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Clinical Prostate Cancer Mar 2004
Review
Topics: Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Metastasis; Oligopeptides; Prostatic Neoplasms
PubMed: 15072602
DOI: 10.1016/s1540-0352(11)70046-4 -
The Medical Letter on Drugs and... Mar 2004
Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Receptors, LHRH
PubMed: 15037857
DOI: No ID Found -
Urology Feb 2004To determine the efficacy of the gonadotropin-releasing hormone antagonist abarelix in patients with androgen-independent prostate cancer progressing after orchiectomy...
OBJECTIVES
To determine the efficacy of the gonadotropin-releasing hormone antagonist abarelix in patients with androgen-independent prostate cancer progressing after orchiectomy and to measure its effect on serum follicle-stimulating hormone (FSH).
METHODS
Sixteen patients with prostate cancer progressing after orchiectomy received abarelix-depot 100 mg by intramuscular injection on days 1, 15, and 29 and then every 28 days for up to 24 weeks (52 weeks in patients who met the criteria for a prostate-specific antigen [PSA] response after 24 weeks). PSA response was the primary endpoint and was defined as a 50% reduction confirmed 4 weeks later. The time to progression and effect of therapy on serum FSH were secondary endpoints.
RESULTS
No patient met the criteria for a PSA response. Five patients (31%, 95% confidence interval 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% confidence interval 6 to 18). The mean serum FSH concentration declined after 4 weeks of study treatment by nearly 90% from a baseline of 45.1 IU/L (95% confidence interval 34.0 to 56.2) and remained suppressed throughout the observation period. Treatment was well tolerated, with one grade 3 allergic reaction.
CONCLUSIONS
Treatment with abarelix in patients with androgen-independent prostate cancer after orchiectomy results in marked reduction in circulating FSH. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Estrogens; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Life Tables; Male; Middle Aged; Neoplasm Proteins; Oligopeptides; Orchiectomy; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Failure
PubMed: 14972486
DOI: 10.1016/j.urology.2003.09.045 -
Urology Dec 2003This article reviews the evidence underlying hormone treatment decisions for men with advanced prostate cancer. Luteinizing hormone-releasing hormone (LHRH) analogs are... (Review)
Review
This article reviews the evidence underlying hormone treatment decisions for men with advanced prostate cancer. Luteinizing hormone-releasing hormone (LHRH) analogs are the mainstays of therapy, but 3 areas of LHRH use need clarification: (1) when to start therapy, (2) what alternatives are available, and (3) how to incorporate a long-term strategy for the individual patient. The Medical Research Council (MRC) study, a randomized clinical trial in 938 patients, shows that immediate hormone therapy in men presenting with advanced prostate cancer (stage > or =T3) imparts a survival advantage over a delayed-treatment approach (7.5 years vs 5.8 years, P = 0.0003). LHRH analogs are also widely used (1) along with definitive radiation therapy, (2) when positive lymph nodes are found after radical prostatectomy, and (3) when prostate-specific antigen increases after any primary treatment (biochemical failure). In these situations, timing of therapy is somewhat controversial. Several new developments in hormone therapy are noteworthy, including high-dose antiandrogen monotherapy, a LHRH antagonist (abarelix), transdermal estrogens, and a subcutaneous implant that releases leuprolide acetate at a constant rate for 1 year (Viadur; Bayer Corporation, West Haven, CT). With 4 years of clinical experience with Viadur now available, the long-term data indicate continued, uniform testosterone suppression into the castrate range and a high degree of patient satisfaction. Thus, a long-term strategy-permitting increased patient freedom and decreased dependence on a fixed injection schedule-has for the first time become possible with the Viadur implant in men requiring hormone therapy for prostate cancer.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Implants; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Time Factors
