abarelix and Prostatic-Neoplasms

Androgen deprivation therapy (ADT) is the lynchpin of treatment for advanced prostate cancer. Prescribing physicians and patients have a choice between orchiectomy, luteinizing hormone releasing hormone (LHRH) agonists, combined androgen deprivation (CAD) or LHRH antagonists.. Literature relating to the use of LHRH antagonists in the management of prostate cancer was reviewed.. Abarelix was the first-in-class LHRH pure antagonist that was Food and Drug Administration (FDA) approved in 2003. Due to a variety of concerns including hypersensitivity reactions it was withdrawn from the United States (U.S.) market in 2005. The only currently commercially available LHRH antagonist in the U.S. is degarelix available as a once-a-month depot injection. The potential clinical advantage of degarelix compared to the LHRH agonists is the very rapid and sustained testosterone suppression with no identifiable physiological or clinical testosterone surge or flare. The main disadvantage of degarelix compared to the LHRH agonists is the monthly dosing and the inconvenience for some patients and practices. Recent studies tout improved disease control for degarelix compared to monthly leuprolide acetate; however, these results remain controversial.. The rapid T-suppression achieved with degarelix may provide a clinical benefit for various groups of men with advanced or locally advanced disease.

Topics: Antineoplastic Agents; Cost-Benefit Analysis; Disease Progression; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Oligopeptides; Prostatic Neoplasms; Testosterone

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.

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Since Huggins and Hodges demonstrated the responsiveness of prostate cancer to androgen deprivation therapy (ADT), androgen-suppressing strategies have formed the cornerstone of management of advanced prostate cancer. Approaches to ADT have included orchidectomy, oestrogens, luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgens and more recently the gonadotrophin-releasing hormone antagonists. The most extensively studied antagonist, degarelix, avoids the testosterone surge and clinical flare associated with LHRH agonists, offering more rapid PSA and testosterone suppression, improved testosterone control and improved PSA progression-free survival compared with agonists. The clinical profile of degarelix appears to make it a particularly suitable therapeutic option for certain subgroups of patients, including those with metastatic disease, high baseline PSA (>20 ng/mL) and highly symptomatic disease. As well as forming the mainstay of treatment for advanced prostate cancer, ADT is increasingly used in earlier disease stages. While data from clinical trials support the use of ADT neoadjuvant/adjuvant to radiotherapy for locally advanced or high-risk localized prostate cancer, it remains to be established whether specific ADT classes/agents provide particular benefits in this clinical setting.

Topics: Androgen Antagonists; Disease-Free Survival; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Neoadjuvant Therapy; Oligopeptides; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Testosterone; Treatment Outcome

Androgen ablation forms a basis for treating prostate cancer and is achieved either by surgical castration, or pharmacologically using oestrogens, anti-androgens and/or gonadotropin-releasing hormone (GnRH) analogues. GnRH antagonists (or blockers) offer a new means of treatment by directly blocking GnRH receptors. Advantages of GnRH antagonists include lack of the initial stimulation of gonadotropin and testosterone production, lack of gonadotropin microsurges and sustained follicle-stimulating hormone suppression; disadvantages include increased histamine release. This review discusses advantages and disadvantages of the GnRH antagonists currently in development, in light of receptor physiology and pre-clinical and clinical data. Comparative clinical trials will ultimately establish their efficacy in comparison to other pharmacotherapies. Therefore, continuing development and refinement is needed to improve prostate cancer treatment.

Topics: Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Design; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Models, Biological; Oligopeptides; Prostatic Neoplasms; Treatment Outcome

At present medical castration employing luteinising hormone releasing hormone (LHRH) agonists is the standard of care for patients with advanced prostate cancer. LHRH agonists suppress the synthesis of testosterone to a castration level. In contrast to surgical castration, medical castration is reversible. However LHRH agonists induce an initial increase of the testosterone level. This so-called testosterone surge leads to tumour growth and increases the disease-specific complaints, known as flare phenomena. It may be possible that the overall survival of these patients is deteriorated. In contrast, gonadotrophin releasing hormone (GnRH) antagonists do not induce a testosterone surge and the level of testosterone decreases as rapidly as that known from a surgical castration.

