Degarelix Accord

Pharmacotherapeutic group: Endocrine therapy, Other hormone antagonists and related agents, ATC code: L02BX02 Mechanism of action Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment. A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The serum concentration of dihydrotestosterone (DHT) decreases in a similar manner to testosterone. Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration level of 0.5 ng/ml. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in 97% of patients for at least one year. No testosterone microsurges were observed after re-injection during degarelix treatment. Median testosterone levels after one year of treatment were 0.087 ng/ml (interquartile range 0.06-0.15) N=167. Results of the confirmatory Phase III study The efficacy and safety of degarelix was evaluated in an open-label, multi-centre, randomised, active comparator controlled, parallel-group study. The study investigated the efficacy and safety of two different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) patients discontinued the study, as compared to 32 (16%) patients in the leuprorelin group. Of the 610 patients treated • 31% had localised prostate cancer • 29% had locally advanced prostate cancer • 20% had metastatic prostate cancer • 7% had an unknown metastatic status • 13% had previous curative intent surgery or radiation and a rising PSA Baseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment. The lowest effective maintenance dose of 80 mg degarelix was chosen. Attainment of serum testosterone (T) ≤0.5 ng/ml FIRMAGON is effective in achieving fast testosterone suppression, see Table 2. Table 2: Percentage of patients attaining T≤0.5 ng/ml after start of treatment. Time Degarelix 240/80 mg Leuprorelin 7.5 mg Day 1 52% 0% Day 3 96% 0% Day 7 99% 1% Day 14 100% 18% Day 28 100% 100% Avoidance of testosterone surge Surge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks. None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease of 94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. This difference was statistically significant (p<0.001). Figure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with interquartile ranges). The primary end-point in the study was testosterone suppression rates after one year treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated. Testosterone Reversibility In a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy and radiation) were administered FIRMAGON for seven months followed by a seven months monitoring period. The median time to testosterone recovery (>0.5 ng/mL, above castrate level) after discontinuation of treatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The median time to testosterone >1.5 ng/mL (above lower limit of normal range) was 168 days. Long-term effect Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was greater than 0.5 ng/ml. Table 3: Cumulative probability of testosterone ≤0.5 ng/ml from Day 28 to Day 364. Degarelix 240/80 mg N=207 Leuprorelin 7.5 mg N=201 No. of responders 202 194 Response Rate (confidence intervals)* 97.2% (93.5; 98.8%) 96.4% (92.5; 98.2%) * Kaplan Meier estimates within group Attainment of prostate specific antigen (PSA) reduction Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 95% reduction after 12 months in median PSA for degarelix. The median PSA in the study at baseline was: • for the degarelix 240/80 mg treatment group 19.8 ng/ml (interquartile range: P25 9.4 ng/ml, P75 46.4 ng/ml) • for the leuprorelin 7.5 mg treatment group 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P75 56.5 ng/ml) Figure 2: Percentage change in PSA from baseline by treatment group until day 56 (median with interquartile ranges). This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28. Prostate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85% after one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one year of treatment. From day 56 to day 364 there were no significant differences between degarelix and the comparator in the percentage change from baseline. Effect on prostate volume, disease related mortality and increased disease free survival Neo-adjuvant androgen deprivation therapy prior to radiotherapy has been shown to impact prostate volume reduction, reduced disease related mortallity and increased disease free survival in patients with high-risk localised or locally advanced prostate cancer (RTOG 86-10, TROG 96-01, RTOG 92-02, and Mason M et al. Clinical Oncology 2013). In a randomised parallel-arm, active-controlled, open-label trial, conducted in 244 men with a UICC prostate cancer TNM category T2 (b or c)/T3/T4, N0, M0, Gleason score >7, or prostate specific antigen >10ng/mL and a total prostate volume >30, three months therapy with degarelix (240/80 mg dose regimen) resulted in a 37% reduction in prostate volume as measured by trans-rectal ultrasound scan (TRUS) in patients requiring hormonal therapy prior to radiotherapy and in patients who were candidates for medical castration. The prostate volume reduction was similar to that attained with goserelin plus anti-androgen protection (Mason M et al. Clinical Oncology 2013). Combination with radiotherapy The effect of degarelix in combination with radiotherapy is based on an indirect comparison to the LHRH agonists efficacy data by using the clinical efficacy surrogate endpoints; testosterone suppression and PSA reduction demonstrating non- inferiority to LHRH agonists and indirectly establish efficacy. In patients with locally advanced prostate cancer several randomised long-term clinical trials provide evidence for the benefit of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) compared to RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863). Clinical data from a phase III clinical trial (EORTC 22961) in 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) have shown that radiotherapy followed by long- term therapy (3 years) is preferable to short-term therapy (6 months). Overall total mortality at 5 years in the short-term hormonal treatment and long-term hormonal treatment groups was 19.0% and 15.2% respectively, with a relative risk of 1.42 (an upper one sided 95.71% CI = 1.79; or two sided 95.71% CI = [1.09; 1.85], p = 0.65 for non-inferiority and p = 0.0082 for post-hoc test of difference between groups of treatment). The 5-year mortality specifically related to the prostate cancer in the short-term hormonal treatment and long-term hormonal treatment groups was 4.78% and 3.2% respectively, with a relative risk of 1.71 (95% CI = [1.14 to 2.57], p = 0.002). The recommended duration of androgen deprivation therapy in medical guidelines for T3-T4 patients receiving radiotherapy is 2-3 years. Evidence for the indication of high-risk localized prostate cancer is based on a number of published studies of radiotherapy combined with GnRH analogues. Clinical data from five published studies were analyzed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10 and D'Amico et al., JAMA 2004), which all demonstrate a benefit for the combination of GnRH analogue with radiotherapy. Clear difference of the respective study populations for the indications locally advanced prostate cancer and high-risk localized prostate cancer was not possible in the published studies. Effect on QT/QTc intervals In the confirmatory study comparing FIRMAGON to leuprorelin periodic electrocardiograms were performed. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients. From baseline to end of study the median change for FIRMAGON was 12.0 msec and for leuprorelin it was 16.7 msec. Anti-degarelix antibodies Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for one year and 29% of patients after treatment with FIRMAGON for up to 5.5 years. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after up to 5.5 years of treatment. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with FIRMAGON in all subsets of the paediatric population (see section 4.2 for information on paediatric use).