PubMed: 14706507
DOI: 10.1016/j.urology.2003.10.029 -
Methods and Findings in Experimental... Nov 2003Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abarelix, ABX-EGF, ademetionine, agomelatine, AMGN-0007, 9-aminocamptothecin, AN-9, anecortave acetate, anidulafungin, AOD-9604, apolizumab, apomate, L-arginine hydrochloride, arzoxifene hydrochloride; Bevacizumab, BP-897, BufferGel; Capravirine, carboxyamidotriazole, carnosine, CC-4047, CEP-701, cerivastatin sodium, clofarabine, conivaptan hydrochloride, CP-461, CS-003; Daptomycin, darifenacin, decitabine, deferasirox, duloxetine hydrochloride; Eberconazole, Ecyd, efalizumab, eglumegad hydrate, EMD-72000, (-)-epigallocatechin gallate, exatecan mesilate, exenatide; Fampridine, fenretinide, ferumoxtran-10; Gadofosveset sodium, garenoxacin mesilate, genistein, glutamine, GPI-15715; Hexyl insulin M2, human insulin, HYB-165; Indisulam, irofulven; KRN-5500, L-796568, laurocapram, lidocaine/prilocaine, lonafarnib, lotrafiban; Melagatran, melatonin, 2-methoxyestradiol, metreleptin, motexafin gadoliniu, motexafin lutetium; Natalizumab, nelarabine, NO-aspirin, NSC-683864; ONO-6126; Pemetrexed disodium, pexelizumab, pirfenidone, PncCRM9, polyglutamate paclitaxel, pramlintide acetate pregabalin, PRO-2000; Ragaglitazar, ramelteon, rasagiline mesilate, rDNA insulin, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human parathyroid hormone (1-84), reolysin RG228, roflumilast, roxifiban acetate, RPI-4610, rubitecan; Safinamide mesilate, solifenacin succinate, SRL-172; T-138067, tafenoquine succinate, tecadenoson, TER-286, tesaglitazar, tetrathiomolybdate, tezosentan disodium, TheraCIM, tigecycline, tipifarnib, tolvaptan, trabectedin, tributyrin, trimegestone, troxacitabine; UCN-01, urokinase alfa; Vinflunine, viscum fraxini 2; Xcellerated T cells, ximelagatran.
Topics: Clinical Trials as Topic; Humans
PubMed: 14685303
DOI: No ID Found -
Urology Nov 2003To evaluate the ability of abarelix, a gonadotropin-releasing hormone antagonist, to provide an alternative treatment to bilateral orchiectomy in men with advanced... (Clinical Trial)
Clinical Trial
OBJECTIVES
To evaluate the ability of abarelix, a gonadotropin-releasing hormone antagonist, to provide an alternative treatment to bilateral orchiectomy in men with advanced prostate cancer symptoms and to evaluate its safety, clinical and biochemical efficacy, and effects on prostate-specific antigen and serum hormone levels.
METHODS
For 168 days, 81 patients from 17 centers received monthly intramuscular injections of open-label abarelix 100 mg (at least one dose). Patients were evaluated for the avoidance of bilateral orchiectomy, efficacy, disease response, percentage of change in prostate-specific antigen level, change in the intensity of pain, neurologic compromise, and other efficacy variables. Safety was evaluated through reports of adverse events and abnormal laboratory values.
RESULTS
No patients required bilateral orchiectomy, but 2 patients were withdrawn from the study because of treatment-related events and were considered as failures to avoid orchiectomy. Treatment produced an 88% (38 of 43) objective response rate on day 85. Sixty-five (90%) of 72 patients experienced improvement in the pain score and/or analgesic use, urinary obstruction, urinary catheter removal, hydronephrosis, and/or azotemia. No patient with impending neurologic compromise at study entry developed spinal cord compression. The median reduction from the baseline prostate-specific antigen value was 75% on day 15 and greater than 95% from day 57 onward. Abarelix was well tolerated, and adverse events were the sequelae of advanced prostate cancer, comorbid medical disorders, or medical castration.
