Skip to main content
NCBI home page
Therapeutic Advances in Urology logoLink to Therapeutic Advances in Urology
. 2015 Jun;7(3):105–115. doi: 10.1177/1756287215574479

Efficacy of degarelix in prostate cancer patients following failure on luteinizing hormone-releasing hormone agonist treatment: results from an open-label, multicentre, uncontrolled, phase II trial (CS27)

Kurt Miller 1,✉, Gabriele Simson 2, Sandra Goble 3, Bo-Eric Persson 4
PMCID: PMC4485413  PMID: 26161141

Abstract

Objective:

To evaluate the efficacy of second-line degarelix in patients with prostate cancer (PCa) after treatment failure with a luteinizing hormone-releasing hormone (LHRH) agonist.

Methods:

This 1-year exploratory, multicentre, open-label phase II trial was performed in 2 patient cohorts (Cohort 1, n = 25; Cohort 2, n = 12) in Germany. Patients with castrate-resistant PCa after primary hormonal treatment received degarelix 240 mg, followed by 11 monthly maintenance doses of 80 mg. The primary endpoint was the proportion of patients with decreasing/stable prostate-specific antigen (PSA) (relative change ⩽+10% of baseline PSA) after 3 months.

Results:

At Month 3, the response rate (intention-to-treat, last observation carried forward analysis) was 16.7% [95% confidence interval (CI): 4.74–37.38] in Cohort 1 and 33.3% (95% CI: 9.92–65.11) in Cohort 2. The probability of completing 12 months without PSA progression was 8.8% (95% CI: 1.51–24.3) in Cohort 1 and 8.3% (95% CI: 0.5–31.1) in Cohort 2. Degarelix was well tolerated; the most frequently reported adverse events were local injection-site reactions.

Conclusions:

In PCa patients who failed LHRH therapy, degarelix was well tolerated and achieved a limited PSA response. Phase III trials show that disease control benefits with degarelix versus agonists are more clearly demonstrated as first-line therapy.

Keywords: degarelix, luteinizing hormone-releasing hormone agonist, prostate cancer

Introduction

Androgen deprivation therapy (ADT) remains the mainstay of advanced prostate cancer (PCa) medical management [Heidenreich et al. 2013]. For many years, luteinizing hormone-releasing hormone (LHRH) agonists were the standard of care in hormonal therapy; however they are associated with an initial testosterone surge, which delays castration and can produce a flare in symptoms in advanced disease [Bubley, 2001; Thompson, 2001]. Gonadotrophin-releasing hormone (GnRH) antagonists offer an alternative approach to ADT which rapidly achieves castrate testosterone levels without the risk of flare [Klotz et al. 2008].

Despite the proven benefit of hormonal therapy, most patients showing an initial response eventually progress to castration-resistant disease in ~18–24 months [Sharifi et al. 2005; Schrijvers, 2007; Hotte and Saad, 2010]. A number of established treatment options for castrate-resistant PCa (CRPC) are now available, including secondary hormone therapy, bone protective therapy in the case of bone metastases, cytotoxic therapy and palliative care [Shore et al. 2012]. Several new therapeutic approaches to CRPC have also been developed in recent years, including sipuleucel-T, an immunotherapeutic vaccine [Kantoff et al. 2010], the cytochrome P450 c17 inhibitor, abiraterone [de Bono et al. 2011], and the androgen receptor antagonist, enzalutamide [Scher et al. 2012].

The use of a GnRH antagonist in patients with disease progression during LHRH agonist therapy has also been investigated. GnRH antagonists suppress follicle-stimulating hormone (FSH), which has been suggested to be implicated in PCa progression, to a greater extent than LHRH agonists [Beer, 2004]. A small, 24 week study evaluated the use of the GnRH antagonist, abarelix, in patients who had progressed on an LHRH agonist [Beer et al. 2003]. Although FSH levels decreased and castrate testosterone levels were maintained, none of the patients had a PSA response [Beer et al. 2003].

The GnRH antagonist, degarelix, has shown similar efficacy to the LHRH agonist, leuprolide, in achieving castration in patients with PCa, but with a faster suppression of testosterone and prostate-specific antigen (PSA), and no testosterone surge [Klotz et al. 2008]. Post hoc analyses have also shown that degarelix improved disease control in terms of superior PSA progression-free survival (PFS) [Tombal et al. 2010] and better control of the bone formation marker serum alkaline phosphatase (S-ALP) [Schröder et al. 2010]. Moreover, a recent pooled analysis of data from five randomised trials of degarelix versus LHRH agonists show higher overall survival during the first year of treatment for men receiving degarelix; since only four patients died from disease progression, this difference was not a consequence of PCa deaths [Klotz et al. 2014]. Pooled analyses also showed that, in patients with a history of cardiovascular disease, there was a significantly lower risk (>50%) of a subsequent cardiovascular event or death over 1 year of treatment with degarelix versus LHRH agonists [Albertsen et al. 2014].

