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Picard M, Leclercq M, Bodein A, Scott-Boyer MP, Perin O, Droit A. Improving drug repositioning with negative data labeling using large language models. J Cheminform 2025; 17:16. [PMID: 39905466 DOI: 10.1186/s13321-025-00962-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025] Open
Abstract
INTRODUCTION Drug repositioning offers numerous advantages, such as faster development timelines, reduced costs, and lower failure rates in drug development. Supervised machine learning is commonly used to score drug candidates but is hindered by the lack of reliable negative data-drugs that fail due to inefficacy or toxicity- which is difficult to access, lowering their prediction accuracy and generalization. Positive-Unlabeled (PU) learning has been used to overcome this issue by either randomly sampling unlabeled drugs or identifying probable negatives but still suffers from misclassification or oversimplified decision boundaries. RESULTS We proposed a novel strategy using Large Language Models (GPT-4) to analyze all clinical trials on prostate cancer and systematically identify true negatives. This approach showed remarkable improvement in predictive accuracy on independent test sets with a Matthews Correlation Coefficient of 0.76 (± 0.33) compared to 0.55 (± 0.15) and 0.48 (± 0.18) for two commonly used PU learning approaches. Using our labeling strategy, we created a training set of 26 positive and 54 experimentally validated negative drugs. We then applied a machine learning ensemble to this new dataset to assess the repurposing potential of the remaining 11,043 drugs in the DrugBank database. This analysis identified 980 potential candidates for prostate cancer. A detailed review of the top 30 revealed 9 promising drugs targeting various mechanisms such as genomic instability, p53 regulation, or TMPRSS2-ERG fusion. CONCLUSION By expanding our negative data labeling approach to all diseases within the ClinicalTrials.gov database, our method could greatly advance supervised drug repositioning, offering a more accurate and data-driven path for discovering new treatments.
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Affiliation(s)
- Milan Picard
- Molecular Medicine Department, CHU de Québec Research Center, Université Laval, Québec, QC, Canada
| | - Mickael Leclercq
- Molecular Medicine Department, CHU de Québec Research Center, Université Laval, Québec, QC, Canada
| | - Antoine Bodein
- Molecular Medicine Department, CHU de Québec Research Center, Université Laval, Québec, QC, Canada
| | - Marie Pier Scott-Boyer
- Molecular Medicine Department, CHU de Québec Research Center, Université Laval, Québec, QC, Canada
| | - Olivier Perin
- Digital Transformation and Innovation Department, L'Oréal Advanced Research, Aulnay-Sous-Bois, France
| | - Arnaud Droit
- Molecular Medicine Department, CHU de Québec Research Center, Université Laval, Québec, QC, Canada.
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Patel S, Saxena B, Mehta P, Niazi SK. GnRH Peptide Antagonist: Comparative Analysis of Chemistry and Formulation with Implications for Clinical Safety and Efficacy. Pharmaceuticals (Basel) 2024; 18:36. [PMID: 39861098 PMCID: PMC11768417 DOI: 10.3390/ph18010036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 12/25/2024] [Accepted: 12/29/2024] [Indexed: 01/27/2025] Open
Abstract
Overexpression of the gonadotropin-releasing hormone receptor (GnRH-R) plays a vital role in the advancement of reproductive malignancies such as ovarian, endometrial, and prostate cancer. Peptidomimetic GnRH antagonists are a substantial therapeutic development, providing fast and reversible suppression of gonadotropins by directly blocking GnRH-R. Unlike typical GnRH agonists, these antagonists prevent the early hormonal flare, have a faster onset of action, and have a lower risk of cardiovascular problems. These characteristics qualify GnRH antagonists as revolutionary therapy for diseases such as advanced prostate cancer, endometriosis, uterine fibroids, and in vitro fertilization procedures. Key GnRH peptide antagonists authorized by the regulatory agencies include Cetrorelix, Ganirelix, Abarelix, Degarelix, and Teverelix. Assisted reproductive technologies (ART) are dominated by Cetrorelix and Ganirelix, while Degarelix and Abarelix have shown significant promise in treating advanced prostate cancer. Teverelix appears as a next-generation GnRH antagonist with an ideal mix of efficacy and safety, showing promise in a variety of reproductive and hormone-dependent illnesses. This review investigates the pharmacological role of GnRH in reproductive physiology and its consequences in disease, emphasizing structural advances in third- and fourth-generation GnRH antagonists. All GnRH peptide-based antagonists were analyzed in detail for formulation strategy, pharmacokinetics, effectiveness, and safety. This review also emphasizes GnRH antagonists' clinical promise, providing insights into their evolution and the possibility for future research in developing safer, more effective treatments for complicated hormonal diseases.
