CAMCEVI Prolonged-release suspension for injection Ref.[50038] Active ingredients: Leuprorelin

Pharmacotherapeutic group: Endocrine therapy, gonadotropin releasing hormone analogues
ATC code: L02AE02

Mechanism of action

Leuprorelin mesilate is a synthetic nonapeptide agonist of naturally occurring GnRH that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males. This effect is reversible upon discontinuation of medicinal product therapy. However, the agonist possesses greater potency than the natural hormone and the time to recovery of testosterone levels may vary between patients.

Pharmacodynamic effects

Administration of leuprorelin results in an initial increase in circulating levels of luteinising hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids, testosterone and dihydrotestosterone in males. Continuous administration of leuprorelin results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤50 ng/dL).

Following the first dose of leuprorelin, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold levels (≤50 ng/dL) within 3-4 weeks, and were maintained below castrate threshold with 6-monthly administration of the medicinal product (Figure 1 below). Long-term studies on leuprorelin have shown that continuation of therapy maintains testosterone below the castrate level for up to seven years, and presumably indefinitely.

Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 97% reduction in mean PSA for leuprorelin.

In a phase III randomised clinical study including 970 patients with locally advanced prostate cancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) of whom 483 were assigned to short-term androgen suppression (6 months) in combination with radiation therapy and 487 to long-term therapy (3 years), a non-inferiority analysis compared the short-term to long- term concomitant and adjuvant hormonal treatment with GnRH agonist (triptorelin or goserelin). The 5-year overall mortality was 19.0% and 15.2%, in the short-term and long-term groups, respectively. The observed hazard ratio (HR) of 1.42 with an upper onesided 95.71% CI of 1.79 or two-sided 95.71% CI of 1.09; 1.85 (p=0.65 for non-inferiority), demonstrate that the combination of radiotherapy plus 6 months of androgen deprivation therapy provides inferior survival as compared with radiotherapy plus 3 years of androgen deprivation therapy. Overall survival at 5 years of long-term treatment and short-term treatment shows 84.8% and 81.0% survival, respectively. Overall quality of life using QLQ-C30 did not differ significantly between the two groups (p=0.37). Results are dominated by the population of patients with locally advanced tumours.

Evidence for the indication of high-risk localised prostate cancer is based on published studies of radiotherapy combined with GnRH analogues, including leuprorelin. Clinical data from five published studies were analysed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 8610, and D’Amico et al., JAMA, 2004), which all demonstrate a benefit for the combination of GnRH analogue with radiotherapy. Clear differentiation of the respective study populations for the indications locally advanced prostate cancer and high-risk localised prostate cancer was not possible in the published studies.

Clinical data have shown that radiotherapy followed by 3 years of androgen deprivation therapy is preferable to radiotherapy followed by 6 months of androgen deprivation therapy. The recommended duration of androgen deprivation therapy in medical guidelines for T3-T4 patients receiving radiotherapy is 2-3 years.

Clinical experience on efficacy with CAMCEVI

The multicentre, single-arm, open-label, 48-week phase 3 study of leuprorelin included 137 male patients with high-risk localised and locally advanced prostate cancer in need for androgen deprivation therapy. The efficacy of the medicinal product (two doses administered 24 weeks apart) was evaluated by the percentage of subjects with serum testosterone concentrations suppressed to castrate threshold levels, the effect on serum LH levels as measure for testosterone level control, and the effect on serum PSA levels. The percentage of patients with serum testosterone levels below the castrate threshold (≤50 ng/dL) by day 28 was 98.5% (135 out of 137 patients; intent-to-treat) and 99.2% (123 out of 124 subjects; per protocol), respectively (Figure 1).

Figure 1. Mean serum testosterone concentration over time with CAMCEVI (n=124; per protocol population):

Dotted line indicates the castrate level (50 ng/dL) of serum testosterone.

Mean serum LH levels were significantly reduced after the first injection, and this effect remained until the end of the study (decrease versus baseline by 98% [day 336]).

Tumour size was not directly measured in this study, but an indirect beneficial tumour response can be presumed for leuprorelin as shown by a significant reduction in mean PSA levels over time after injection of the medicinal product (mean of 70 ng/mL at baseline decreased to a mean minimum of 2.6 ng/mL [per-protocol population] at Day 168.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing leuprorelin in all subsets of the paediatric population in prostate carcinoma (see section 4.2 for information on paediatric use).