The current paper reports results of an exploratory phase II trial evaluating the efficacy of degarelix as a second-line hormonal treatment in patients with PCa after failure of treatment with an LHRH agonist.

Patients and methods

Trial design

A 1 year uncontrolled exploratory, multicentre, two-phase open-label trial was performed in Germany. The trial was designed to include two cohorts of 25 patients in each phase: seven sites enrolled patients for Cohort 1 (July 2008 to September 2009); and five sites participated for Cohort 2 (May 2010 to December 2011). Recruitment into Cohort 2 was to begin if the primary endpoint was reached for Cohort 1. Although this was not reached, the decision was made to progress with Cohort 2 following adjustments to the inclusion criteria (see below). Patients in both cohorts were scheduled to receive an initiation dose of subcutaneously administered degarelix 240 mg, followed by 11 monthly maintenance doses of degarelix 80 mg.

The trial was performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Guidelines for Good Clinical Practice, and with local regulatory requirements. Study protocols were approved by independent ethics committees and all patients provided written informed consent.

Patients

Patients ⩾18 years of age with histologically confirmed PCa (any stage) who were hormone refractory after primary hormonal treatment were eligible for inclusion. All patients had received ⩾1 year of prior LHRH agonist therapy. Patients had experienced rising PSA levels [two consecutive increases (50% above nadir) ⩾2 weeks apart and ⩾1 PSA value >2.5 ng/ml within the previous 6 months] although receiving LHRH agonist therapy. Testosterone levels ⩽0.5 ng/ml at inclusion were required in Cohort 1. In Cohort 2, testosterone ⩽0.5 ng/ml at inclusion was initially required; however, protocol amendments changed this to ⩾0.32 ng/ml (October 2009) and then to ⩾0.2 ng/ml (January 2011) at inclusion. Patients had an Eastern Cooperative Oncology Group performance status of 0–2 and an estimated life expectancy ⩾12 months. Patients with a previous history/presence of another malignancy, other than PCa or treated squamous/basal cell carcinoma of the skin in the last 5 years, or who had received previous chemotherapy for PCa, were excluded. Pre trial secondary hormonal manipulation after PSA increase was not allowed and anti-androgens as part of complete androgen blockade had to be discontinued ⩾3 months before the first degarelix dose. In Cohort 1, the last dose of LHRH agonist had to be received before Visit 1. In Cohort 2, the first dose of GnRH antagonist had to be administered when the next LHRH agonist dose would have been due.

Assessments

Efficacy assessments

The primary endpoint for both cohorts was the proportion of patients showing decreasing or stable PSA, defined as a relative change from baseline ⩽+10% of baseline PSA, after 3 months’ treatment.

Secondary endpoints were: proportion of patients with castrate testosterone level (⩽0.5 ng/ml) (both cohorts); proportion of patients showing decreasing or stable PSA (relative change from baseline ⩽+10% of baseline PSA, after 1 and/or 2 months’ treatment) (Cohort 2 only); proportion of patients at testosterone levels ⩽0.2 and ⩽0.32 ng/ml (Cohort 2 only); serum levels of testosterone, PSA, luteinizing hormone (LH) and FSH over time (both cohorts); and PSA PFS (PSA progression defined as PSA >+10% from baseline) (both cohorts).

Blood samples for PSA analyses were collected at each visit; samples for testosterone, LH and FSH analyses were taken at screening and prior to degarelix dosing at Months 0–3, 6 and during the end of trial visit. In Cohort 1, PSA analyses and all clinical chemistry, haematology and urinalysis parameters were performed by Esoterix CTS, Mechelen, Belgium, and testosterone, LH and FSH analyses were performed by Esoterix CTS, CA, USA. In Cohort 2, MLM Medical Labs Mönchengladbach GmbH, Germany, performed analyses of PSA, all clinical chemistry, haematology, urinalysis parameters, LH and FSH; analyses for hormone levels of testosterone were performed by Nuvisan GmbH, Neu-Ulm, Germany. In both cohorts, PSA and testosterone values for confirmation of inclusion criteria were based on local laboratory results.

Safety assessments

Safety and tolerability assessments included monitoring of adverse events (AEs), laboratory values (biochemistry, haematology and urine analysis) and clinical variables [electrocardiogram (ECG), a physical examination, vital signs and body weight].

Statistical analyses

The intention-to-treat (ITT) analysis set comprised the data of all patients who received at least one dose of degarelix and had at least one efficacy assessment after dosing. The per-protocol (PP) population comprised ITT patients without any major protocol deviations. The safety population comprised all patients who received at least one dose of degarelix.