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Affiliation(s)
- Shikha Patel
- Department of Pharmaceutical Analysis, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India; (S.P.); (P.M.)
| | - Bhagawati Saxena
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India;
| | - Priti Mehta
- Department of Pharmaceutical Analysis, Institute of Pharmacy, Nirma University, Ahmedabad 382481, India; (S.P.); (P.M.)
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Li X, Sun F, Zhang X, Lin P, Shen K, Shen Y, Ma L, Cao Y, Wang C. Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone receptor antagonist, in healthy men: a randomized, double-blind, placebo-controlled phase 1 study. BMC Med 2023; 21:129. [PMID: 37013610 PMCID: PMC10071678 DOI: 10.1186/s12916-023-02834-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 03/13/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Gonadotropin-releasing hormone (GnRH) antagonists are a promising therapeutic approach for treating hormone-dependent prostate cancer. Currently, the mainstream GnRH antagonists are polypeptide agents administered through subcutaneous injection. In this study, we evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral small molecule GnRH antagonist, in healthy men. METHODS This phase 1 trial was a randomized, double-blind, placebo-controlled, and dose-ascending study. Eligible healthy men were randomized in a 4:1 ratio to receive either oral SHR7280 tablets or placebo twice daily (BID) for 14 consecutive days. The SHR7280 dose was initiated at 100 mg BID and then sequentially increased to 200, 350, 500, 600, 800, and 1000 mg BID. Safety, PK, and PD parameters were assessed. RESULTS A total of 70 subjects were enrolled and received the assigned drug, including 56 with SHR7280 and 14 with placebo. SHR7280 was well-tolerated. The incidence of adverse events (AEs, 76.8% vs 85.7%) and treatment-related AEs (75.0% vs 85.7%), as well as the severity of AEs (moderate AEs, 1.8% vs 7.1%) were similar between the SHR7280 group and placebo group. SHR7280 was rapidly absorbed in a dose-dependent manner, with a median Tmax of each dose group ranging from 0.8 to 1.0 h on day 14 and a mean t1/2 ranging from 2.8 to 3.4 h. The PD results demonstrated that SHR7280 exhibited a rapid and dose-proportional suppression of hormones, including LH, FSH, and testosterone, with maximum suppression achieved at doses of 800 and 1000 mg BID. CONCLUSIONS SHR7280 showed an acceptable safety profile, as well as favorable PK and PD profiles within a dose range of 100 to 1000 mg BID. This study proposes a rationale for further investigation of SHR7280 as a potential androgen deprivation therapy. TRIAL REGISTRATION Clinical trials.gov NCT04554043; registered September 18, 2020.
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Affiliation(s)
- Xin Li
- Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China
| | - Feifei Sun
- Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China
| | - Xiaolei Zhang
- Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China
| | - Pingping Lin
- Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China
| | - Kai Shen
- Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Yu Shen
- Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Lingyu Ma
- Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China
| | - Yu Cao
- Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
| | - Chenjing Wang
- Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
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Bahl A, Rajappa S, Rawal S, Bakshi G, Murthy V, Patil K. A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone-releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix). Indian J Cancer 2022; 59:S160-S174. [PMID: 35343199 DOI: 10.4103/ijc.ijc_1415_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Luteinizing hormone-releasing hormone agonist (LHRH-A), goserelin, and antagonist, degarelix, are both indicated for the treatment of advanced prostate cancer (PCa); however, large comparative trials evaluating their efficacy and safety are lacking. In this review, we assessed the available evidence for both the drugs. Although degarelix achieves an early rapid decline in testosterone (T) and prostate-specific antigen (PSA) levels, median T and PSA levels, in addition to prostate volume and International Prostate Symptom Scores, become comparable with goserelin over the remaining treatment period. Degarelix causes no initial flare, therefore it is recommended in patients with spinal metastases or ureteric obstruction. Goserelin achieves lower PSA, improved time to progression, and better survival outcomes when administered adjunctively to radiotherapy compared with radiotherapy alone, with significant results even over long-term follow-up. The evidence supporting adjuvant degarelix use is limited. Goserelin has better injection site safety, single-step delivery, and an efficient administration schedule compared with degarelix, which has significantly higher injection site reactions and less efficient administration mechanism. There is conflicting evidence about the risk of cardiovascular disease (CVD), and caution is required when using LHRH-A in patients with preexisting CVD. There is considerable long-term evidence for goserelin in patients with advanced PCa, with degarelix being a more recent option. The available comparative evidence of goserelin versus degarelix has several inherent limitations related to study design, sample size, conduct, and statistical analyses, and hence warrants robust prospective trials and long-term follow-up.
