Neal Shore, Carolina Urologic Research Center/Atlantic Urology Clinics, 823 82nd Parkway, Myrtle Beach, SC 29572, USA. e-mail: email@example.com
Study Type – Therapy (individual cohort)
Level of Evidence 2b
What's known on the subject? and What does the study add?
Androgen deprivation therapy with a gonadotropin-releasing hormone agonist is an effective option for the palliative treatment of advanced prostate cancer.
This study demonstrated the safety and efficacy of the histrelin acetate implant over successive one year treatment cycles for up to four years in an open-label extension trial.
• To evaluate the efficacy and tolerability of a once-yearly histrelin implant during an open-label extension of a pivotal study.
PATIENTS AND METHODS
• Men with advanced prostate cancer and a clinical response to 52 weeks of treatment with the histrelin implant.
• Implants were placed annually. The primary efficacy variable was achievement of serum testosterone levels of ≤50 ng/dL. Secondary efficacy variables were disease progression, analgesia use, performance status and tolerability of therapy.
• Of 104 patients enrolled, over 70% received three consecutive histrelin implants, and the longest, single treatment period was greater than 4 years. Serum testosterone was consistently suppressed below 50 ng/dL in all patients and mean testosterone levels were 13.1, 14.8 and 10.8 ng/dL after 104 weeks (year 2), 156 weeks (year 3) and 208 weeks (year 4) of treatment, respectively.
• Most patients showed no clinical worsening of their disease, were able to continue normal daily activities, and did not require analgesic medication during the extension period.
• Mean (sd) time to place the histrelin implant was 4.5 (6.2) min, with only three patients having insertions that were considered difficult.
• Adverse events were reported in 100 (96.2%) patients. The eight deaths and 28 (26.9%) serious adverse events were judged as unrelated to the study drug. The most commonly reported drug-related adverse events was hot flashes in 67 (64.4%) patients. Most of these cases was judged as mild or moderate.
• The once-yearly histrelin implant maintained testosterone suppression for repeated treatment cycles and was generally well tolerated.
• The histrelin implant provides a clinically attractive option for long-term androgen deprivation therapy in patients with advanced prostate cancer seeking fewer office visits and repeated injections.
Prostate cancer is the most frequently diagnosed male cancer in the USA, with an estimated 217 730 new cases and 32 050 deaths predicted in 2010 . Despite its high prevalence, mortality from the disease has fallen in recent years, presumably as a result of increased surveillance and the accessibility of PSA screening programs. At diagnosis, most patients are asymptomatic, with clinically localized disease. Treatment is based on an assessment of risk and available therapeutic options, which include radical prostatectomy, radiotherapy or cryotherapy . An alternative option, active surveillance or monitoring, may be considered for patients with low-risk disease assessment and/or a limited life expectancy .
In patients with locally advanced or metastatic disease, androgen deprivation therapy (ADT) is a routinely used treatment option. Testosterone promotes the growth of prostate cancer cells, and a reduction of serum levels of this androgen can be achieved by bilateral orchiectomy or medical castration through the administration of pharmacologic therapies such as LHRH agonists. When LHRH agonists are given, increases in serum levels of LH are initially observed, leading to transient increases in serum testosterone. Testosterone production is then suppressed as LHRH receptors become desensitized to continued LHRH agonist exposure . The aim of ADT is to achieve serum testosterone concentrations of <50 ng/dL, the threshold defined as an acceptable serological castrate level . Included among the LHRH agonists indicated for the palliative treatment of advanced prostate cancer in the USA are leuprolide, goserelin acetate, triptorelin acetate and histrelin acetate. Although recent concerns have been raised regarding an association between LHRH agonists and the development of cardiovascular disease and diabetes mellitus, these drugs continue to be a mainstay for patients with advanced prostate cancer .
Patients with advanced prostate cancer generally receive LHRH agonist-based therapy for extended periods, and multiple administrations of these drugs are usually required throughout the year. Histrelin, which is delivered via a subdermal hydrogel implant, is the only LHRH agonist approved for once-yearly administration.
The histrelin implant is a 3-cm long by 3.5-mm diameter permeable hydrogel device containing 50 mg of histrelin acetate and is placed s.c. in the inner aspect of the upper arm during an office-based procedure. Histrelin is released after insertion and continues to diffuse through the hydrogel wall over ≈12 months .