The primary efficacy endpoint was analysed for both ITT and PP populations; the ITT analysis was considered primary. For the primary endpoint, the percentage change in PSA from baseline to 3 months or the last available visit, i.e. last observation carried forward (LOCF), within the first 3 months was used to assess treatment response. Due to between-patient variability in PSA, all values are expressed as percentage change from baseline. The proportion of patients with a response was summarized for the ITT population. Response (stabilization or decrease) was defined as a PSA difference ⩽+10% of baseline level. The imprecision in the proportion estimate was expressed using the exact Clopper–Pearson 95% confidence interval (CI; two-sided). Percentage change in PSA from baseline was also summarized with descriptive statistics.

Secondary efficacy endpoints were analysed for both ITT and PP populations. The change and percentage change from baseline for serum levels of testosterone, PSA, LH and FSH, and the proportion of patients at castrate level was summarized with descriptive statistics using both observed case (OC) and LOCF methodology.

Time to first occurrence of PSA progression was the number of days from the first degarelix dose to the first event of PSA progression. PSA PFS was estimated using Kaplan–Meier methodology.

Sensitivity analyses included the proportion of patients with PSA change from baseline ⩽+10% after 3 months for the PP population (LOCF and OC); OC analysis of this variable was performed for both ITT and PP populations.

No formal power calculation was performed to assess the sample size as this was an explorative pilot trial. The chosen sample size of 25 patients planned to be enrolled in Cohort 1 was considered sufficient to determine treatment effect, assuming a 20% response rate would justify the continuation of the trial with a second cohort. The response rate of 20% was based on the estimated response rate in the hormone-refractory/castrate-resistant situation when adding, for example, anti-androgens [Kucuk et al. 2001].

Results

Patients

In Cohort 1, 25 patients received trial medication (safety population). The ITT population comprised 24 patients (1 did not have any efficacy assessment after dosing). Four ITT patients with ⩾1 major protocol deviation were excluded from the PP analysis (n = 20). In addition, one patient had a major protocol violation at the 5-month visit and so only data up to and including the 4-month visit were used in the PP analysis; he was included in the primary analysis after 3 months. In Cohort 1, 24 patients discontinued treatment due to lack of efficacy (n = 19), AEs (n = 1), protocol violation (n = 1) and withdrawal of informed consent (n = 3). In Cohort 2, due to poor recruitment and a high number of screening failures, enrolment ceased at 12 patients (ITT and safety populations); 10 patients were included in the PP population. A total of 11 patients discontinued due to lack of efficacy (n = 8), protocol violation (n = 2) or withdrawal of consent (n = 1). Baseline patient characteristics for Cohorts 1 and 2 are summarized in Table 1.

Table 1.

Patient demographics and baseline characteristics for patients in Cohorts 1 and 2.

Characteristic Cohort 1 Cohort 2
Median (SD) age, years 73.5 (52–85) 75 (72–88)
Median (range) BMI, kg/m2 28.7 (22.9–44.8) 28.7 (23.5–35.8)
Median (range)
Testosterone, ng/ml 0.085 (0.015–1.00) 0.075 (0.05–1.44)
PSA, ng/ml 10.4 (2.1–201.8) 9.13 (0.587–669)
Stage of disease at enrolment, n (%)
 Localized 1 (4) 2 (17)
 Locally advanced 9 (38) –
 Metastatic 7 (29) 5 (42)
 Not classifiable 7 (29) 5 (42)
Gleason score
 2–4 1 (4) 3 (25%)
 5–6 4 (17) 2 (17%)
 7–10 19 (79) 7 (58%)
Open in a new tab

Localized = T 1/2 and NX or N0, and M0; locally advanced = [T3/4 and (NX or N0) and M0] or [N1 and M0]; metastatic = M1.

BMI, body mass index; PSA, prostate-specific antigen; SD, standard deviation.

Characteristics were broadly similar between groups, mainly comprising patients with advanced/metastatic disease. Testosterone levels were also similar in the two cohorts, despite differences in the inclusion criteria. In total, 16 patients (67%) in Cohort 1 and seven patients (58%) in Cohort 2 had received previous anti-androgen treatment.

Efficacy

Primary endpoint

Cohort 1

At Month 3, the response rate (LOCF analysis) was 16.7% (95% CI: 4.74–37.38) (4/24 patients). PSA profiles for the 3 responders in the trial at Month 3 are shown in Figure 1a; a fourth responder (not shown in Figure 1) withdrew from the trial at 2 months but was included as a responder in the LOCF analysis.

Figure 1.

Figure 1.

Open in a new tab

PSA profiles of patients in (a) Cohort 1 (Patients A1–C1) and (b) Cohort 2 (Patients A2–D2) who responded to degarelix treatment and remained in the study at Month 3.