CONCLUSIONS
These results suggest that abarelix provides a safe and effective medical alternative to surgical castration in symptomatic patients with advanced prostate cancer without the risk of the clinical flare associated with luteinizing hormone-releasing hormone agonists.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Middle Aged; Oligopeptides; Pain Measurement; Prostate-Specific Antigen; Prostatic Neoplasms; Safety; Testosterone; Treatment Outcome; Urinary Bladder Neck Obstruction
PubMed: 14624912
DOI: 10.1016/s0090-4295(03)00656-3 -
Drugs in R&D 2003Abarelix [Abarelix-Depot-F, Abarelix-Depot-M, Abarelix-L, PPI 149, R 3827, Plenaxis] is a peptide consisting of natural and artificial amino acids. In females, abarelix... (Review)
Review
Abarelix [Abarelix-Depot-F, Abarelix-Depot-M, Abarelix-L, PPI 149, R 3827, Plenaxis] is a peptide consisting of natural and artificial amino acids. In females, abarelix is an estrogen production antagonist with potential for the treatment of breast cancer, endometriosis and other reproductive hormone diseases. In males it is a testosterone production antagonist and has potential as hormonal therapy of prostate cancer. Depot formulations of abarelix (abarelix-depot-M and abarelix-depot-F) are being developed for hormonally responsive prostate cancer and endometriosis, respectively. Clinical development of the depot formulations is currently being conducted by Praecis Pharmaceuticals, the originators of the agent. A non-depot formulation, abarelix-L, was also being conducted for prostate gland volume reduction. Praecis Pharmaceuticals has entered into a number of licensing agreements covering abarelix. However, all agreements have since been terminated leaving Praecis to develop and commercialise the agent on its own. The terminated agreements include an agreement between Praecis and Roche for the commercialisation of abarelix in the US. This agreement was terminated in November 1998. Praecis Pharmaceuticals also entered into a collaborative agreement with Amgen in March 1999, whereby the companies would develop abarelix and Amgen would commercialise the drug in the US, Canada, Australia, Asia and several secondary markets. However, in September 2001, Praecis and Amgen announced that they were terminating the agreement for all indications. Praecis stated at the time that it remained committed to developing abarelix for both prostate cancer and endometriosis. Amgen had submitted 'Lotestrol' to the US Patent and Trademarks Office as a possible tradename for abarelix-depot-M. Lotestrol may also have been under consideration as a tradename for abarelix-depot-F. Praecis had also sold European, African, Latin American and Middle Eastern rights to abarelix to Sanofi-Synthélabo. However, in October 2001, Sanofi-Synthélabo announced that it had waived its rights to abarelix. Praecis confirmed in December 2000 that it had filed an NDA seeking FDA approval for abarelix in the US. In January 2001, the FDA granted the abarelix application priority review status. However, in June 2001, the FDA rejected the NDA for prostate cancer. The FDA requested that Praecis use existing data from the completed trials to analyse the allergic reactions that occurred in a small subset of patients. The FDA also expressed concerns over the lack of maintenance of testosterone suppression beyond the 3-month timeframe that occurred in a subset of patients. In February 2003, Praecis announced the re-submission of its NDA to the US FDA. The submission seeks approval for the use of abarelix in a defined subpopulation of advanced prostate cancer patients for whom the current hormonal therapies are not appropriate. Praecis plans to submit its regulatory application in Europe during the second quarter of 2003. Following the completion of a phase I/II trial of abarelix-L in prostate gland volume reduction, a phase IIIb study of the depot formulation was initiated in September 2001. The trial is comparing the effects of neoadjuvant hormonal therapy with depot formulations of leuprorelin or abarelix for prostate gland volume reduction. Abarelix-L is no longer mentioned on Praecis' website, suggesting that development of this formulation is no longer being pursued. The Financial Times (ft.com) reported in May 2001 that approximately 12 new anti-cancer agents are expected to be approved by the FDA through to the end of 2002, with the potential to generate total sales of US dollars 2.6 billion--abarelix is one of these products. The paper quoted analysts at Salomon Smith Barney predicting that abarelix could reach sales of US dollars 120 million for the indication of prostate cancer. However, in June 2001 the FDA rejected Praecis Pharmaceuticale FDA rejected Praecis Pharmaceuticals' NDA filing; this was later re-submitted in February 2003. A year earlier, in May 2000, the Financial Times (ft.com) stated that Credit Suisse First Boston had forecast abarelix to reach peak sales of 1 billion US dollars . Other analysts, at SG Cowen, predicted annual sales of US dollars 200 million for the first 3 years; however, this could increase to 1 billion US dollars if abarelix is also approved for the indication of endometriosis. Abarelix' main competitors at the time were said to be Lupron [TAP Pharmaceuticals], Viadur [Alza] and Zoladex [AstraZeneca].
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Endometriosis; Estrogen Antagonists; Female; Humans; Male; Oligopeptides; Prostatic Neoplasms
PubMed: 12757402
DOI: 10.2165/00126839-200304030-00004 -
Expert Review of Anticancer Therapy Apr 2003
Topics: Antineoplastic Agents, Hormonal; Electrocardiography; Humans; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome
PubMed: 12722871
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Apr 2003Our objective was to evaluate the pharmacokinetic and pharmacodynamic characteristics of abarelix after continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1) in...