Topics: Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Neoplasm Staging; Oligopeptides; Orchiectomy; Palliative Care; Prognosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone

Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer. Luteinizing hormone-releasing hormone (LHRH) agonists, such as buserelin, goserelin, leuprorelin and triptorelin, stimulate the pituitary's gonadotrophin-releasing hormone (GnRH) receptor, ultimately leading to its de-sensitization and subsequent reduction of LH and testosterone levels. However, this reduction is accompanied by a well described increase or 'surge' in LH and testosterone levels, necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity. Two pure GnRH antagonists have been developed, abarelix and degarelix, that are devoid of any agonist effect on the GnRH receptor and consequently do not result in testosterone flare. Abarelix was the first GnRH antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone-dependent prostate carcinoma, when rapid androgen suppression is necessary. Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co-administration of an antiandrogen, and with a very low complication rate in the short term.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Epidemiologic Methods; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome

Prostate cancer is the most common nonskin cancer in the United States, with more than 2 million men currently living with the disease (Prostate Cancer Foundation, 2005). Hormone ablation therapy has resulted in much improved outcomes for thousands of men with this disease; however, there are often side effects that impact patients' quality of life. An overview of the use of hormone ablation therapy and the critical role nurses play for patients undergoing this treatment is provided.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Monitoring; Finasteride; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Mass Screening; Neoplasm Staging; Nurse's Role; Nursing Assessment; Oligopeptides; Patient Education as Topic; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Quality of Life; Treatment Outcome

Abarelix, a gonadotropin-releasing hormone antagonist, with its indication for advanced symptomatic prostate cancer, represents the newest category of hormonal therapy introduced in the past 15 years. Results from Phase II and III clinical trials demonstrate the advantages of abarelix over commonly used luteinizing hormone-releasing hormone (LHRH) agonist therapy: abarelix does not cause a surge in serum testosterone that can precipitate a flare phenomenon or worsening of disease, particularly dangerous for patients with metastatic, symptomatic disease, and produces medical castration more quickly. Abarelix was also demonstrated to promptly and substantially reduce follicle-stimulating hormone levels to lower than LHRH agonist. Study results demonstrate effective anticancer responses during extended exposure to abarelix: improvements in pain score and/or analgesic use, improvements in urinary symptoms (including urinary catheter removal) and complete avoidance of bilateral orchiectomy for patients undergoing at least 12 weeks of treatment. In Phase III clinical trials, abarelix demonstrated a similar overall safety profile when compared with LHRH agonist monotherapy, and a superior safety profile when compared with LHRH agonist plus antiandrogen combination therapy. Abarelix patients experienced a greater incidence of immediate-onset systemic allergic reactions as compared with control arms.

Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome

Topics: Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Metastasis; Oligopeptides; Prostatic Neoplasms

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

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome

The high incidence of prostate cancer makes it a major healthcare problem and the second leading cancer-related cause of death among men in developed countries. The hormonal treatment of prostate cancer is indicated for the palliation of symptomatic and metastatic disease in older patients, and as neoadjuvant treatment of different modalities of radiotherapy. This hormonal treatment is based on the study conducted by Huggins in 1940 and consists of androgen suppression. Since the clinical availability of the first luteinising hormone-releasing hormone (LHRH) agonist, no significant improvement has been made in the field of medical castration. Taking these data into consideration, the recent approval of abarelix by the FDA, the first gonadotrophin-releasing hormone (GnRH) antagonist, appears to be promising news. The pharmacology of the molecule and the clinical studies that led to FDA approval will be reviewed. The place of GnRH antagonists in the treatment modalities of prostate cancer will then be discussed.