PSA, prostate-specific antigen.

The sensitivity analyses showed that the response rate was 15.0% (95% CI: 3.21–37.89) (3/20 patients) for ITT OC analysis, 10.0% (95% CI: 1.23–31.70) (2/20 patients) for the PP LOCF analysis, and 11.1% (95% CI: 1.38–34.71) (2/18 patients) for the PP OC analysis.

Cohort 2

At 3 months, the response rate was 33.3% (95% CI: 9.92–65.11) (4/12 patients). PSA profiles for the responders in the trial at month 3 are shown in Figure 1b.

There were no notable differences between the different estimations of the sensitivity analyses and no worsening of the outcome at Month 3 compared with the primary analysis. Thus, the response rates were 44.4% (95% CI: 13.70–78.80) for the ITT OC analysis, 40.0% (95% CI: 12.16–73.76) for the PP LOCF analysis and 44.4% (95% CI: 13.70–78.80) for the PP OC analysis.

Secondary endpoints

Cohort 1

Changes from baseline in testosterone, PSA, LH and FSH at Month 3 are summarized in Table 2. Overall, PSA levels showed a slight increase, whereas LH, FSH and testosterone all decreased at Month 3. In LOCF analyses, LH levels were below the limit of detection in 22 patients and had decreased from baseline in two patients; FSH had decreased in 19 patients and testosterone had decreased in 10 patients (40%).

Table 2.

Changes from baseline in serum levels of PSA, LH, FSH and testosterone at Month 3.

Cohort 1 Cohort 2
PSA, ng/ml (n = 20) (n = 9)
Mean (± SD) 13.6 (27.1) −6 (70.3)
Median (range) 4.1 (−18.2, 83.2) 0.63 (−178, 83.5)
Median % 41.7 (−84.8, 194.4) 18.4 (−26.6, 1195)
LH, IU/l (n = 19) (n = 9)
Mean ± SD −0.54 (2.27) −0.7 (2.1)
Median (min., max.) NA (−9.9, 0.2) 0 (−6.3, 0)
FSH, IU/l (n = 19) (n = 9)
Mean ±SD −1.68 (3.21) −2.09 (1.71)
Median (min., max.) NA (−14, 1.3) −1.2 (−4.9, −0.1)
Testosterone, ng/ml (n = 21) (n = 9)
Mean ± SD −0.03 (0.19) −0.165 (0.473)
Median (min; max) NA (−0.9, 0.1) 0 (−1.38, 0.259)
Open in a new tab

ITT analysis set, observed cases.

FSH, follicle-stimulating hormone; ITT, intent-to-treat; IU, international units; LH, luteinizing hormone; NA, not available; PSA, prostate-specific antigen; SD, standard deviation.

Testosterone was ⩽0.5 ng/ml in all patients throughout the trial with only small changes versus baseline. PSA increased during the first 3 months. After this time, when a majority of patients discontinued treatment, the median change (increase) from baseline in PSA in those remaining (four patients remained at Month 4 onwards) was 2.8 ng/ml. However, of the four patients remaining in the trial at Month 4, three were characterized as responders at Month 3. FSH levels had decreased by about 40% at the 1-month visit and stayed at this low level for the rest of the trial.

PSA progression (ITT analysis) occurred in 21 patients, most around Day 28. The probability of completing the trial without PSA progression was 8.8% (95% CI: 1.51–24.3). Similar results were observed for the PP population. A Kaplan–Meier estimate of time to PSA >10% (ITT) is shown in Figure 2a.

Figure 2.

Figure 2.

Open in a new tab

Kaplan–Meier estimates of time to PSA increase >10% (primary efficacy endpoint; ITT analysis) for (a) Cohort 1 and (b) Cohort 2.

Shaded areas show range of the 95% confidence interval.

ITT, intent-to-treat; PSA, prostate-specific antigen.

Cohort 2

The proportion of patients showing a response was 66.7% (95% CI: 29.9–92.51) (6/9 patients) after 1 month and 40.0% (95% CI: 12.16 to 73.76) (4/10 patients) after 2 months of treatment, using OC results in the ITT. Similar results were observed in the PP analysis.

Changes from baseline in testosterone, PSA, LH and FSH at Month 3 are summarized in Table 2. All of these variables showed a reduction at Month 3; of nine patients with documented values at this time point, all showed a reduction in FSH, while testosterone had decreased in four (44.4%) patients; LH was reduced in one (11.1%) patient and below the limit of detection [0.1 international unit (IU)/l] in the remainder.

Overall, there were only minor median changes from baseline in testosterone and PSA levels of patients who remained in the study. No median change from baseline in LH was observed in patients who remained in the study until Day 112, and there was a slight increase on Days 168 and 336. FSH levels in patients who remained in the study tended to decrease over time until Day 112 and then returned to near baseline levels until Day 336.

