Introduction

Hormonal therapy involving luteinizing hormone (LH)-releasing hormone agonists (LHRHas) is a widely used systemic treatment for prostate cancer and is recommended in the European Association of Urology guidelines on prostate cancer for use in patients with locally advanced and metastatic disease.¹ LHRHas were initially administered as daily injections to patients but treatment advances have made possible the delivery of depot formulations of monthly, 3-monthly and, more recently, 6-monthly dosages.² Sustained-release parenteral depot formulations, in which the hydrophilic leuprorelin acetate is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide is released from these depot formulations at a functionally constant daily rate for 1 or 3 months, dependent on the type of polymer used. In patients with prostate cancer, serum testosterone levels are reduced to castrate levels (50 ng per 100 ml) within 1 month of the first injection of either the 1-month (1M) depot of 3.75 mg or the 3-month (3M) depot of 11.25 mg leuprorelin acetate.³ Both formulations have been shown to be equally effective in delaying tumour progression and alleviating symptoms of locally advanced and metastatic prostate cancer.³

The availability of a choice of the 1- and 3M depot formulations provides more individualized, patient-orientated treatment. The 3M depot coincides with regular oncological patient checkup visits of 3 and 6 months. The development of a 6-month (6M) formulation extends this principle. The reduction in the number of injections may also reduce the stress that injections cause to this often elderly population of patients.

The primary objectives of this study were to evaluate the safety and tolerability of two new 6M depot formulations of leuprorelin acetate in prostate cancer patients compared with the 3M depot over a treatment period of 1 year. The secondary objective was comparative efficacy, for example clinical response based on European Organization for Research and Treatment of Cancer (EORTC) criteria, response rate by time point for testosterone suppression.

Patients and methods

The study was a randomized, open-label, European multicentre, three-armed study in men with newly diagnosed prostate cancer or prostate-specific antigen (PSA) relapse after radiotherapy or radical prostatectomy. In total, 42 centres in Germany, Austria and Poland participated in the study. Included in the study were patients aged 18–85 years with histologically confirmed prostate cancer of any grade and stage requiring endocrinological castration with a life expectancy of more than 12 months and WHO performance status 0–3. For patients who had not received prior hormonal therapy, testosterone and PSA levels at screening were required to be 150 ng per 100 ml and 1 ng ml^-1, respectively. For patients who had received an LHRHa for <3 months, testosterone level was to be <80 ng per 100 ml before randomization. Main exclusion criteria were prior orchiectomy, cytostatic treatment of prostate cancer or any other cancer within 6 months before study entry, prior hormonal treatment of prostate cancer for >3 months and hormone refractory prostate cancer.

Patients were randomized to one of three groups. Group 1 received four injections of the 3M depot of 11.25 mg leuprorelin acetate at intervals of 3 months (baseline, months 3, 6 and 9); group 2 received two injections of a 6M depot containing 22.5 mg leuprorelin acetate at baseline and month 6; and group 3 received two injections of a 6M depot of 30 mg leuprorelin acetate at baseline and month 6. The primary end points of the study were the number of adverse and serious adverse events (AEs); changes in haematology, biochemistry and vital sign variables and local tolerability. The secondary end points were clinical assessment of prostate cancer and clinical responses based on EORTC criteria (objective) and the Eastern Cooperative Oncology Group/World Health Organization performance status (subjective). Following the injection of the study drugs, testosterone, PSA and leuprorelin acetate levels were measured as additional parameters. Patients were classified as responders if their testosterone level did not reach >50 ng per 100 ml on two consecutive occasions. Response rate by time point at month 12 was defined as response at month 12 if testosterone levels were 50 ng per 100 ml.

Safety analyses were conducted on all patients with at least one injection of study drug (safety population). Efficacy analyses were conducted on the intention-to-treat population, which comprised all patients with at least one injection of study medication and at least one efficacy assessment after the first injection of study medication.

Statistics

Randomization was performed according to the randomization scheme 1:2:2 (11.25:22.5:30 mg). Descriptive statistics were used for demographic and baseline characteristics and for the primary safety end points in the safety population. Testing was performed for statistical significance of progression (objective response based on EORTC criteria), using a ² test, giving a P-value for a test of no difference between treatment groups. No adjustment was performed for multiple tests, and the tests were not pre-specified. The secondary efficacy end points were analysed using the intention-to-treat population. The trial was conducted in accordance with the Declaration of Helsinki, the The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines and ethics committee approval for each investigator. All patients gave written informed consent.

Results

The 6M 30 mg depot was selected for submission for approval in European countries due to superior efficacy in terms of response rates and a similar safety profile compared with the 22.5 mg depot.⁴ Thus, only data on the 11.25 mg 3M depot and 6M depot containing 30 mg are reported here. Of the 296 patients enrolled in the study, 58 patients were randomized to treatment with the 11.25 mg 3M depot and 120 with the 30 mg 6M depot. Baseline patient characteristics are shown in Table 1. The treatment groups were well balanced with regard to WHO performance status; the majority of patients showed status 0 or 1 and few patients had grade 2 or 3. Overall, 21% of patients had previously received treatment with an LHRHa.

