Prostatakarzinom : Ergebnisse der ProComD-Studie.

BACKGROUND: Androgen deprivation therapy (ADT) with a GnRH agonist or the GnRH antagonist degarelix is a central component in the treatment of prostate cancer (PCa). Little is currently known regarding the decision criteria. Knowledge of these could improve the success of treatment in the future. OBJECTIVES: To identify factors influencing the treatment decision in patients with hormone-sensitive prostate cancer receiving ADT and to determine the incidence of concomitant disease in both treatment groups. METHODS: The two-arm, prospective, non-interventional study "ProComD" was conducted from September 2014 to June 2019 at 80 study centers in Germany. After the therapy decision was made, patients with hormone-sensitive prostate cancer needing ADT were included in the study. Data were collected during routine visits. RESULTS: Data from 413 patients were evaluated (degarelix N = 268; GnRH agonists N = 145). Key factors influencing the therapy decision for both treatment options included comorbidities (42% of all patients), compliance (64%), and age (81%). The source of information consulted most frequently regarding existing comorbidities was the patient's medical history conducted by the treating urologist themselves (65% in both groups). For patients with pre-existing cardiovascular diseases, the doctor's letter (45.8% degarelix vs. 38.9% GnRH agonists) or the medical history questionnaire (38.9% degarelix vs. 20% GnRH agonists) was additionally taken into account. CONCLUSION: Comorbidities along with age and compliance are among the key factors influencing the treatment decisions made by urologists.

The Efficacy and Safety of Relugolix Compared with Degarelix in Advanced Prostate Cancer Patients: A Network Meta-analysis of Randomized Trials.

CONTEXT: Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients. OBJECTIVE: This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix. EVIDENCE ACQUISITION: A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis. EVIDENCE SYNTHESIS: Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses. CONCLUSIONS: We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available. PATIENT SUMMARY: We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients.

Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

BACKGROUND: Phase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. OBJECTIVE: To compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. DESIGN SETTING AND PARTICIPANTS: Patients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. INTERVENTION: Patients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. RESULTS AND LIMITATIONS: For the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1-17%], arm 2: 17.1% [95% CI: 7-32%], arm 3: 11.9% [95% CI: 4-26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9-36.1]) relative to degarelix (52.9 wk [95% CI: 49.0-56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. CONCLUSIONS: Rates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. PATIENT SUMMARY: We evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

[Cardiovascular side effects in patients undergoing androgen deprivation therapy: superiority of gonadotropin-releasing hormone antagonists? An update]. / Kardiovaskuläre Komplikationen unter Androgenentzugstherapie: Vorteil für Gonadotropin-Releasing-Hormon-Antagonisten? Ein Update.

BACKGROUND: Androgen deprivation therapy (ADT) plays a crucial role in treatment of advanced prostate cancer (PCa). The additional application of new drugs results in prolonged overall survival, both in the hormone sensitive and castration resistant state. Consequently, the long-term use of ADT moves potential side effects into the focus of interest. In this context special consideration must be given to cardiovascular events. OBJECTIVES: Review of current evidence on potential differences regarding the cardiovascular risk profile of gonadotropin-releasing hormone (GnRH) agonists compared to GnRH antagonists. METHODS: Narrative review based on an expert consensus supported by a literature search in PubMed (MEDLINE) and the abstract databases of ASCO and ESMO was conducted for publications published between January 2015 and January 2021. Significant meta-analyses, randomized controlled trials (RCTs) and real-world data (RWD) revealing relevant results for clinical practice were taken into account. Selection of studies was performed based on the clinical relevance for everyday practice. RESULTS: The search yielded three relevant meta-analyses, two prospective RCTs as well as three RWD publications that are of importance for clinical practice. Overall, a decreased incidence of cardiovascular events was reported for GnRH antagonists compared to GnRH agonists. Only one RWD publication described comparable rates of complications for both drug classes. CONCLUSION: GnRH antagonists have a lower risk of treatment related cardiovascular events compared to GnRH agonists. Risks should be minimized by taking known cardiovascular risk factors into account before initiating therapy.

Does Exist a Differential Impact of Degarelix Versus LHRH Agonists on Cardiovascular Safety? Evidences From Randomized and Real-World Studies.

The main systemic therapy for the management of hormone-sensitive prostate cancer (PC) is androgen deprivation therapy (ADT), with the use of long-acting luteinizing hormone releasing-hormone (LHRH) agonists considered the main form of ADT used in clinical practice to obtain castration in PC. The concomitant administration of antiandrogens for the first weeks could reduce the incidence of clinical effects related to the testosterone flare-up in the first injection of LHRH. On the contrary, Gonadotropin Rh (GnRH) antagonists produce a rapid decrease of testosterone levels without the initial flare-up, with degarelix commonly used in clinical practice to induce castration in PC patients. Even if no long-term data are reported in terms of survival to define a superiority of GnRH or LHRH, for oncological efficacy and PC control, data from randomized clinical trials and from real-life experiences, suggest a difference in cardiovascular risk of patients starting ADT. The age-related decline in testosterone levels may represent a factor connected to the increase of cardiovascular disease risk, however, the role of ADT in increasing CV events remains controversial. For these reasons, the aim of the paper is to synthesize the difference in cardiovascular risk between LHRH and degarelix in patients undergoing ADT. A difference in cardiovascular risk could be indeed an important parameter in the evaluation of these two forms of castration therapy. The Randomized trials analyzed in this paper sustain a possible protective role for degarelix versus LHRH agonists in reducing the rate of new CV events and interventions in the short-term period. On the contrary, real-word data are contradictory in different national experiences and are strongly conditioned by huge differences between the LHRH agonists group and the degarelix group.