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Affiliation(s)
- Ankur Bahl
- Senior Consultant, Medical Oncology and Hematology, Max Cancer Centre, New Delhi, India
| | - Senthil Rajappa
- Consultant Medical Oncologist, Basavatarakam Indo-American Cancer Hospital & Research Institute, Hyderabad, India
| | - Sudhir Rawal
- Medical Director, Chief Genito Uro-Oncology, RCGI, Delhi, India
| | - Ganesh Bakshi
- Department of Uro oncology, P D Hinduja National Hospital, Mahim, Mumbai, India
| | - Vedang Murthy
- Professor & Radiation Oncologist, Tata Memorial Center, Mumbai, India
| | - Ketaki Patil
- Medical Affairs, AstraZeneca Pharma India Ltd, Manyatha Tech Park, Rachenahalli, Bangalore, India
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The Effect of Testosterone on Cardiovascular Disease and Cardiovascular Risk Factors in Men: A Review of Clinical and Preclinical Data. CJC Open 2021; 3:1238-1248. [PMID: 34888506 PMCID: PMC8636244 DOI: 10.1016/j.cjco.2021.05.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/09/2021] [Indexed: 11/20/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. The effects of testosterone, the primary male sex hormone, on cardiovascular risk have been of special interest due to the increased risk of CVD in men. Although it is well established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear. Observational and randomized studies on the effects of endogenous and exogenous testosterone have produced conflicting data, and meta-analyses have been inconclusive, suggesting significant study heterogeneity. Despite a lack of adequately powered randomized controlled trials, large observational studies in the early 2010s led to advisories on the use of testosterone replacement therapy. Similar advisories have been mandated for certain types of androgen deprivation therapy. Additional research suggests that testosterone shortens the heart-rate-corrected QT interval, improves glycemic control, induces vasodilation, is prothrombotic, and has anti-obesity effects, whereas associations with atherosclerosis and inflammation are less clear. Despite inconclusive evidence on cardiovascular risk and inconsistencies among clinical practice guidelines, millions of men continue to use testosterone replacement and androgen deprivation therapy. In addition to summarizing clinical and preclinical data, this review provides insight on potential mechanisms of action of testosterone on CVD, applications of this knowledge to clinical settings, and avenues for future research.
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George DJ, Dearnaley DP. Relugolix, an oral gonadotropin-releasing hormone antagonist for the treatment of prostate cancer. Future Oncol 2021; 17:4431-4446. [PMID: 34409852 DOI: 10.2217/fon-2021-0575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.
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Affiliation(s)
- Daniel J George
- Department of Medicine & Surgery, Duke Cancer Institute, Duke University, Durham, NC 27710, USA
| | - David P Dearnaley
- The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK
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Ikegami T. Hydrophilic interaction chromatography for the analysis of biopharmaceutical drugs and therapeutic peptides: A review based on the separation characteristics of the hydrophilic interaction chromatography phases. J Sep Sci 2019; 42:130-213. [DOI: 10.1002/jssc.201801074] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 11/17/2018] [Accepted: 11/18/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Tohru Ikegami
- Faculty of Molecular Chemistry and Engineering; Kyoto Institute of Technology; Kyoto Japan
- Institute of Pharmaceutical Sciences; Pharmaceutical (Bio-) Analysis; Eberhard-Karls Universität Tübingen; Tübingen Germany
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Clinton TN, Woldu SL, Raj GV. Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer. Expert Opin Pharmacother 2017; 18:825-832. [PMID: 28480768 PMCID: PMC7171911 DOI: 10.1080/14656566.2017.1328056] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Androgen deprivation therapy (ADT) is the mainstay for advanced, hormone-sensitive prostate cancer, and options include surgical castration, luteinizing hormone-releasing hormone (LHRH) agonist, and more recently, gonadotropin releasing hormone (GnRH) antagonist therapy. Our understanding of the mechanisms and adverse effects of ADT has increased substantially, including the class-specific adverse effects of ADT. Areas covered: This review will summarize the pharmacodynamic and pharmacokinetic properties of the GnRH antagonist degarelix and its role in the management of advanced prostate cancer, the clinical evidence supporting its regulatory approval, as well as potential benefits and disadvantages over traditional LHRH agonist therapy. Expert opinion: Degarelix represents a newer class of ADT that results in a rapid and reliable decline in serum testosterone, a quality that makes it particularly advantageous in men presenting with symptomatic, hormone-sensitive prostate cancer. Due to differences in mechanism of action, there is observational data suggesting a potential cardiovascular and even oncologic benefit over traditional LHRH agonist therapy. Further research is ongoing to more clearly define this potential benefit.
