Safety and Clinical Efficacy of a New 6-Month Depot Formulation of Leuprorelin Acetate in Patients with Prostate Cancer in Europe

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Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe

UW Tunn1 and K Wiedey2 1Urological Department, Sta¨dtisches Klinikum, Offenbach, Germany and 2ARCUS Pharma Consult, Konstanz, Germany

This multicentre European study compared the safety and tolerability of the existing 11.25 mg 3-month depot of leuprorelin acetate with a new 30 mg 6-month depot in men with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or prostatectomy. The primary end points were safety and tolerability and secondary end points were clinical response based on European Organization for Research and Treatment of Cancer (EORTC) criteria and response rate by time point for testosterone suppression (castrate level p50 ng per 100 ml). Results showed that the incidence of adverse events was similar with the different depot formulations, with hot flushes being the most common. The assessment of EORTC response criteria showed comparable results in each arm with a tumour progression rate of o10% at the final examination at month 12. Testosterone suppression was comparable with the different formulations. In conclusion, the 6-month depot formulation of leuprorelin acetate containing 30 mg is well tolerated and safe and has been shown to be as effective as the widely used 3-month depot containing 11.25 mg leuprorelin acetate in the treatment of prostate cancer. Prostate Cancer and Prostatic Diseases (2009) 12, 83–87; doi:10.1038/pcan.2008.52; published online 25 November 2008

Keywords: leuprorelin acetate; 6-month depot; testosterone

Introduction been shown to be equally effective in delaying tumour progression and alleviating symptoms of locally Hormonal therapy involving luteinizing hormone (LH)- advanced and metastatic prostate cancer.3 releasing hormone agonists (LHRHas) is a widely used The availability of a choice of the 1- and 3M depot systemic treatment for prostate cancer and is recom- formulations provides more individualized, patient- mended in the European Association of Urology guide- orientated treatment. The 3M depot coincides with lines on prostate cancer for use in patients with locally regular oncological patient checkup visits of 3 and 6 advanced and metastatic disease.1 LHRHas were initially months. The development of a 6-month (6M) formula- administered as daily injections to patients but treatment tion extends this principle. The reduction in the number advances have made possible the delivery of depot of injections may also reduce the stress that injections formulations of monthly, 3-monthly and, more recently, cause to this often elderly population of patients. 6-monthly dosages.2 Sustained-release parenteral depot The primary objectives of this study were to evaluate formulations, in which the hydrophilic leuprorelin the safety and tolerability of two new 6M depot acetate is entrapped in biodegradable highly lipophilic formulations of leuprorelin acetate in prostate cancer synthetic polymer microspheres, have been developed to patients compared with the 3M depot over a treatment avoid daily injections. The peptide is released from these period of 1 year. The secondary objective was compara- depot formulations at a functionally constant daily rate tive efficacy, for example clinical response based on for 1 or 3 months, dependent on the type of polymer European Organization for Research and Treatment of used. In patients with prostate cancer, serum testosterone Cancer (EORTC) criteria, response rate by time point for levels are reduced to castrate levels (p50 ng per 100 ml) testosterone suppression. 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 Patients and methods The study was a randomized, open-label, European multicentre, three-armed study in men with newly Correspondence: Professor UW Tunn, Department of Urology, diagnosed prostate cancer or prostate-specific antigen Sta¨dtisches Klinikum Offenbach, Starkenburgring 66, Offenbach (PSA) relapse after radiotherapy or radical prostatect- 63069, Germany. E-mail: [email protected] omy. In total, 42 centres in Germany, Austria and Poland Received 14 July 2008; accepted 28 July 2008; published online 25 participated in the study. Included in the study were November 2008 patients aged 18–85 years with histologically confirmed Leuprorelin acetate 6M depot in prostate cancer UW Tunn and K Wiedey