Gonadotropin-releasing hormone antagonist associated with lower cardiovascular risk compared with gonadotropin-releasing hormone agonist in prostate cancer: A nationwide cohort and in vitro study.

BACKGROUND: We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages. RESULTS: GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively. CONCLUSION: GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.

Current and emerging gonadotropin-releasing hormone (GnRH) antagonists for the treatment of prostate cancer.

Introduction:Androgen deprivation therapy (ADT) is currently the backbone treatment of metastatic prostate cancer and is also used in combination with external beam radiotherapy (EBRT). Castration may be achieved either by bilateral orchiectomy or by administration of LHRH agonists or GnRH antagonists.Areas covered: In this article, the authors assess the current and emerging role of GnRH antagonists for the treatment of prostate cancer focusing on oncological results and safety (i.e. cardiovascular risk). In addition, updated data regarding the first orally administered GnRH antagonist, relugolix, is presented.Expert opinion: Studies demonstrate that GnRH antagonists are at least equal with LHRH agonists in terms of testosterone suppression and PSA progression free survival with a major advantage being rapid testosterone suppression. Thus, the optimal group of patients included symptomatic metastatic prostate cancer patients especially if cardiovascular comorbidities or LUTS are also present. Emerging data regarding benefit of the use of GnRH antagonists in patients with concomitant cardiovascular disease are of great interest. Relugolix has emerged as the first orally administered GnRH antagonist able to achieve and maintain testosterone castration levels and it is associated with a profound reduction of major cardiovascular events.

Progress in Clinical Research on Gonadotropin-Releasing Hormone Receptor Antagonists for the Treatment of Prostate Cancer.

Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.

Sexual Motivation and Sexual Reward in Male Rats are Attenuated by the Gonadotropin-Releasing Hormone Receptor Antagonist Degarelix.

BACKGROUND: Preclinical studies that have examined the effects of androgen deprivation therapies (ADTs) on sexual outcomes have either relied on a surgical castration model of ADTs or have largely focused on consummatory sexual behaviors. AIM: The aim of this study was to examine the effects of a single administration of the gonadotropin-releasing hormone receptor antagonist, degarelix, on sexual incentive motivation (SIM), sexual reward, consummatory sexual behaviors, anxiety-like behavior, and androgen receptor signaling in male rats, and to determine if sexual stimulation attenuates the effects of degarelix on SIM. METHODS: Male rats were treated with degarelix, or vehicle, and half of the rats in each condition were briefly exposed to a sexually receptive female immediately before SIM trials (experiment 1). Rats treated with degarelix or vehicle were also given a sex-conditioned place preference test (experiment 2A), weekly mating tests (experiment 2B), and an elevated zero maze test (experiment 3). Androgen-sensitive tissues were excised upon completion of testing. OUTCOMES: SIM was indicated by the percentage of time spent near a sexually receptive female on the SIM tests. The percentage of time spent in the chamber of a conditioned place preference maze associated with sexual experience was indicative of sexual reward. The percentage of trials in which a mount, intromission, and ejaculation occurred was indicative of copulatory ability. Sexual performance was characterized by the average latencies to first exhibit these behaviors, as well as the average frequency of these behaviors. Anxiety-like behavior was indicated by the percentage of time in the open zones of an elevated zero maze. Relative weights of the seminal vesicles and bulbourethral glands were used to quantify androgen activity. RESULTS: Rats treated with degarelix exhibited lower levels of SIM. In rats treated with degarelix, contact with a female immediately before SIM testing increased activity, but not SIM. Treatment with degarelix reduced the rewarding aspects of sexual behavior, as well as most aspects of copulatory ability and sexual performance. Degarelix treatment reduced androgen signaling, but did not impact anxiety-like behavior. CLINICAL IMPLICATIONS: The behavioral side effects associated with the use of degarelix may be restricted to sexual behaviors. STRENGTHS & LIMITATIONS: Strengths include the objective measurement of sexual behaviors. The study is limited in that only one ADT was examined. CONCLUSION: These findings serve as an extension of previous preclinical studies as they indicate that gonadotropin-releasing hormone receptor antagonism in male rats also attenuates sexual motivation and sexual reward, in addition to copulatory ability and sexual performance. Hawley WR, Kapp LE, Green PA, et al. Sexual Motivation and Reward in Male Rats are Attenuated by the Gonadotropin-Releasing Hormone Receptor Antagonist Degarelix. J Sex Med 2021;18:240-255.