Efficacy and tolerability of the once-yearly histrelin implant were shown in a pivotal, open-label, single-arm study in 138 patients with advanced adenocarcinoma of the prostate . Patients who received histrelin implants were evaluated for 52 weeks, at which point their implants were replaced. Patients were assessed for an additional 8 weeks until week 60. Serum testosterone concentrations were generally reduced to a serum level well below 50 ng/dL by week 4 (mean serum level, 15.8 ng/dL) and were maintained for the duration of the study. No serum testosterone biochemical surge was detected when the implants were replaced after 1 year of treatment.
The present study enrolled eligible patients from the pivotal clinical trial into an open-label extension phase. The primary objective of the extension study was to assess the efficacy and tolerability of histrelin implants placed annually for ≥2 years.
PATIENTS AND METHODS
Complete inclusion and exclusion criteria for entry into the original pivotal study have been reported elsewhere . Briefly, patients ≥45 years of age with histologically confirmed American Joint Committee on Cancer (AJCC) stage III or IV adenocarcinoma of the prostate, or progressively increasing PSA level, serum testosterone ≥150 ng/dL, and a life expectancy of at least 1 year, were included. Patients were excluded if they received bilateral orchiectomy or hormonal agents in the previous year or had brain metastases or vertebral metastases at risk for spinal cord compression. Patients eligible for inclusion in the open-label extension study had completed 1 year of therapy during the pivotal study, had also received a replacement histrelin implant at week 52, and had a PSA and clinical response at week 60. In these patients, implants were replaced at week 104 and every 52 weeks thereafter as long as they elected to continue treatment with the histrelin implant, or until the histrelin implant gained US Food and Drug Administration approval in the USA.
Histrelin acetate was delivered via a sterile, diffusion-controlled reservoir drug delivery system (VANTAS®; Endo Pharmaceuticals, Chadds Ford, PA, USA) inserted s.c. during an aseptic office-based procedure. The implant contains a 50-mg histrelin acetate drug core inside a non-biodegradable cylindrical hydrogel reservoir that releases the drug at a rate of 50 µg daily .
During the extension phase of the study, evaluations of serum testosterone and PSA levels were made at weeks 78, 91 and 104, and every 3 months thereafter. Also reported were vital signs, weight, concomitant medications, disease progression, pain scale and WHO performance status, and adverse events (AEs).
Disease progression was assessed by measurement of PSA levels and clinical evaluation. A complete response was defined as two consecutive post-baseline PSA measurements ≥2 weeks apart in the normal range or decreased by ≥50%. Progression was defined as an increase in PSA levels ≥0.1 ng/mL on three consecutive post-baseline measurements ≥2 weeks apart, whereas stable disease was defined as either complete response without evidence of clinical or radiological progression. Patients' pain levels were assessed using a five-point scale: 0 = no analgesics required; 1 = non-narcotic analgesics used irregularly; 2 = non-narcotic analgesics used regularly; 3 = narcotic analgesics used irregularly; and 4 = narcotic analgesics used regularly. WHO performance status was based on a five-point scale: 0 = normal activity; 1 = symptoms displayed but patient was ambulatory and able to perform self-care; 2 = ambulatory >50% of the time and required occasional assistance; 3 = ambulatory <50% of the time and required nursing care; and 4 = bedridden .
The primary efficacy variable was the number and proportion of patients maintaining at least a castration level of testosterone, defined as ≤50 ng/dL. PSA levels at each assessment point and the change from baseline were also measured. Secondary efficacy variables were PSA status as a marker for disease progression and patients' pain level and performance status.
Tolerability was assessed by AE reporting, and any relationships to the study drug were determined by the investigators. The insertion site was also visually inspected by the investigator, and patients were actively queried regarding the implant and discomfort at the site at all clinical visits. In addition, data regarding the ease and duration of the implant insertion, as well as the removal procedure, were also collected.
Descriptive methods were used to report outcomes. At each visit, the numbers and proportions of patients attaining castration levels of serum testosterone (≤50 ng/dL) were determined. Pain levels and patient activity (WHO performance status) were summarized at each assessment interval. AEs were coded to the Medical Dictionary of Regulatory Activities, and incidence rates were tabulated. All analyses were performed using SAS, version 6.12 or later (SAS Institute Inc., Cary, NC, USA).
In total, 18 study sites participated in this clinical trial between 17 April 2001 and 12 October 2004. Of the 104 patients who entered the extension study, 90 (86.5%) completed 1 year of treatment (week 104; Fig. 1). Of the 14 patients who did not complete the first year of the study, only one discontinued because of an AE (hot flashes). A total of 79 (76.0%) patients received another implant at week 104. Of the patients who discontinued after week 104, only one (1.0%) discontinued because of an AE (implant site soreness). The study was terminated when the histrelin implant received marketing approval in the USA, at which point there were 59 patients remaining in the study as of the data collection endpoint of 12 October 2004. Over 70% of patients received three or more consecutive histrelin implants replaced annually, and nine patients were treated for >4 years (48–51 months).