Topics: Animals; Clinical Trials, Phase III as Topic; Drug Hypersensitivity; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Oligopeptides; Palliative Care; Prostatic Neoplasms; Testosterone

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 o

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Endometriosis; Estrogen Antagonists; Female; Humans; Male; Oligopeptides; Prostatic Neoplasms

In the 60 years since Huggins first demonstrated the hormone dependency of prostate cancer, the introduction of various means of hormonal manipulation has resulted in modest achievements. Orchiectomy reduced testosterone but was irreversible and associated with reduced quality of life. Diethylstilbestrol (DES) represented the first alternative to surgical castration. However, cardiovascular adverse events severely limited its use. The luteinizing hormone-releasing hormone (LHRH) agonists offered true medical castration but suffered from problems of testosterone surge and tumor flare. The introduction of antiandrogens in combination with LHRH agonists appears on meta-analysis not to have improved survival and has implications for the cost and convenience of therapy, as well as added toxicity. Gonadotropin-releasing hormone (GnRH) antagonists offer for the first time a truly rapid medical means of reducing testosterone and also suppress follicle-stimulating hormone (FSH). However, the clinical benefit of this new class of drugs remains to be evaluated.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Diethylstilbestrol; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Oligopeptides; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Abarelix (PPI-149) is a luteinizing hormone-releasing hormone (LHRH) receptor antagonist under development by Praecis, Amgen and Sanofi-Synthelabo for the potential treatment of prostate cancer, breast cancer and hormone-related disorders [285672,328910]. Abarelix has entered phase III clinical trials for hormonally responsive prostate cancer [311887], and a sustained-release formulation is in a phase I/II clinical trial for endometriosis [317822]. In June 1997, Praecis entered into a collaboration with Sanofi-Synthelabo for the continued development and future marketing of Abarelix for the treatment of prostate cancer and other hormone-related disorders in Europe [248307]. In June 1998, Roche gained marketing rights in the US and elsewhere, under a joint development agreement [289677], which was later terminated. In March 1999, Amgen gained rights to develop Abarelix in the US, Canada, Australia, Asia and other secondary markets [317822]. Sanofi-Synthelabo expects to launch the compound in Europe in 2001 [345341,346302]. In March 1999, Merrill Lynch predicted sales in 2001 of US$75 million, with peak sales of up to US$400 million [336561]. In October 1999, Merrill Lynch predicted sales in 2003 of EUR 100 million [346209] and Lehman Brothers predicted sales of US$50 million in 2002 rising to a peak of US$150 million in 2010 [346267].

Topics: Animals; Antineoplastic Agents; Biotechnology; Endometriosis; Female; Humans; Male; Neoplasms, Hormone-Dependent; Oligopeptides; Prostatic Neoplasms; Receptors, LHRH

Study Type - Therapy (prospective cohort). Level of Evidence 2a. What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues.. • To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin-releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone-releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer.. • A multicentre, open-label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate-specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment. • All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks • The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy. • PSA, LH and follicle-stimulating hormone (FSH) levels were measured and adverse events were monitored.. • A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%). • At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85-92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114-12) it was 93.3%. • A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86. • Mean (sd) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase. • Treatment-related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases.. • Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated. • This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen. • Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Goserelin; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; United States

Follicle-stimulating hormone has been shown to be a mitogen in preclinical models of androgen-independent prostate cancer and abarelix has been previously shown to significantly reduce follicle-stimulating hormone levels in patients when administered monthly. Consequently, we evaluated the safety of more frequent (biweekly) dosing of abarelix and characterized the effect of this dosing schedule on serum follicle-stimulating hormone levels in men with prostate cancer that is progressing despite luteinizing hormone-releasing hormone agonist therapy. Twenty-one patients with prostate cancer progressing on gonadotropin-releasing hormone agonist therapy discontinued the gonadotropin-releasing hormone agonist and received abarelix-depot 100 mg by intramuscular injection every 2 weeks for up to 12 weeks. Safety profile and effect on serum follicle-stimulating hormone were the primary end-points, while prostate-specific antigen response was a secondary end-point. Abarelix therapy was generally well tolerated. One patient experienced an acute immediate allergic reaction. The mean follicle-stimulating hormone serum concentration declined from 3.5 mIU/ml (95% confidence interval: 2.7-4.3) to 2.0 mIU/ml (95% confidence interval: 1.3-2.6) on day 57 and to 2.0 mIU/ml (95% confidence interval: 0.9-3.0) on day 85 (P=0.008 in a Kruskal-Wallis test), but no patient's follicle-stimulating hormone has reached the lower limit of quantitation (below 0.15 mIU/ml). No patient met criteria for prostate-specific antigen response. At the end of 12 weeks of therapy, three (14.3%) patients had no change in prostate-specific antigen levels on days 57 and 85 compared with baseline. Twelve patients (57%) had stable disease throughout treatment defined as percent change from baseline within -50 to 50% at a given time-point confirmed by a second measurement at least 4 weeks later. Treatment with biweekly abarelix in patients with androgen-independent prostate cancer is feasible with no unexpected toxicity, but fails to completely suppress serum follicle-stimulating hormone levels or produce prostate-specific antigen responses.