The estimated probability of no PSA failure was 75.0% (95% CI: 40.8–91.2) after 1 month and 41.7% (95% CI: 15.2–66.5) after 2 months. In the ITT analysis, 11 patients had experienced PSA progression (PSA > +10% from baseline) by Month 12. The probability of completing the 12-month trial without PSA progression was 8.3% (95% CI: 0.5–31.1). The Kaplan–Meier estimate of time to PSA >10% (ITT) is shown in Figure 2b.

The estimated probability of no testosterone escape: to >0.2 ng/ml was 100% after 1 month, 71% after 2–4 months, and 47% after 7–12 months; to >0.32 ng/ml was 100% after 1–2 months, 89% after 3–4 months, 67% after 5 months and 44% after 7–12 months; and to >0.5 ng/ml was 100% after 1–2 months, 89% after 4 months, 67% after 5 months and 44% after 7–12 months. Kaplan–Meier estimates of time to testosterone escape >0.2, >0.32 and >0.5 ng/ml are shown in Figure 3.

Figure 3.

Figure 3.

Open in a new tab

Kaplan–Meier estimates of time to testosterone escape in Cohort 2 to (a) first >0.2 ng/ml, (b) first >0.32 ng/ml and (c) first >0.5 ng/ml (ITT analysis).

Shaded areas show range of the 95% confidence interval.

ITT, intent-to-treat.

Safety

No deaths occurred in either cohort

Cohort 1

In total, AEs were reported by 18 patients (72%); most were mild (n = 14 patients) or moderate (n = 8 patients) with only three patients reporting severe AEs. Treatment-emergent AEs occurring in more than one patient were: injection-site erythema (10 patients), injection-site swelling (eight patients), injection-site pain (three patients), injection-site induration (two patients) and hot flush (two patients). Only one patient (4%) discontinued due to an AE (carotid artery stenosis). The three serious AEs reported (bladder tamponade, carotid artery stenosis and colon cancer) were considered by the investigators to be unrelated or unlikely to be related to study treatment.

Mean changes from baseline in clinical chemistry and haematology parameters were small, with no consistent trends. No patients had any markedly abnormal changes in vital signs or any abnormal, clinically significant ECG alterations. One patient had an abnormal, clinically significant physical examination finding (suspected bone metastases), which was present at screening.

Cohort 2

Treatment-emergent AEs occurred in 10 (83%) patients; most were mild (seven patients) or moderate (six patients), while 1 patient experienced severe AEs. One patient also experienced serious AEs (anaemia and anaemia of malignant disease), which were considered unrelated to degarelix treatment. No patient discontinued due to an AE. The most frequent AE was injection-site erythema (six patients), followed by injection-site swelling (five patients); apart from two events of anaemia of malignant disease in one patient, other AEs occurred once in single patients only.

None of the few markedly abnormal changes in laboratory parameters was considered clinically significant and there were no markedly abnormal changes in any vital sign parameters. There was no clinically significant abnormal ECG at end of trial and no ECG worsened from screening. Weight gain in one patient was considered a mild AE that was not related to degarelix.

Discussion

Head-to-head comparison with an LHRH agonist has shown advantages of degarelix as first-line hormonal therapy for PCa [Schröder et al. 2010; Tombal et al. 2010; Shore et al. 2012]; moreover, the differential efficacy versus agonists is notable in advanced disease. Thus, PSA failure rates with degarelix were significantly lower in those at highest risk of PSA failure (baseline PSA >20 ng/ml) [Tombal et al. 2010] and there was better S-ALP control with degarelix in metastatic disease, which may indicate prolonged control of skeletal metastases [Schröder et al. 2010].

CRPC cells show a high concentration of GnRH receptors [Straub et al. 2001], providing a rationale for targeting this site and blocking GnRH receptors directly with an antagonist. Studies on human PCa cell lines in vivo showed a possible direct effect of GnRH antagonists on hormone-refractory cell lines [Jungwirth et al. 1997a, 1997b; Lamharzi et al. 1998a, 1998b]. The current exploratory study examines degarelix in patients with PCa after LHRH agonist therapy failure, and primarily whether degarelix could stabilize or reverse PSA progression.