The baseline characteristics of the study cohort are presented in Table 1. For the purposes of the present study, week 60 of the pivotal study was established as the baseline of the extension phase . Of the 104 patients, 75 (72.1%) were Caucasian, 25 (24.0%) were Black and four (3.8%) were Hispanic. Most patients were elderly, with a mean age of 74.8 years, and more than 90% of patients were older than 65 years. All patients entered the extension study with serum testosterone concentrations <50 ng/dL, with a mean (range) of 15.1 (8.5–41.5) ng/dL. Mean (range) PSA levels were 2.4 (0.0–107.3) ng/mL.
Table 1. Baseline demographics of the 104 patients
Race, n (%)
Serum testosterone (ng/dL)
Re-administration of histrelin implants confirmed the results presented in the pivotal study . Long-term treatment with histrelin maintained serum testosterone concentrations well below accepted castrate levels of 50 ng/dL. Mean serum testosterone concentrations were consistently below 20 ng/dL, except at week 195 (Fig. 2). The primary efficacy variable (i.e. achievement of serum testosterone concentration ≤50 ng/dL) was attained at every time point in all patients except at week 195. At week 195, one patient had a value of 75.6 ng/dL, although, when this patient received his next implant 3 months later, his serum testosterone level decreased to <20 ng/dL.
Disease progression was assessed throughout the study and included evaluation of PSA levels and clinical observation. Median PSA levels were no greater than 0.3 ng/mL up to week 156 of the extension study (data not shown). Rising PSA levels were a concern for seven patients who discontinued from the study. Clinically, most patients (≥90% at any observation point) showed no worsening of their disease during treatment with the histrelin implant (Fig. 3).
Most patients (59.7–90.0%) also reported no use of analgesic medication at any time point during the extension study (Fig. 4). Patients who required pain medication generally used non-narcotic analgesics (regular or irregular use). No more than 12.1% of patients required the use of narcotic analgesia at any time point during the study. Most patients in the study (≥88.9%) were able to continue normal daily activities during the extension period, as assessed by evaluation of the WHO performance status of each individual (Fig. 5).
AEs were reported in 100 of 104 (96.2%) patients who entered the extension study (Table 2). There were eight patients who died during the study and there were 28 (26.9%) serious AEs. None of the deaths or serious AEs were considered to be related to the study treatment. A total of two (1.9%) patients discontinued the study as a result of AEs, and their implants were removed; one patient reported mild hot flashes and the other mild implant site soreness. These events were considered to be probably related to the study treatment, and both events subsequently resolved.
Table 2. Safety
All safety evaluable patients
AE, adverse event.
Patients with any AE, n (%)
Patients with any serious AE, n (%)
Patients with AE leading to discontinuation of medication, n (%)
Patients with any drug-related AE, n (%)
Drug-related AEs occurring in ≥2 patients, n (%)
Hot flashes aggravated
Most of the insertion and removal procedures over the course of the extension study were unremarkable. The mean (sd) time to place the histrelin implant was 4.5 (6.2) min. There were three patients who had insertions that were categorized as difficult by the investigators. The longest procedure time of the insertions reported as difficult was 6 min; the other two were accomplished in 4 and 1 min, respectively. Difficult retrievals were reported in 16 patients, with either difficulty locating the implant (n= 7) or in removing the implant (n= 9). There were no spontaneous expulsions of implants during the extension study.
Drug-related AEs were reported in 78 (75.0%) patients and events that occurred in two or more patients are presented in Table 2. Drug-related AEs were considered by the investigators to be consistent with those expected in patients with advanced adenocarcinoma of the prostate undergoing ADT with an LHRH agonist. Hot flashes were the most frequently reported drug-related AE and occurred in 67 (64.4%) patients. These were considered as mild or moderate in most of the cases. Other less frequently reported drug-related AEs were fatigue and testicular atrophy (n= 8; 7.7%), gynaecomastia (n= 5; 4.8%) and constipation (n= 3; 2.9%).
A total of 46 (44%) patients had clinically relevant changes in clinical chemistry laboratory values. The most frequently observed marker was serum glucose >160 mg/dL, with 36 (35%) patients having at least one occurrence of elevated serum glucose. There were seven (7%) patients who had more than two occurrences of elevated serum glucose. In addition, seven patients had seated systolic blood pressure (BP) >180 mmHg or diastolic BP >100 mmHg. No patients were withdrawn because of changes in serum glucose or BP.