Topics: Aged; Aged, 80 and over; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

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.. 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.. 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.. 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

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.. 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.. 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.. 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

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

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Middle Aged; Nitriles; Oligopeptides; Prostatic Neoplasms; Tosyl Compounds

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

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Goserelin; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testis; Testosterone

To evaluate the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate.. Patients (n = 269) were randomized to receive open-label abarelix 100 mg or leuprolide acetate 7.5 mg by intramuscular injection. The results of the first 84 days of the study are reported. The primary efficacy endpoints included avoidance of testosterone surge, castration on day 8, and achievement and maintenance of castration from days 29 through 85. The secondary endpoints included castration on days 2, 4, and 15; a reduction in prostate-specific antigen level; and measurements of other hormones. Patients were monitored for clinical adverse events and laboratory abnormalities.. No men in the abarelix group and 82% of men in the leuprolide acetate group experienced a testosterone surge (P <0.001). Abarelix caused rapid medical castration: 24% of men 1 day after treatment and 78% after 7 days compared with 0% of men treated with leuprolide acetate on either day. A comparable percentage of men achieved and maintained castration between days 29 and 85 in each group. Prostate-specific antigen had a statistically significant decrease for the first month in patients treated with abarelix. Dihydrotestosterone, luteinizing hormone, prostate-specific antigen, and follicle-stimulating hormone showed similar rapid reductions without an initial increase. The overall occurrence of adverse events was similar across the treatment groups, and most were sequelae of comorbid disorders.. Treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, luteinizing hormone, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Castration; Follicle Stimulating Hormone; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors

Abarelix (PPI-149) is a luteinizing hormone-releasing hormone (LHRH) receptor antagonist under development by Praecis, Amgen and Sanofi-Synthelabo for the potential treatment of prostate cancer, breast cancer and hormone-related disorders [285672,328910]. Abarelix has entered phase III clinical trials for hormonally responsive prostate cancer [311887], and a sustained-release formulation is in a phase I/II clinical trial for endometriosis [317822]. In June 1997, Praecis entered into a collaboration with Sanofi-Synthelabo for the continued development and future marketing of Abarelix for the treatment of prostate cancer and other hormone-related disorders in Europe [248307]. In June 1998, Roche gained marketing rights in the US and elsewhere, under a joint development agreement [289677], which was later terminated. In March 1999, Amgen gained rights to develop Abarelix in the US, Canada, Australia, Asia and other secondary markets [317822]. Sanofi-Synthelabo expects to launch the compound in Europe in 2001 [345341,346302]. In March 1999, Merrill Lynch predicted sales in 2001 of US$75 million, with peak sales of up to US$400 million [336561]. In October 1999, Merrill Lynch predicted sales in 2003 of EUR 100 million [346209] and Lehman Brothers predicted sales of US$50 million in 2002 rising to a peak of US$150 million in 2010 [346267].

Topics: Animals; Antineoplastic Agents; Biotechnology; Endometriosis; Female; Humans; Male; Neoplasms, Hormone-Dependent; Oligopeptides; Prostatic Neoplasms; Receptors, LHRH

Topics: Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Oligopeptides; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Humans; Male; Oligopeptides; Prostatic Neoplasms