The response rates with degarelix in these two cohorts (16.7% in Cohort 1 and 33% in Cohort 2) should be viewed within the context of other therapeutic options for patients with progressive disease after ADT. According to the European Association of Urology guidelines, in relapsing patients, anti-androgen withdrawal should be systematically considered as a first-line modality [Heidenreich et al. 2013]. With anti-androgen withdrawal, around a third of patients respond (>50% PSA decrease), for a median duration of ~4 months [Heidenreich et al. 2013]. Addition of the anti-androgen bicalutamide in patients with advanced PCa who failed first-line hormonal therapy has been associated with a 20% response rate [Kucuk et al. 2001]. Substitution of one anti-androgen for another has also been used in patients on complete androgen blockade experiencing PSA progression; in one study, an overall >50% PSA decrease was observed in 35.8% of men, irrespective of any previous withdrawal effect [Suzuki et al. 2008]. Agents such as aminoglutethimide, ketoconazole and corticosteroids have also been used second-line [Heidenreich et al. 2013]. For example, second-line ketoconazole added to previous or simultaneous anti-androgen withdrawal produced a greater PSA response than anti-androgen withdrawal alone [Small et al. 2004]. PSA responses have also been achieved with diethylstilboestrol; however, this carries the risk of potentially serious thromboembolic AEs [Heidenreich et al. 2013]. Moreover, European drug licensing authorities do not indicate the use of ketoconazole and oestrogens in this setting [Shore et al. 2012]. Also, recent trials with newer agents, such as abiraterone [Ryan et al. 2013] and enzalutamide [Beer et al. 2014], have shown significantly higher PSA response rates than controls in patients with metastatic CRPC who failed on prior ADT but had not yet received chemotherapy.

The probability of completing 12 months without PSA progression was approximately 8% in both cohorts and only 1 patient (in Cohort 2) completed the 12-month trial. This likely reflects the predominantly advanced and aggressive nature of the disease in this population who failed on previous LHRH agonists and had rising PSA; only 4–17% of patients had localized disease and 58–79% had a Gleason score ⩾7 at enrolment. The high frequency of withdrawal due to lack of efficacy/rising PSA is not unexpected in such complicated patient groups.

The observation of decreased FSH in both cohorts, but only a modest response rates appears to agree with earlier trials with the GnRH antagonist, abarelix, in patients with PCa progression during LHRH agonist therapy or following orchiectomy, which demonstrated decreasing levels of FSH and maintained castrate levels of testosterone but without a clear clinical response [Beer et al. 2003, 2004; Beer, 2004]. Accordingly, the hypothesis [Beer et al. 2003, 2004; Beer, 2004] that FSH signalling may contribute to progression of hormone-refractory PCa remains to be confirmed. Alternative explanations for the lack of correlation between FSH and PSA-based clinical response in this patient population include tumours becoming FSH-independent, or that local PCa cell FSH synthesis [Dirnhofer et al. 1998; Ben-Josef et al. 1999] may be more important than circulating FSH for tumour progression and, hence, clinical response.

Both cohorts showed reduced testosterone levels at 3 months. Some studies suggest beneficial effects associated with achieving and maintaining testosterone at castrate levels or lower. In patients with nonmetastatic PCa receiving LHRH agonists (± anti-androgens), androgen-independent PFS was significantly shorter in patients with breakthrough testosterone >0.32 ng/ml versus those not experiencing breakthrough [Morote et al. 2007]. In addition, long-term testosterone control has been suggested to reduce mortality risk among patients with metastatic PCa; a high testosterone at 6 months was associated with a 1.33-fold increase in PCa-specific mortality risk [Perachino et al. 2010]. Furthermore, the effect of testosterone breakthrough above conventional castrate levels was examined in a large localized PCa population database while on continuous LHRH agonists adjuvant to curative radiotherapy. Achieving consistent castrate testosterone levels <0.5 ng/ml was associated with a lower PSA nadir before and after radiotherapy and a lower risk of subsequent biochemical relapse [Pickles and Tyldesley, 2011].

Degarelix was well tolerated in our trial, displaying an overall safety profile in line with previous studies [Gittelman et al. 2008; Klotz et al. 2008; Van Poppel et al. 2008]. Long-term treatment with ADT is anticipated to produce AEs associated with testosterone suppression (e.g. hot flush, loss of libido, impotence, infertility, increased sweating). In this trial, the most frequently reported AEs were local injection-site reactions such as injection-site erythema and swelling. Testosterone suppression-related AEs were infrequently reported; for example, hot flush [occurring in only two patients (8%) in Cohort 1] was much less frequent than previously reported in 1-year degarelix trials [Gittelman et al. 2008; Klotz et al. 2008; Van Poppel et al. 2008]. This may reflect the fact that patients previously received ADT before entering the trial. In previous degarelix trials, the incidence of AEs associated with testosterone suppression (e.g. hot flush) tended to diminish over time [Crawford et al. 2011].

The small patient numbers and the high withdrawal rates in the current study make it difficult to draw firm conclusions on efficacy. Another limitation is the lack of a control group. However, this hypothesis-generating trial opens the way for further larger controlled trials in this population of patients with suboptimal testosterone suppression after first-line therapy with LHRH agonists.