The present study met the primary objective of showing the long-term efficacy and tolerability of the s.c. histrelin acetate implant in patients with adenocarcinoma of the prostate over multiple years of continuous treatment with yearly implantation. These long-term data were consistent with the results of the pivotal study from which the extension study population originated . Most patients who entered the pivotal study were elderly, had failed localized therapy, and had been classified with AJCC stages III or IV or with PSA levels ≥5 ng/mL. In the pivotal study, serum testosterone levels were maintained below 50 ng/dL. Serum testosterone levels were consistently maintained below this threshold for the duration of this extension study, and mean concentrations were in the range 10.8–20.8 ng/dL at any time point. A serum testosterone level >50 ng/dL was reported in only one patient during the 3 years of the extension study. It was an isolated occurrence; when the implant was replaced, the patient's serum testosterone levels decreased below 20 ng/dL at the next protocol measurement. The patient remained in the study until its discontinuation.
The primary endpoint of the extension study was achievement of serum testosterone ≤50 ng/dL, generally referred to as the threshold for castrate level of suppression. However, in this extension study, mean serum testosterone levels were maintained well below this threshold in most patients. In a different prospective study of 35 men conducted by Oefelein et al. , serum testosterone levels were measured after bilateral orchiectomy and the median testosterone value after orchiectomy was ≈15 ng/dL, leading to the suggestion that a more appropriate serum testosterone value indicating ‘castration’ may be <20 ng/dL. The testosterone suppression achieved with the histrelin implant in the present extension study was generally similar to that achieved by bilateral orchiectomy as reported by Oefelein et al. .
The extent of testosterone suppression shown in the present study may have important implications for long-term disease progression. In a study of 73 patients, a clinical threshold of serum testosterone of 32 ng/dL was identified . In that study, androgen-independent progression (AIP) was described as three consecutive increases in PSA levels after nadir. Patients with serum testosterone <32 ng/dL had a mean survival free of androgen-independent progression of 137 months (95% CI, 104–170) compared to 88 months (95% CI, 55–121) for those with any breakthrough increase >32 ng/dL (P= 0.03). Thus, there may be clinical advantages in employing ADTs that reduce serum testosterone levels similar to those achieved after bilateral orchiectomy .
In the pivotal clinical trial and during the present open-label extension study, testosterone surges were not observed after reimplantation of histrelin implants . Flares or surges in testosterone levels have been reported with the administration of depot injection formulations of LHRH agonists. In a survey of studies of LHRH agonists, a 2–13% incidence of breakthrough testosterone surges was reported in patients receiving depot formulations .
ADT is the mainstay of management for advanced prostate cancer and is used for the long-term palliative care of patients. Studies have shown that there may be benefits if ADT is employed earlier in treatment in selected patients. In a study of patients with nodal metastases undergoing radical prostatectomy and pelvic lymphadenectomy, 98 men were randomized to observation, with treatment deferred until progression or, in the other arm, immediate antiandrogen therapy (bilateral orchiectomy or 3.6 mg of goserelin administered s.c. every 28 days) . After a median of 7.1 years of follow-up, seven out of 47 men (14.9%) in the immediate antiandrogen treatment group died compared to 18 out of 51 men (35.3%) in the observation group (P= 0.02), suggesting that immediate antiandrogen therapy improved survival and may have reduced the risk of recurrence in these patients. These benefits persisted after a median follow-up of 11.9 years .
A small increase in the risk for development of diabetes mellitus and/or cardiovascular disease has been reported in patients using ADT [5,14–18]. This extension study was not designed to evaluate these outcomes, although blood glucose and BP were monitored. Clinically significant changes in blood glucose and BP were reported, although it is difficult to assess their significance without a placebo arm comparator. Furthermore, these changes are confounded because of commonly reported comorbidities in the elderly male population. The decision to initiate ADT in men with advanced prostate cancer should be made on an individual basis after considering all relevant clinical risk factors, and patients should be monitored for the development of cardiovascular disease and diabetes .