Table 1 - Baseline patient characteristics in patients with newly diagnosed prostate cancer or PSA relapse after radiotherapy or radical prostatectomy treated over a 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate.

Full table

Safety analysis

Safety analyses were conducted for all patients with at least one injection of study drug (safety population). A total of 58 and 120 patients were eligible in the 3- and 6M depot arms, respectively. The incidence of the most common adverse drug reactions (adverse drug reactions, defined as definite, probable, possible or unknown relationship to study drug) is shown in Table 2. The most common adverse drug reaction was flushing. No significant findings or apparent differences between the treatment groups were observed in mean changes from baseline to last value in any haematological, biochemistry or vital sign variables.

Table 2 - Incidence of most common ADRs in patients treated over a 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate.

Full table

The number of injection-site reactions reported and the number of patients experiencing them increased with a higher dose. Of the total number of injections given, injection-site reactions occurred with 4/197 (2%) injections in the 3M depot arm and 26/221 (11.8%) injections in the 6M depot arm. None of these events were assessed as severe and about two-thirds were considered mild. Injection-site indurations were seen in two patients (3.4%) and seven patients (5.8%) with the 3M and the 6M depot groups, respectively.

The incidence of AEs and serious AEs are shown in Table 3. The percentage of patients who experienced any AE was similar in both groups as were the adverse drug reactions. There were no serious AEs with positive causal relationship to the study medication. Overall, the number of patients withdrawing due to AEs was very low at 3.9% (7/178). During the treatment period, two patients died in the 3M group (n=58) and four in the 6M group (n=120); all deaths were unrelated to the study drug.

Table 3 - Patients with AEs and SAEs treated over a 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate.

Full table

Efficacy analyses

Efficacy analyses were conducted for the intention-to-treat population where 58 and 120 patients were evaluable for the 3M and the 6M groups, respectively. The EORTC response criteria assessed at the final visit indicate that complete remission was not seen in either group. Partial remission was seen in 46.6% in the 3M group and in 50.8% in the 6M group, and objective stabilization in 46.6 and 34.2% in the 3M and the 6M groups, respectively. Objective progression was documented in 3.4 and 9.2% in the 3M and the 6M groups, respectively, at any point during the study conduct. No data were given for 3.4% of patients in the 3M group and 5.8% of patients in the 6M group. There was no relevant difference between the 3M 11.25 mg depot and the 6M depot 30 mg in terms of EORTC response criteria. The difference in progression rates was not statistically significant between the two groups (P=0.1570, ² test). At final examination at month 12, more than 90% of patients in both groups had not progressed.

The Eastern Cooperative Oncology Group/World Health Organization performance status at final examination revealed that 56.9 and 58.3% in the 3- and 6M groups, respectively, were assessed as grade 0, whereas 36.2 and 28.3% were assessed as grade 1. No difference was observed between the groups with regard to performance scale at baseline and at final visit.

Further efficacy parameters were serum levels of testosterone, LH, follicle-stimulating hormone, PSA and leuprorelin in responders. No relevant differences could be seen between the treatment groups for all parameters. The median values of testosterone (Figure 1) ranged from 12.0 to 15.0 ng per 100 ml for the 3M depot and from 12.0 to 15.0 ng per 100 ml for the 6M depot from months 1 to 12 during the treatment course. The response rate by time point at month 12 was 100% (42/42) for the 3M depot and 98% (96/98) for the 6M depot group. If all measured serum testosterone levels from months 1 to 12 were taken into account, 96% (1257/1310) of levels were 50 ng per 100 ml in the 6M group and 94% (565/602) in the 3M depot group. Serum testosterone levels 20 ng per 100 ml were achieved in 81 and 90% of the patients at month 12 in the 3- and 6M depot groups, respectively.

Figure 1.

Change in log median testosterone values in responders with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or radical prostatectomy treated over a 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate. The 3M depot was administered at baseline and months 3, 6 and 9, and the 6M depot at baseline and month 6.

Full figure and legend (55K)

The observed decrease in PSA was similar in both groups (Figure 2). PSA, as a marker for tumour response, showed decreases of 88% in the 3M depot and 89% in the 6M depot group at month 12 of the study, with no differences observed between the treatment groups. From month 1 to the end of the study, median PSA levels ranged from 1.0 to 0.2 ng ml^-1 in the 3M group and from 1.1 to 0.3 ng ml^-1 in the 6M group. With regard to leuprorelin levels, the 6M group showed higher concentrations due to the higher dosage, with median values ranging from 76.0 to 139.5 pg ml^-1 for the 3M group and from 186.5 to 124.0 pg ml^-1 for the 6M group from months 1 to 12 (Figure 3).