Conclusion

This phase II trial showed that in PCa patients who failed on a LHRH agonist, further ADT with degarelix is well tolerated and can produce a limited treatment response in terms of stabilization or decrease in PSA. While the small size of these exploratory studies and high withdrawal rate prevents firm conclusions on efficacy, some of these advanced and symptomatic patients did gain a measure of PSA control from degarelix use after failure of LHRH agonist therapy. Further studies are required to confirm this and to evaluate the most effective treatment sequence in patients with symptomatic and nonsymptomatic disease who fail first-line treatment with LHRH agonists. Indeed, results from phase III pivotal trials indicate that benefits with regard to better disease control (compared with agonists) are more clearly demonstrated when degarelix is used as first-line ADT.

Acknowledgments

Medical writing assistance (funded by Ferring Pharmaceuticals) was provided by Thomas Lavelle of Bioscript Medical.

Footnotes

Funding: This study was funded by Ferring Pharmaceuticals.

Conflict of interest statement: K.M. received consultancy fees from Ferring and Astellas. S.G. and B.-E.P. are Ferring employees.

G.S. declares no conflicts of interest in preparing this article.

Contributor Information

Kurt Miller, Department of Urology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

Gabriele Simson, Urologische Praxis, Lauenburg Elbe, Germany.

Sandra Goble, Ferring Pharmaceuticals A/S, Copenhagen, Denmark.

Bo-Eric Persson, Ferring Pharmaceuticals, Saint-Prex, Switzerland.