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Affiliation(s)
- Timothy N Clinton
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Solomon L Woldu
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Ganesh V Raj
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
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Schally AV, Block NL, Rick FG. Discovery of LHRH and development of LHRH analogs for prostate cancer treatment. Prostate 2017; 77:1036-1054. [PMID: 28449236 DOI: 10.1002/pros.23360] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 01/06/2023]
Abstract
The discovery, isolation, elucidation of structure, synthesis, and initial testing of the neuropeptide hypothalamic luteinizing hormone-releasing hormone (LHRH), which regulates reproduction, is briefly described. The design, synthesis, and experimental and clinical testing of agonistic analogs of LHRH is extensively reviewed focusing on the development of new methods for the treatment of prostate cancer. Subsequent development of antagonistic analogs of LHRH is then faithfully recounted with special emphasis on therapy of prostate cancer and BPH. The concepts of targeted therapy to peptide receptors on tumors are re-examined and the development of the cytotoxic analogs of LHRH and their status is reviewed. The endeavor to develop better therapies for prostate cancer, based on LHRH analogs, guided much of our work.
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Affiliation(s)
- Andrew V Schally
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida
- Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Norman L Block
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida
- Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida
- Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida
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GNRH-agonist or antagonist in the treatment of prostate cancer: a comparision based on oncological results. Urologia 2016; 83:173-178. [PMID: 27768220 DOI: 10.5301/uro.5000194] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2016] [Indexed: 11/20/2022]
Abstract
On the basis of the trials available, are we ready to consider GnRH antagonists better than agonists? Is there a population of patients who may benefit from antagonists more than agonists?We specifically focused our analysis on the significance of oncological results obtained in phase III trials directly comparing Degarelix with GnRH agonists. Oncological results were evaluated only in 1 trial (CS21) with some subanalysis and they were not the primary endpoints of the study. The follow-up duration was 364 days, and therefore, the number of events (all causes deaths and prostate cancer (PC), Prostate Specific Antigen (PSA), Hazard ratio (HR)-related deaths) was very low in both groups and this aspect strongly reduces the significance of overall survival evaluation. In our opinion, the CS21A open-label extension does not consent to obtain useful clinical data and the design of the study loses the possibility to have a longer randomized comparison between degarelix and agonist. Moreover, the fact that the crossover from leuprolide to degarelix was pre-defined at 12 months and not at agonist failure does not allow to gather data also on the effect of sequential treatment.The answer to the question whether we are ready to consider antagonists better than agonists, based on oncological results, is probably no. We have data in terms of testosterone suppression and PSA control rather than overall survival or clinical progression free survival. A PSA progression-free survival is a secondary endpoint that in our opinion is not sufficient. Large prospective comparative trials with long-term follow-up are needed to clarify this critical clinical question.
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Klotz L. Pharmacokinetic and pharmacodynamic profile of degarelix for prostate cancer. Expert Opin Drug Metab Toxicol 2015; 11:1795-802. [PMID: 26513436 DOI: 10.1517/17425255.2015.1085506] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Luteinizing hormone-releasing hormone (LHRH) agonists have been the mainstay of androgen deprivation therapy (ADT) for advanced prostate cancer for over two decades. However, their limitations include a transient initial rise in testosterone, failure to reduce testosterone to castrate levels in some patients, incomplete suppression of follicle-stimulating hormone (FSH), and an increased risk of cardiovascular (CV) events in those with pre-existing CV disease. This article considers whether the LHRH antagonist degarelix offers significant advantages over LHRH agonists. AREAS COVERED This review covers the development and introduction of degarelix, its pharmacodynamic and pharmacokinetic properties, and the efficacy and safety results of Phase II and III clinical studies. EXPERT OPINION Degarelix has clear pharmacodynamic advantages over the LHRH agonist leuprolide in terms of almost immediate suppression of testosterone to castrate levels and sustained suppression of FSH levels. It reduces the risk of CV events vs agonists in men with pre-existing CV disease. This finding, which may reflect differential effects on FSH and/or endothelial plaques, requires confirmation in a prospective study; however, it is the view of the author that the differential effects on CV events are real and suggest that men with pre-existing CV disease requiring ADT should preferentially be treated with degarelix.