Combining ADT with radiotherapy has also been shown to improve overall survival in patients with locally advanced prostate cancer. In a study by European Organisation for the Research and Treatment of Cancer, 415 patients with prostate cancer, with intermediate or high-risk disease classification, were randomized to external beam irradiation alone or radiotherapy combined with an LHRH agonist . Patients in the combined treatment arm received 3.6 mg of goserelin s.c. on the first day of radiotherapy and every 4 weeks thereafter for 3 years. Patients in the radiotherapy alone arm received hormone therapy if their disease progressed. The primary endpoint was clinical disease-free survival. More patients achieved the primary endpoint in the combined treatment arm (74%) compared to patients who received radiotherapy alone (40%; P= 0.001). The 5-year overall survival was 78% in the combined treatment arm compared to 62% in the group treated only with radiotherapy (P= 0.001). Therefore, receipt of adjuvant ADT for 3 years showed a significant clinical benefit. The duration of treatment was chosen empirically, and Bolla et al.  suggest that a shorter treatment period may have reduced the incidence of AEs.
Histrelin acetate implants were well tolerated during the extended treatment period in the present study, and some patients received therapy yearly for more than 4 years. Increased incidences of hot flashes, skeletal complications such as decreased bone mineral density and higher fracture risks, sexual dysfunction, and raised body mass index are common class effects of ADT with an LHRH agonist . In the present study, the most frequently reported drug-related AEs were hot flashes (67 patients), which were generally mild to moderate in severity, decreased libido and erectile dysfunction (four patients each).
In the extension study, one patient requested removal of the implant as a result of hot flashes reported as mild. The implant was removed and the AE resolved. This uncommon clinical scenario represents a potential clinical advantage of the implant in that the source of histrelin can be removed if necessary. Recovery of the hypothalamic-pituitary-gonadal axis after implant removal has been described with histrelin in a small study conducted in patients with advanced prostate cancer who were previously treated with a histrelin implant or depot LHRH agonists . Of the patient cohorts, one group had received a histrelin implant 29–37 months previously (n= 7), the second group had received LHRH depot injections every 2 months (n= 3) or 3 months (n= 5), and the third group of newly diagnosed patients received bicalutamide antiandrogen therapy alone (n= 7) and served as a control. Histrelin implants were removed and depot LHRH agonist treatments were discontinued in the first two groups and bicalutamide or flutamide were administered aiming to maintain antiandrogen therapy and prevent disease exacerbation. Serum LH, PSA and testosterone levels were measured in all patients every week. In the group of patients who previously received histrelin implants, testosterone levels increased within 4 weeks in six out of seven (87%) patients and within 10 weeks in one patient after removal. In the LHRH agonist group, testosterone remained suppressed in seven out of eight (87%) patients some 9 months after the last depot injection .
Delays in restoration of testosterone levels after 3-month LHRH depot treatments have been reported previously . The profile of hypothalamic-pituitary-gonadal axis recovery may be different in patients receiving histrelin implants compared to depot injection formulations, and this may represent a clinical advantage in uncommon clinical situations. If these data are confirmed in a larger study, the use of histrelin implants may provide a robust methodology for applying intermittent ADT. Intermittent therapy may improve the health-related quality of life of patients requiring long-term palliative treatment for prostate cancer . There is no current consensus on the optimum period for the interruption of treatment, although long-term studies such as SWOG-9546 (NCT00002651)  may provide supporting evidence for the role of intermittent therapy in the management of prostate cancer.
During the extension study, long-term treatment over multiple years, with histrelin acetate implants replaced annually, confirmed the results obtained in the pivotal clinical trial. Mean serum testosterone levels were consistently suppressed to <20 ng/dL, and treatment was well tolerated with no unexpected side effects or serious drug-related AEs. Replacement of histrelin implants was not associated with a testosterone biochemical surge. Thus, the once-yearly histrelin acetate replacement schedule may offer certain benefits to both patients and physicians.
The study investigators were Drs Neal Shore, Laurence Belkoff, Joseph Chin, H. Jeoffrey Deeths, Hugh Fisher, Marc C. Gittelman, Mark Immergut, E. James Seidmon, Chris Tiegland, David Beccia, Giovanni Columbo, Martin Dineen, James Vestal, John Freeman, Paul Sieber, Walter Pittman, Daniel Saltzstein and Coleman Oswalt.
CONFLICT OF INTEREST
Dr N. Shore has served as a consultant for Amgen, Endo Pharmaceuticals, Ferring, Orion, Sanofi-aventis and Watson Pharmaceuticals. Dr M. S. Cookson has served as a speaker and consultant for Endo Pharmaceuticals. Dr M. C. Gittelman has served as a researcher for Endo Pharmaceuticals. This study was originally supported by Valera Pharmaceuticals. Medical writing and editorial services were supported by Endo Pharmaceuticals, Inc. and provided by Christopher J. Jones, PhD, of inScience Communications, a Wolters Kluwer business.