References

  1. Albertsen P., Klotz L., Tombal B., Grady J., Olesen T., Nilsson J. (2014) Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 65(3): 565–573. [DOI] [PubMed] [Google Scholar]
  2. Beer T. (2004) Experimental use of GnRH antagonists as second-line hormonal therapy. Rev Urol 6(Suppl. 7): S33–S38] [PMC free article] [PubMed] [Google Scholar]
  3. Beer T., Armstrong A., Rathkopf D., Loriot Y., Sternberg C., Higano C., et al. (2014) Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371: 424–433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beer T., Garzotto M., Eilers K., Lemmon D. (2003) Phase II study of abarelix depot for androgen independent prostate cancer progression during gonadotropin-releasing hormone agonist therapy. J Urol 169: 1738–1741. [DOI] [PubMed] [Google Scholar]
  5. Beer T., Garzotto M., Eilers K., Lemmon D., Wersinger E. (2004) Targeting FSH in androgen-independent prostate cancer: abarelix for prostate cancer progressing after orchiectomy. Urology 63: 342–347. [DOI] [PubMed] [Google Scholar]
  6. Ben-Josef E., Yang S., Ji T., Bidart J., Garde S., Chopra D., et al. (1999) Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 161: 970–976. [PubMed] [Google Scholar]
  7. Bubley G. (2001) Is the flare phenomenon clinically significant? Urology 58(2 Suppl. 1): 5–9. [DOI] [PubMed] [Google Scholar]
  8. Crawford E., Tombal B., Miller K., Boccon-Gibod L., Schröder F., Shore N., et al. (2011) A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol 186: 889–897. [DOI] [PubMed] [Google Scholar]
  9. de Bono J., Logothetis C., Molina A., Fizazi K., North S., Chu L., et al. (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364: 1995–2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dirnhofer S., Berger C., Hermann M., Steiner G., Madersbacher S., Berger P. (1998) Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. Prostate 35: 212–220. [DOI] [PubMed] [Google Scholar]
  11. Gittelman M., Pommerville P., Persson B., Jensen J., Kold Olesen T. (2008) A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America. J Urol 180: 1986–1992. [DOI] [PubMed] [Google Scholar]
  12. Heidenreich A., Bastian P., Bellmunt J., Bolla M, Joniau S., Mason M., et al. (2013) Guidelines on prostate cancer 2013. Arnhem, Netherlands: European Association of Urology. [Google Scholar]
  13. Hotte S., Saad F. (2010) Current management of castrate-resistant prostate cancer. Curr Oncol 17(Suppl. 2): S72–S79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jungwirth A., Galvan G., Pinski J., Halmos G., Szepeshazi K., Cai R., et al. (1997a) Luteinizing hormone-releasing hormone antagonist cetrorelix (SB-75) and bombesin antagonist RC-3940-II inhibit the growth of androgen-independent PC-3 prostate cancer in nude mice. Prostate 32: 164–172. [DOI] [PubMed] [Google Scholar]
  15. Jungwirth A., Pinski J., Galvan G., Halmos G., Szepeshazi K., Cai R., et al. (1997b) Inhibition of growth of androgen-independent DU-145 prostate cancer in vivo by luteinising hormone-releasing hormone antagonist cetrorelix and bombesin antagonists RC-3940-II and RC-3950-II. Eur J Cancer 33: 1141–1148. [DOI] [PubMed] [Google Scholar]
  16. Kantoff P., Higano C., Shore N., Berger E., Small E., Penson D., et al. (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363: 411–422. [DOI] [PubMed] [Google Scholar]
  17. Klotz L., Boccon-Gibod L., Shore N., Andreou C., Persson B., Cantor P., et al. (2008) The efficacy and safety of degarelix: a 12-month, comparative, randomized, open label, parallel-group phase III study in patients with prostate cancer. BJU Int 102: 1531–1538. [DOI] [PubMed] [Google Scholar]
  18. Klotz L., Miller K., Crawford E., Shore N., Tombal B., Karup C., et al. (2014) Disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists. Eur Urol published online ahead of print on Jan 9, 2014. [DOI] [PubMed] [Google Scholar]
  19. Kucuk O., Fisher E., Moinpour C., Coleman D., Hussain M., Sartor A., et al. (2001) Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235). Urology 58: 53–58. [DOI] [PubMed] [Google Scholar]
  20. Lamharzi N., Halmos G., Jungwirth A., Schally A. (1998) Decrease in the level and mRNA expression of LH-RH and EGF receptors after treatment with LH-RH antagonist cetrorelix in DU-145 prostate tumor xenografts in nude mice. Int J Oncol 13: 429–435. [DOI] [PubMed] [Google Scholar]
  21. Lamharzi N., Schally A., Koppan M. (1998) Luteinizing hormone-releasing hormone (LH-RH) antagonist cetrorelix inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of IGF-II in tumors. Regul Pept 77: 185–192. [DOI] [PubMed] [Google Scholar]
  22. Morote J., Orsola A., Planas J., Trilla E., Raventós C., Cecchini L., et al. (2007) Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol 178: 1290–1295. [DOI] [PubMed] [Google Scholar]
  23. Perachino M., Cavalli V., Bravi F. (2010) Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int 105: 648–651. [DOI] [PubMed] [Google Scholar]
  24. Pickles T., Tyldesley S. (2011) Testosterone breakthrough during LHRH agonist androgen deprivation with curative radiation: impact on PSA kinetics and subsequent biochemical outcomes. Eur Urol Suppl 10: 239 (abstract 752). [Google Scholar]
  25. Ryan C., Smith M., de Bono J., Molina A., Logothetis C., de Souza P., et al. (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368: 138–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Scher H., Fizazi K., Saad F., Taplin M., Sternberg C., Miller K., et al. (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367: 1187–1197. [DOI] [PubMed] [Google Scholar]
  27. Schrijvers D. (2007) Androgen-independent prostate cancer. Recent Results Cancer Res 175: 239–249. [DOI] [PubMed] [Google Scholar]
  28. Schröder F., Tombal B., Miller K., Boccon-Gibod L., Shore N., Crawford E., et al. (2010) Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int 106: 182–187. [DOI] [PubMed] [Google Scholar]
  29. Sharifi N., Dahut W., Steinberg S., Figg W., Tarassoff C., Arlen P., et al. (2005) A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int 96: 985–989. [DOI] [PubMed] [Google Scholar]
  30. Shore N., Mason M., de Reijke T. (2012) New developments in castrate-resistant prostate cancer. BJU Int 109(Suppl. 6): 22–32. [DOI] [PubMed] [Google Scholar]
  31. Small E., Halabi S., Dawson N., Stadler W., Rini B., Picus J., et al. (2004) Antiandrogen withdrawal alone or in combination with ketoconazole in androgen independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 22: 1025–1033. [DOI] [PubMed] [Google Scholar]
  32. Straub B., Müller M., Krause H., Schrader M., Goessi C., Heicappell R., et al. (2001) Increased incidence of luteinizing hormone-releasing hormone receptor gene messenger RNA expression in hormone-refractory human prostate cancers. Clin Cancer Res 7: 2340–2343. [PubMed] [Google Scholar]
  33. Suzuki H., Okihara K., Miyake H., Fujisawa M., Miyoshi S., Matsumoto T., et al. (2008) Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade. J Urol 180: 921–927. [DOI] [PubMed] [Google Scholar]
  34. Thompson I. (2001) Flare associated with LHRH-agonist therapy. Rev Urol 3(Suppl. 3): S10–S14. [PMC free article] [PubMed] [Google Scholar]
  35. Tombal B., Miller K., Boccon-Gibod L., Schröder F., Shore N., Crawford E., et al. (2010) Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 57: 836–842. [DOI] [PubMed] [Google Scholar]
  36. Van Poppel H., Tombal B., de la Rosette J., Persson B., Jensen J., Kold Olesen T. (2008) Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker-results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer. Eur Urol 54: 805–813. [DOI] [PubMed] [Google Scholar]

Articles from Therapeutic Advances in Urology are provided here courtesy of SAGE Publications

RESOURCES