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Affiliation(s)
- Laurence Klotz
- a Sunnybrook Health Sciences Centre , 2075 Bayview Ave, Room MG 204, Toronto, ON, M4N 3M5, Canada +1 416 480 610 ;
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Abstract
Degarelix (Firmagon(®); Gonax(®)) is a gonadotropin-releasing hormone receptor antagonist that is approved for the treatment of advanced (hormone-dependent) prostate cancer in the US and EU and the treatment of prostate cancer in Japan. In a pivotal randomized, controlled, 12-month phase III study, degarelix (initial subcutaneous dose of 240 mg followed by monthly dosages of 80 mg) was noninferior to leuprolide (monthly intramuscular dosages of 7.5 mg) in patients with prostate cancer of any stage for which endocrine treatment was indicated (except neoadjuvant hormonal therapy) with regard to suppression of testosterone to castration levels (i.e. ≤0.5 ng/mL). Suppression of testosterone and prostate-specific antigen (PSA) levels was faster with degarelix than with leuprolide, and no testosterone surges or microsurges were seen in degarelix recipients. Suppression of testosterone and PSA levels was maintained for the 12-month study duration and continued for up to 5 years in an extension to the main trial (including in patients switching from leuprolide to degarelix in the extension). The drug was generally well tolerated, with most adverse events being mild to moderate in severity. Injection-site reactions and events reflecting the expected effects of testosterone suppression (e.g. hot flushes, weight increase) were the most common treatment-emergent adverse events. Thus, degarelix is a useful option for the treatment of prostate cancer in patients for whom endocrine treatment is indicated.
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Affiliation(s)
- Natalie J Carter
- Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand,
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Popovics P, Schally AV, Block NL, Rick FG. Preclinical therapy of benign prostatic hyperplasia with neuropeptide hormone antagonists. World J Clin Urol 2014; 3:184-194. [DOI: 10.5410/wjcu.v3.i3.184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 06/26/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Benign prostatic hyperplasia (BPH) is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells. BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes. Current medical therapies mostly consist of inhibitors of 5α-reductase or α1-adrenergic blockers; their efficacy is often insufficient. Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH. At first, antagonists of luteinizing hormone-releasing hormone (LHRH) have been introduced to the therapy aimed to reduce serum testosterone levels. However, they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects. Since then, several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH. In contrast, antagonists of growth hormone-releasing hormone (GHRH) and gastrin-releasing peptide (GRP) have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH. They act at least in part, by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate, and by inhibition of autocrine insulin-like growth factors-I/II and epidermal growth factor production. GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone. This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH, GHRH and GRP in BPH, as well as suggesting a potential role for somatostatin analogs in experimental therapies.
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Crawford ED, Shore ND, Moul JW, Tombal B, Schröder FH, Miller K, Boccon-Gibod L, Malmberg A, Olesen TK, Persson BE, Klotz L. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology 2014; 83:1122-8. [PMID: 24661333 DOI: 10.1016/j.urology.2014.01.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 12/23/2013] [Accepted: 01/07/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVE To demonstrate the safety and efficacy of up to 5 years of degarelix treatment and the effects of crossing over from leuprolide to degarelix in the extension phase of a phase III pivotal 1-year trial. METHODS Patients receiving degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points). RESULTS Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). CONCLUSION Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for degarelix over leuprolide during year 1 remained consistent at 5 years.
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Affiliation(s)
- E David Crawford
- Department of Urologic Oncology, School of Medicine, University of Colorado Denver, Aurora, CO.
