Trade Name Drug: Plenaxis
Generic Name Drug: Abarelix
Company: Praecis Pharmaceuticals
Indication/Use: Prostate cancer
Approval Date: Nov. 25, 2003
FDA Class: 1P
Development
Abarelix (Plenaxis) is an injectable decapeptide antagonist of leutinizing hormonereleasing hormone (LHRH) that was approved by the FDA in November 2003 for the treatment of advanced prostate cancer. Because of an increased risk of serious, and potentially life-threatening, allergic reactions associated with the use of abarelix, the drug will be marketed under a voluntary risk management program (RMP) intended to restrict distribution of the drug to patients with advanced prostate cancer who have no alternative therapy. About 5% to 10% of men with prostate cancer have the type of advanced, symptomatic disease that would make them candidates for abarelix therapy. The RMP for abarelix is called the PLUS (Plenaxis User Safety) Program.
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients, especially those with localized tumors, may die of other illnesses or old age without ever having suffered significant disability from their cancer. The approach to treatment is influenced by age and coexisting medical problems. Several different hormonal approaches are available for prostate cancer chemotherapy including bilateral orchiectomy, estrogen therapy, LHRH analogs, antiandrogens, ketoconazole, and aminoglutethimide.
Mechanism of Action
Agonists of natural leutinizing hormonereleasing hormone were first synthesized in the 1970s. It was soon realized that the repeated administration of LHRH agonists produced a decrease in gonadal function, associated with a significant drop in sex steroid levels after an initial increase. These agonists were then made available for the treatment of prostate cancer in the 1980s. Use of LHRH agonists initiated a revolution in the treatment of prostate cancer. Two LHRH agonists are commonly used in treatment of prostate cancer; leuprolide acetate (Lupron) and goserelin acetate (Zoladex).
As indicated, treatment with a LHRH agonist analog results in an initial rise in gonadotropin secretion due to its binding to pituitary gland LHRH receptors and their subsequent activation. Secondarily, in relation to the continuous occupation of the receptors, luteinizing hormone (LH) levels decrease and follicle-stimulating hormone (FSH) levels decrease also but to a lesser degree, due to the desensitization process. The transient rise in LH (seven to 10 days) stimulates production of testosterone resulting in transient stimulation and increased growth of prostate and prostate cancer cells, with such associated symptoms as increased bone pain, if the patient already has metastases to the bone. This has become known as the “flare response.” Following the initial stimulative phase, continuous high levels of LHRH agonist result in termination of natural leutinizing hormonereleasing hormone synthesis and release. As a consequence, there is no further production of either LH or testosterone. In the absence of testosterone production, the level of testosterone in the body rapidly drops to a “castrate level” of 90% to 95% of its normal level. Hence, the decrease in testosterone levels to castrate level slows growth of prostate cells and prostate cancer cells to very low levels.
Abarelix (Plenaxis) and other LHRH antagonists differ in their mechanism of antiandrogenic from agonists. Abarelix binds to LHRH receptors with high affinity (KD = 0.1 nM) but, characteristic of competitive receptor antagonism, is unable to activate receptor signaling activity. Due to the direct inhibition of the secretion of LH by abarelix, there is no initial increase in serum testosterone concentrations thereby avoiding the flare response characteristic of leutinizing hormonereleasing hormone agonist activity. The site of binding of LHRH antagonists seems to differ from those of agonists.
LHRH antagonists, like agonist structures, are produced by substitution of four to six amino acids of natural LHRH by non-natural D-amino acid residues. The structure of abarelix (Plenaxis) is illustrated in the figure:
Structure of abarelix (Trade Name Drug: Plenaxis)
Abarelix (Plenaxis): Pharmacokinetics
The labile peptide nature of abarelix rules out its oral bioavailability. Hence the drug is administered by an intramuscular route. Abarelix (100 mg) is absorbed slowly after IM administration with a mean peak concentration of 43.4 ng/mL observed approximately three days after the injection. The apparent volume of distribution during the terminal phase determined after IM administration of abarelix was 4040 ± 1607 liters, implying that the drug likely distributes extensively within the body. Abarelix (Plenaxis) is highly bound to plasma proteins (96% to 99%). In-vitro studies using animal and human hepatocytes and in-vivo studies in animals indicate that the major metabolites of abarelix are formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix have been noted either in vitro or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix. In humans, approximately 13% of unchanged abarelix is recovered in urine after a 15 µg/kg IM injection and no detectable abarelix metabolites were found in urine. Renal clearance of abarelix is 14.4 L/day after a 100-mg dose of the drug.
Clinical Profile
Abarelix (Plenaxis) is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and who have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia. As part of the manufacturer’s PLUS program, abarelix injections will only be distributed to physicians who attest to certain qualifications and are formally enrolled in the program.