Figure 2.

Median prostate-specific antigen (PSA) levels in responders with newly diagnosed prostate cancer or PSA relapse after radiotherapy or radical prostatectomy treated over a 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate. The 3M depot was administered at baseline and months 3, 6 and 9, and the 6M depot at baseline and month 6.

Full figure and legend (50K)

Figure 3.

Median serum leuprorelin acetate levels in responders with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or radical prostatectomy treated over a 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate. The 3M depot was administered at baseline and months 3, 6 and 9, and the 6M depot at baseline and month 6.

Full figure and legend (55K)

Discussion

The study showed good tolerance of the new leuprorelin acetate 6M depot by the patients. Overall, there was no observed difference in terms of safety between the 6M depot and the well-established 3M depot except for local reactions of which none was assessed as severe and about two-thirds were assessed as mild in severity and were considered not clinically relevant. Injection-site reactions occurred in 11.8% of all injections in patients treated with the 6M depot formulation, which is within the range described in other studies with long-acting preparations of LHRHas.^{3, 5} Hot flushes were the most commonly reported AEs and these are due to effective suppression of testosterone and directly related to the mechanism of action of LHRHas.

Objective response described by the established EORTC criteria did not show relevant differences between the treatment groups. Partial remission and objective stabilization of the disease as indicators of success of treatment were seen in 93% of patients in the 3M depot group and in 85% of patients in the 6M depot group. These results are consistent with other study results published with the well-established 3M depot of leuprorelin acetate showing clinical response rates of 76, 72, 84 and 85%.^{3, 6, 7, 8} Objective progression rate at any time point during the study was slightly higher, but not statistically significant, in the 6M depot group, which may be due to more advanced tumour stages in this group, that is more distant metastases, more lymph node involvement, higher tumour grade, higher Gleason Scores and longer time since first diagnosis. By final examination at month 12, more than 90% of patients in both groups showed no progression.

Response in terms of testosterone suppression to levels equal to or below 50 ng per 100 ml is the well-accepted castration level shown to be effective for treatment of prostate cancer patients. The response rate by time point at month 12 was comparable between the 3M depot and the 6M depot groups, 100% (42/42) and 98% (96/98), respectively. Non-responders are described for all marketed LHRHas.⁹

Prostate-specific antigen as a marker for tumour response showed decreases of 88% and more during the course of the study, with no differences observed between the treatment groups in those patients with adequate testosterone suppression. Leuprorelin serum levels were higher with the 6M depot, inferring at least a similar reliability as with the 3M depot but with the added benefit of fewer injections per year and a potentially more convenient treatment option for certain patients.

Conclusion

A 6M 30 mg depot formulation of leuprorelin acetate has been shown to be as safe and effective as the established 3M 11.25 mg depot. This new formulation is expected to broaden patient options for treatment of prostate cancer.

References

1. EAU Guidelines on prostate cancer. 2007. www.uroweb.org.
2. Schulman C, Alcaraz A, Berges R, Montorsi F, Teillac P, Tombal B. Expert opinion on 6-monthly luteinizing hormone-releasing hormone agonist treatment with the single-sphere depot system for prostate cancer. BJU Int 2007; 100 (Suppl 1): 1–5. | Article | PubMed | ChemPort |
3. Wechsel HW, Zerbib M, Pagano F, Coptcoat MJ. Randomized open labelled comparative study of the efficacy, safety and tolerability of leuprorelin acetate 1M and 3M depot in patients with advanced prostatic cancer. Eur Urol 1996; 30 (Suppl 1): 7–14. | PubMed |
4. Data on file, Takeda.
5. Khan MS, O'Brien A. An evaluation of pharmacokinetics and pharmacodynamics of leuprorelin acetate 3M-depot in patients with advanced and metastatic carcinoma of the prostate. Urol Int 1998; 60: 33–40. | Article | PubMed | ChemPort |
6. Jocham D. Leuprorelin three-month depot in the treatment of advanced and metastatic prostate cancer: long-term follow-up results. Urol Int 1998; 60 (Suppl 2): 18–24. | Article | PubMed | ChemPort |
7. Kienle E, Lübben G. Efficacy and safety of leuprorelin acetate depot for prostate cancer. The German Leuprorelin Study Group. Urol Int 1996; 56 (Suppl 1): 23–30. | PubMed | ChemPort |
8. Tunn UW, Bargelloni U, Cosciani S, Fiaccavento G, Guazzieri S, Pagano F. Comparison of LH-RH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer. Urol Int 1998; 60 (Suppl 1): 9–16. | Article | PubMed | ChemPort |
9. Oefelein MG, Cornum R. Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm. J Urol 2000; 164: 726–729. | Article | PubMed | ChemPort |