| | - Neal D Shore
- Carolina Urologic Research Center, Myrtle Beach, SC
| | - Judd W Moul
- Division of Surgery and Urology, Duke University Medical Center, Durham, NC
| | - Bertrand Tombal
- Department of Urology, University Clinics Saint Luc/Catholic University of Leuven, Brussels, Belgium
| | - Fritz H Schröder
- Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Kurt Miller
- Department of Urology, Charité University Medicine Berlin, Berlin, Germany
| | | | | | | | | | - Laurence Klotz
- Division of Urology, University of Toronto, Ontario, Canada
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Limonta P, Manea M. Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies. Cancer Treat Rev 2013; 39:647-63. [DOI: 10.1016/j.ctrv.2012.12.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 12/03/2012] [Indexed: 12/28/2022]
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Rick FG, Block NL, Schally AV. An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer. Onco Targets Ther 2013; 6:391-402. [PMID: 23620672 PMCID: PMC3633549 DOI: 10.2147/ott.s32426] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Androgen deprivation therapy remains the mainstay of medical treatment for advanced prostate cancer. Commonly, this is achieved with medical androgen deprivation rather than surgical intervention as the permanence and psychological effects of the latter are unacceptable for most patients. Degarelix is a third generation antagonist of luteinizing hormone-releasing hormone (LHRH, also termed gonadotropin-releasing hormone) for the first-line treatment of androgen-dependent advanced prostate cancer. Degarelix acts directly on the pituitary receptors for LHRH, blocking the action of endogenous LHRH. The use of degarelix eliminates the initial undesirable surge in gonadotropin and testosterone levels, which is produced by agonists of LHRH. Degarelix is the most comprehensively studied and widely available LHRH antagonist worldwide. Clinical trials have demonstrated that degarelix has a long-term efficacy similar to the LHRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. Degarelix, however, produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surges or microsurges, and thus prevents the risk of clinical flare in advanced disease. Recent clinical trials demonstrated that treatment with degarelix results in improved disease control when compared with an LHRH agonist in terms of superior PSA progression-free survival, suggesting that degarelix likely delays progression to castration-resistant disease and has a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is usually well tolerated, with limited toxicity and no evidence of systemic allergic reactions in clinical studies. Degarelix thus represents an important addition to the hormonal armamentarium for therapy of advanced androgen-dependent prostate cancer.
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Affiliation(s)
- Ferenc G Rick
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, University of Miami, Miller School of Medicine, Miami, Florida, USA
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Tombal B, Crawford ED. Landmarks in hormonal therapy for prostate cancer. BJU Int 2013; 111:E12-3. [DOI: 10.1111/bju.12020_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Bertrand Tombal
- Service d'Urologie; Cliniques Universitaires Saint Luc; Université Catholique de Louvain Brussels; Belgium
| | - E. David Crawford
- Department of Urologic Oncology; School of Medicine; University of Colorado; Aurora; CO; USA
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Abstract
Degarelix is a gonadotrophin-releasing hormone (GnRH) antagonist for the first-line treatment of androgen-dependent advanced prostate cancer. It has a direct mechanism of action that blocks the action of GnRH on the pituitary with no initial surge in gonadotrophin or testosterone levels. Degarelix is the most extensively studied and widely available GnRH antagonist worldwide. Clinical studies have demonstrated similar efficacy to the GnRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. However, degarelix produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surge or microsurges, thus preventing the risk of clinical flare in advanced disease. Clinical trials have demonstrated that degarelix can offer improved disease control when compared with a GnRH agonist in terms of superior PSA progression-free survival (suggesting that degarelix likely delays progression to castration-resistant disease), and a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is generally well tolerated, with no reports of systemic allergic reactions in any clinical studies. In conclusion, degarelix offers clinicians a rational first-line hormonal monotherapy option for the management of advanced prostate cancer.
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Affiliation(s)
- Neal D Shore
- Atlantic Urology Clinics, 823 82nd Parkway, Myrtle Beach, SC 29572, USA
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New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists. Prostate Cancer Prostatic Dis 2012; 16:7-15. [PMID: 22751146 DOI: 10.1038/pcan.2012.25] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability.
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Van Poppel H, Klotz L. Gonadotropin-releasing hormone: an update review of the antagonists versus agonists. Int J Urol 2012; 19:594-601. [PMID: 22416801 DOI: 10.1111/j.1442-2042.2012.02997.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
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.
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Affiliation(s)
- Hein Van Poppel
- Department of Urology, University Hospitals Leuven, Belgium Division of Urology, University of Toronto, Toronto, Ontario, Canada.
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Current world literature. Curr Opin Obstet Gynecol 2011; 23:301-5. [PMID: 21734502 DOI: 10.1097/gco.0b013e3283491e27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Boccon-Gibod L. An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer. Ther Adv Urol 2011; 3:127-40. [PMID: 21904569 PMCID: PMC3159401 DOI: 10.1177/1756287211414457] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostate-specific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.
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Affiliation(s)
- Laurent Boccon-Gibod
- Bichat-Claude Bernard University Hospital, Department of Urology, University of Paris VII Paris, France
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