The mean age of the patients was 75 years. Further demographic and medical characteristics of the patients are summarised in Table . Approximately half of the patients (48%) were treated with leuprolide acetate for the first time. Of the remaining patients, one third were pre-treated with a different monthly depot formulation (either 1- month or 3- monthly) of the Astellas leuprolide acetate, and two thirds were pre-treated with other GnRH analogues. The majority of patients received GnRH analogue monotherapy, and 35.3% were given additional treatment. In most cases the additional treatment was anti-androgen therapy (78,9%, Table ). A punch biopsy had been performed in 95% of the patients before the start of the study. The mean Gleason sum (2-10) was 6.8. Premature discontinuation of therapy was documented for 6% of the patients (n = 76). The most common reasons for discontinuation were loss to follow-up (26%, n = 20) and patient death during the study (22%, n = 17).
Characteristics of documented male patients with advanced prostate cancer (total number = 1273)
Classification of patients receiving monotherapy or combination therapy
Effective reduction of PSA and testosterone levels
Within the first six months, a 94% decrease in the median PSA value from 11.6 ng/mL to 0.7 ng/mL was observed (Figure ). PSA decreased further to a median value of 0.5 ng/mL at the end of the observational period (corresponding to a 96% decrease). At this time point, 50% of the patients had PSA values between 0.1 and 1.9 ng/mL (interquartile range). Measurement of serum testosterone was optional. Testosterone concentrations were available for up to 350 patients, i.e. up to 29% of patients with PSA measurements, at each visit (Figure ). The median serum testosterone concentration decreased from 89 ng/dL to 10 ng/dL during the first six months, and decreased further to 9 ng/dL at the end of the observational period, corresponding to a 90% decrease in serum testosterone.
Median serum concentrations of PSA and testosterone during treatment with 6-monthly leuprolide acetate.
PSA and testosterone concentrations were also analysed in two subpopulations of patients who were pre-treated with other GnRH analogues (patients with complete data only). One of the subpopulations consisted of patients who switched from leuprolide acetate, Takeda Pharmaceutical (Trenantone®) to 6-monthly leuprolide acetate monotherapy (n = 99); the second subpopulation consisted of patients who switched from goserelin acetate, AstraZenca (Zoladex®) to 6-monthly leuprolide acetate monotherapy (n = 57). Within the first six months, a 93% decrease in the median PSA value was observed in the subpopulation that switched from leuprolide acetate, Takeda Pharmaceutical to leuprolide acetate, Astellas Pharma GmbH, from 5.8 ng/mL to 0.4 ng/mL. A 96.5% decrease in the median PSA value from 8.6 ng/mL to 0.3 ng/mL was observed in the subpopulation that switched from goserelin acetate to leuprolide acetate, Astellas Pharma GmbH. The median serum testosterone levels decreased from 150 ng/dL to 17.3 ng/dL during the first six months in the leuprolide acetate, Astellas Pharma GmbH subpopulation, corresponding to an 88% decrease. The median serum testosterone levels decreased from 72.3 ng/dL to 18.0 ng/dL during the first six months in the goserelin acetate subpopulation, and decreased further to 16.3 ng/dL at the end of the observational period, corresponding to a 77% decrease. These data demonstrate an effective reduction of PSA and testosterone levels by leuprolide acetate, Astellas Pharma GmbH in patients who either received a GnRH analogue for the first time or were switched from another GnRH analogue to leuprolide acetate, Astellas Pharma GmbH.
Favourable therapy evaluation
The most frequent reason (90%) for prescribing 6-monthly leuprolide acetate, as given by the participating urologists, was the long dosing interval of the 6-months depot (Figure ). Other common reasons were the small injection volume (20%) and the short needle of the pre-filled syringe (15%). A doctor's assistant prepared the syringe for more than half of the patients (57%), whereas physicians prepared the syringe in 42% of the cases (data was missing for 1% of patients). Handling of the pre-filled syringe was regarded as convenient or very convenient by the majority of users (72%; Figure ).
Figure 2 Final assessment of 6-monthly leuprolide acetate therapy by the participating urologists. Legend. Diagnosis and treatment decisions were at the sole discretion of the treating physicians. The physicians stated that the most frequent reasons for choosing (more ...)
The local tolerability of the product was assessed as good or very good for most patients (92%) (Figure ). Adverse events (AEs) occurred in 108 (9%) of 1273 documented patients (Table ). Non-serious AEs were reported for 69 patients (5%) and serious adverse events (SAEs) were documented in 39 patients (3%). No systematic allergic reactions were reported for any patient. For 17 of 69 patients, a causal relationship between the occurrence of a non-serious AE and the administration of 6-monthly leuprolide acetate was excluded, whereas 34 patients had AEs which were assessed by the physicians as definitely related to treatment. A causality assessment was missing or was deemed not possible for 18 patients with non-serious AEs. Most reported SAEs were tumour progression (i.e. metastasis) or the requirement of surgical measures including radical prostatectomy, surgery and hospitalisation. 25 patients (2%) died during the study. For 33 of 39 patients with SAEs, a causal relationship between the SAE and treatment with 6-monthly leuprolide acetate was excluded or assessed as being unlikely. For one SAE (tumour progression with fatal outcome) in an 82-year-old patient, a causal relationship to 6-monthly leuprolide acetate could not be excluded. A causality assessment was missing for 5 patients with SAEs.
The most common non-serious adverse events
Comparison to previous experiences with 6-monthly leuprolide acetate
In the above-mentioned clinical trial by Crawford and colleagues [4
], 6-monthly leuprolide acetate achieved a 97% decrease in PSA. At the end of the study (Month 12), the mean testosterone concentration of 103 patients was 12.3 ng/dL (corresponding to 0.426 nmol/L), which is well below the castration level. The present study is the first non-interventional study performed since the launch of 6-monthly leuprolide acetate in Germany in 2007. The results of the study show that under the conditions of daily urological practice, PSA and testosterone levels could be decreased to a similar extent as in the clinical trial, confirming the therapeutic benefit of the 6-month depot. In the current investigation, the non-interventional study design provided a valuable tool, despite its known methodological limitations, for the evaluation of the efficacy and tolerability of a new formulation. This study was based on biochemical data that were extrapolated to be an attribute of patient improvement, which might not be realised for every patient in this non-interventional study. An additional limitation could be that interpretation of the data was influenced by approximately 50% of the patients who previously received androgen blockade therapy. In contrast to clinical trials, a larger and more heterogeneous group of patients could be included, and a broader range of physicians could be involved. Furthermore, this non-interventional study allowed the collection of data that was not accounted for in the Crawford clinical trial, such as data on the handling of the syringe and a global assessment of the therapy by the physicians. With regard to the tolerability data, the low incidence of documented hot flushes was notable. Results from clinical trials show that the occurrence of hot flushes is usually very common (> 1/10) [6
]. A possible explanation for this discrepancy may be that many physicians rate the occurrence of hot flushes not as an AE, which needs to be documented, but rather as a 'normal' reaction under hormone deprivation, indicating the effectiveness of the GnRH therapy.