OBJECTIVES
Our objective was to evaluate the pharmacokinetic and pharmacodynamic characteristics of abarelix after continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1) in patients with prostate cancer and to identify a plasma concentration of abarelix that may provide a sustained pharmacodynamic effect.
METHODS
This was a multicenter, open-label trial to evaluate abarelix, administered as a continuous subcutaneous infusion for up to 84 days (12 weeks) in 36 men with clinically localized or regional prostate cancer. All patients were treated at a dosage of 50 microg x kg(-1) x d(-1) for at least 28 days (4 weeks). The pharmacokinetic characteristics and the pharmacologic activities of abarelix on testosterone, prostate-specific antigen, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone during and after treatment with abarelix were measured.
RESULTS
After a continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1), abarelix concentrations peaked with the median observed time to reach peak concentration at approximately 28 days. The mean observed maximum plasma drug concentration and average plasma concentration were 56.1 and 48.6 ng/mL, respectively. The mean observed half-life of abarelix was 10.0 days. Mean testosterone, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone inhibition of 94.2%, 88.7%, 79.7%, and 82.8%, respectively, were achieved by study day 15 (14 days after dosing started), and inhibition continued to be maintained until the last dosing day. For the prostate-specific antigen levels, mean inhibition of 52.5% was achieved by 28 days after dosing started. The inhibition progressively increased and peaked at 81.9% on the final day of dosing. The inhibition for prostate-specific antigen was extended to 94.6% during the final follow-up visit (28 to 35 days after treatment ended). The median prostate gland volume reduction at treatment exit was 35%. The population pharmacodynamic estimates (percent coefficient of variation) of the 50% inhibitory concentration, maximum organ extraction ratio, and slope and sigmoidicity of the effect-concentration curve of abarelix to testosterone were 3.47 ng/mL (12.4%), 94.9 (1.3%), and 2.92 (16.2%), respectively.
CONCLUSIONS
The results show that abarelix given as a subcutaneous infusion of 50 microg x kg(-1) x d(-1) is sufficient to produce clinically significant effects on the basis of prostate gland volume reduction and the suppression of gonadotropins.
Topics: Aged; Aged, 80 and over; Area Under Curve; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Oligopeptides; Prostatic Neoplasms
PubMed: 12709720
DOI: 10.1016/s0009-9236(02)17637-5 -
The Journal of Urology May 2003We determine the clinical efficacy of the gonadotropin-releasing hormone (Gn-RH) antagonist abarelix in patients with androgen independent prostate cancer, and measure... (Clinical Trial)
Clinical Trial
PURPOSE
We determine the clinical efficacy of the gonadotropin-releasing hormone (Gn-RH) antagonist abarelix in patients with androgen independent prostate cancer, and measure its effect on serum follicle-stimulating hormone (FSH) and testosterone.
MATERIALS AND METHODS
A total of 20 patients with prostate cancer progression during Gn-RH agonist therapy received 100 mg. abarelix depot by intramuscular injection on days 1, 15 and 29, and then every 28 days for up to 24 weeks. Gn-RH agonist therapy was not continued. Patients who met criteria for prostate specific antigen (PSA) response after 24 weeks of therapy could receive treatment for up to 52 weeks. PSA response was the primary end point and was defined as a 50% decrease confirmed 4 weeks later. Secondary end points of this study were the effect of therapy on serum FSH and testosterone.
RESULTS
No patient met the criteria for PSA response. At the end of the 6 cycles of therapy 2 patients remained stable without PSA progression or other signs of disease progression. Median time to progression was 8 weeks (95% CI 5.7-10.3). Mean serum FSH decreased by more than 50% from a baseline of 5.7 IU/l. (95% CI 4.2-7.1) and remained suppressed throughout the observation period. Mean serum testosterone did not change after 4 and 8 weeks of therapy and remained in the anorchid range. Treatment was well tolerated with no grade 3 or higher toxicity.
CONCLUSIONS
Treatment of androgen independent prostate cancer with abarelix decreases circulating FSH and maintains anorchid testosterone but does not result in clinical responses.
Topics: Aged; Aged, 80 and over; Androgens; Delayed-Action Preparations; Disease Progression; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms; Testosterone
PubMed: 12686821
DOI: 10.1097/01.ju.0000059584.47272.9d