Although prostate cancer specific mortality is decreasing, there is little effect on overall mortality in this population, suggesting the possibility of an increased risk of death from nonprostate cancer related causes. Androgen deprivation therapy could adversely affect cardiovascular health. We investigated changes in lipid and glucose during androgen deprivation therapy.. We performed an exploratory analysis of pooled data from 3 prospective clinical trials aimed at achieving medical castration by comparing the gonadotropin releasing hormone antagonist abarelix, the gonadotropin releasing hormone agonist leuprolide acetate and leuprolide acetate plus the antiandrogen bicalutamide. Most patients were treated in the neoadjuvant setting or because of biochemical recurrence. Fasting serum lipid, glucose and hemoglobin A1C were determined in 1,102 men at baseline, and on treatment days 85 and 169. In the current study men were categorized into 3 treatment groups according to the type of androgen deprivation therapy, that is leuprolide acetate, leuprolide acetate plus bicalutamide or abarelix, and statin therapy.. Significant increases in total cholesterol, triglyceride and high density lipoprotein-cholesterol were observed in patients on leuprolide acetate or abarelix but not in patients on leuprolide acetate plus bicalutamide. Consistent changes in low density lipoprotein-cholesterol were not detected. Increased total cholesterol was usually due to an increase in high density lipoprotein-cholesterol. Hemoglobin A1C increased from baseline to day 85 only and there were no significant changes in fasting glucose measurements. The type of androgen deprivation therapy did not affect these parameters.. Short-term androgen deprivation therapy affects serum lipid and hemoglobin A1C independent of statin therapy.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Blood Glucose; Cholesterol; Fasting; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Nitriles; Oligopeptides; Prostatic Neoplasms; Tosyl Compounds

A 66-year-old man with androgen-independent prostate cancer was treated with abarelix, a gonadotropin-releasing hormone antagonist, for 20 weeks in an experimental protocol. He did not respond to therapy, but his serum prostate-specific antigen level dropped from 15.8 ng/mL to a confirmed 0.8 ng/mL after abarelix was stopped. His prostate-specific antigen level did not return to greater than 15.8 ng/mL for 14 months. This is the first report of a withdrawal response after therapy with a gonadotropin-releasing hormone antagonist, a new class of agents for prostate cancer. Additional observations are needed to determine whether this is an isolated case or a harbinger of a more common phenomenon.

Topics: Aged; Androgens; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms

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).. 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.. 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.. 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

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Prostatic Neoplasms; Receptors, LHRH

Topics: Antineoplastic Agents; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Gonadotropin-Releasing Hormone; Humans; Male; Nurse's Role; Oligopeptides; Oncology Nursing; Patient Education as Topic; Patient Selection; Prostatic Neoplasms

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.. 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.. 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.. 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

Topics: Antineoplastic Agents, Hormonal; Electrocardiography; Humans; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

Luteinizing hormone-releasing hormone (LHRH) antagonists work by directly inhibiting LHRH without any initial stimulation of the LHRH receptor. The physiologic response is a direct and rapid decrease in luteinizing hormone, follicle-stimulating hormone, and testosterone without any flare. Although there has been extensive basic-science work on these medications, practical shortcomings have limited clinical studies in prostate cancer. Many of these compounds induce significant histamine-mediated side effects, and until recently, no depot form existed. In 2 recent phase-3 studies comparing abarelix depot with leuprolide and with leuprolide plus bicalutamide, abarelix lowered serum testosterone more quickly. None of the 89 patients on leuprolide alone were castrate on day 8 as opposed to 72% of the 180 patients randomized to abarelix (P <0.001). Similarly, none of the combination group were castrate by day 8, whereas 68% of the abarelix patients were castrate (P <0.001). In addition, 82% of the patients treated with leuprolide and 86% of those given leuprolide/bicalutamide had testosterone surge, whereas none of the abarelix patients did (P <0.001 for both studies). Both phase 2 and phase 3 data show abarelix to be well tolerated. In conclusion, LHRH antagonists offer the physiologic response of orchiectomy without surgery. These medications are well tolerated and a depot form now exists. The expansion of indications for androgen deprivation, such as downsizing or intermittent therapy, could provide many opportunities for their use. Despite these encouraging advances, however, their routine use for advanced prostate cancer may depend on demonstration of a survival advantage in avoiding flare.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease-Free Survival; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Male; Oligopeptides; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone; Therapeutics; Treatment Outcome