The effectiveness of abarelix in suppressing serum testosterone has been studied in two randomized, open-label, active-comparator trials. Patients were not those with advanced symptomatic prostate cancer. They were randomized in a 2:1 ratio to abarelix 100 mg IM versus LHRH agonist (Study 1) or to abarelix versus LHRH agonist plus nonsteroidal antiandrogen (Study 2). Abarelix (Plenaxis) was administered IM on Days 1, 15, 29 (Week 4), then every four weeks thereafter for at least six months (24 weeks). Leutinizing hormonereleasing hormoneagonist and nonsteroidal antiandrogen were administered in standard fashion. After completing six months of treatment, patients could continue randomized treatment for an additional six months. In both studies combined, 100% (348/348) of abarelix patients and 16% (28/172) of comparator patients avoided a testosterone surge. The percentage of patients who attained serum testosterone concentration ~50 ng/dL on Study Days 2, 8, 15 and 29 were 24, 70, 73 and 94, respectively. Successful response was defined as attainment of medical castration on Day 29 and maintenance through Day 85 (where no two consecutive serum testosterone concentrations between Days 29 and 85 were greater than 50 ng/dL). In Study 1, 92% of abarelix patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of abarelix patients and 95% of LHRH agonist plus nonsteroidal antiandrogen patients responded.
A study of abarelix (Plenaxis) was conducted in 72 men with advanced symptomatic prostate cancer who were at risk for clinical exacerbation if treated with an LHRH agonist (“flare response”). The objective of this open-label, multicenter, uncontrolled, single-arm study was to demonstrate that such patients could avoid orchiectomy through at least 12 weeks of treatment. In this trial, treatment was to be given for at least six months with the option to continue treatment in an extension trial. The specific reasons given for enrollment of the 72 patients were: bone pain from prostate cancer skeletal metastases (n = 31); an enlarged prostate gland or pelvic mass causing bladder neck outlet obstruction (n = 25); bilateral retroperitoneal adenopathy with ureteral obstruction (n = 9); impending neurological compromise from spinal, spinal cord, or epidural metastases (n = 6); or other (n = 1). The median age was 73 years, range 40 to 94 years. There were 62 Caucasians, six African-Americans and four Hispanics.
Abarelix (Plenaxis) 100 mg was administered via IM injection on Days 1, 15, and 29, then every four weeks thereafter. Twelve patients discontinued prior to Day 169 for the following reasons: adverse event (n = 2), voluntary withdrawal (n = 3), death (n = 4), and other (n = 3). Sixty patients were treated for at least 24 weeks; in the extension phase, 33 patients for at least 48 weeks and 15 patients for at least 96 weeks. None (0%) of the 72 patients required orchiectomy while being treated with abarelix; including during the extension phase (median combined duration of therapy was 40 weeks). However, two patients were withdrawn before week 12 for treatment-related adverse events (immediate-onset systemic allergic reactions consisting of urticaria and pruritus) and received alternate therapy. In this trial, medical castration (serum testosterone concentration of 50 ng/dL) was achieved in 57 of the 72 patients (79%) by Day 8, and by 68 of 71 patients (96%) by Week 4.
Also observed in this study was that none of eight patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms; 10 of 13 patients with bladder outlet obstruction and a bladder drainage catheter had the catheter removed by 12 weeks; 11 of 15 patients with pain due to skeletal metastases were able to reduce the potency, dose and/or frequency of narcotic analgesia at 12 weeks.
Adverse Reactions
The most common side effects seen in clinical trials were hot flashes, sleep disturbances, pain, including back pain, breast enlargement or pain, and constipation.
The labeling for abarelix contains a black box warning concerning immediate-onset systemic allergic reactions, some resulting in hypotension and syncope following administration of the drug. The cumulative risk of such a reaction increases with the duration of treatment. Patients should be observed for at least 30 minutes following each injection of abarelix in the event of an allergic reaction and, if such a reaction should occur, managed appropriately. In the clinical trial of patients with advanced, symptomatic prostate cancer 3.7% of patients experienced an immediate-onset systemic allergic reaction within minutes of receiving abarelix. The allergic reactions were urticaria (Day 15), urticaria and pruritus (Day 29), and hypotension and syncope (Day 141).
Abarelix (Plenaxis): Drug Interactions
No formal drug/drug interaction studies with abarelix (Plenaxis) have been reported. Cytochrome P-450 isozymes are not known to be involved in the metabolism of this decapeptide.
Dosage and Administration
Abarelix for injection is supplied as a sterile dry powder. Dilution with 0.9% Sodium Chloride Injection, USP generates the depot suspension intended for intramuscular injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide supplied in an abarelix-carboxymethylcellulose (CMC) complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1.
The recommended dose of abarelix (Plenaxis) is 100 mg administered intramuscularly to the buttock on Days 1, 15, 29 (Week 4) and every four weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to abarelix administration, beginning on Day 29 and every eight weeks thereafter.