84 prostate cancer of any grade and stage requiring Statistics endocrinological castration with a life expectancy of Randomization was performed according to the rando- more than 12 months and WHO performance status 0–3. mization scheme 1:2:2 (11.25:22.5:30 mg). Descriptive For patients who had not received prior hormonal statistics were used for demographic and baseline therapy, testosterone and PSA levels at screening were characteristics and for the primary safety end points in required to be X150 ng per 100 ml and X1ngmlÀ1, the safety population. Testing was performed for respectively. For patients who had received an LHRHa statistical significance of progression (objective response for o3 months, testosterone level was to be o80 ng per based on EORTC criteria), using a w2 test, giving a P- 100 ml before randomization. Main exclusion criteria value for a test of no difference between treatment were prior orchiectomy, cytostatic treatment of prostate groups. No adjustment was performed for multiple tests, cancer or any other cancer within 6 months before study and the tests were not pre-specified. The secondary entry, prior hormonal treatment of prostate cancer for 43 efficacy end points were analysed using the intention-to- months and hormone refractory prostate cancer. treat population. The trial was conducted in accordance Patients were randomized to one of three groups. with the Declaration of Helsinki, the The International Group 1 received four injections of the 3M depot of Conference on Harmonisation of Technical Requirements 11.25 mg leuprorelin acetate at intervals of 3 months for Registration of Pharmaceuticals for Human Use (baseline, months 3, 6 and 9); group 2 received two (ICH) guidelines and ethics committee approval for each injections of a 6M depot containing 22.5 mg leuprorelin investigator. All patients gave written informed consent. 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 Results study were the number of adverse and serious adverse events (AEs); changes in haematology, biochemistry and The 6M 30 mg depot was selected for submission for vital sign variables and local tolerability. The secondary approval in European countries due to superior efficacy end points were clinical assessment of prostate cancer in terms of response rates and a similar safety profile and clinical responses based on EORTC criteria (objec- compared with the 22.5 mg depot.4 Thus, only data on tive) and the Eastern Cooperative Oncology Group/ the 11.25 mg 3M depot and 6M depot containing 30 mg World Health Organization performance status (subjec- are reported here. Of the 296 patients enrolled in the tive). Following the injection of the study drugs, study, 58 patients were randomized to treatment with the testosterone, PSA and leuprorelin acetate levels were 11.25 mg 3M depot and 120 with the 30 mg 6M depot. measured as additional parameters. Patients were Baseline patient characteristics are shown in Table 1. The classified as responders if their testosterone level did treatment groups were well balanced with regard to not reach 450 ng per 100 ml on two consecutive WHO performance status; the majority of patients occasions. Response rate by time point at month 12 showed status 0 or 1 and few patients had grade 2 or was defined as response at month 12 if testosterone 3. Overall, 21% of patients had previously received levels were p50 ng per 100 ml. treatment with an LHRHa. 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- Safety analysis treat population, which comprised all patients with at Safety analyses were conducted for all patients with at least one injection of study medication and at least one least one injection of study drug (safety population). A efficacy assessment after the first injection of study total of 58 and 120 patients were eligible in the 3- and 6M medication. depot arms, respectively. The incidence of the most

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 3M depot 11.25 mg 6M depot 30 mg

No. of patients 58 120 Mean (s.d.) age (years) 72.9±5.6 73.6±6.2 Median PSA level (ng mlÀ1) 1.5 1.1

WHO performance scale 0 63.8% 60.8% 1 31.0% 30.8% 2 5.2% 7.5% 3 0% 0.8%

Tumour stage at study entry Newly diagnosed 82.8% 85.8 % PSA relapse post-radical prostatectomy 12.1% 10.0 % PSA relapse after radiotherapy 3.4% 1.7 % Others 1.7% 2.5 % Median (range) time since first tumour diagnosis in patients with PSA relapse (months) 28.5 (2–160) 47.9 (1–148)

Abbreviation: PSA, prostate-specific antigen.

Prostate Cancer and Prostatic Diseases Leuprorelin acetate 6M depot in prostate cancer UW Tunn and K Wiedey

Table 2 Incidence of most common ADRs in patients treated over a 12-month period with either a 3-month (3M) depot formulation 85 containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate

ADR 3M depot 11.25 mg N (%) 6M depot 30 mg N (%)

Flushing 25 (43.1) 41 (34.2) Increased sweating 6 (10.3) 7 (5.8) Injection-site induration 2 (3.4) 7 (5.8) Fatigue 1 (1.7) 2 (1.7)

Abbreviation: ADRs, adverse drug reactions.

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 3M depot 11.25 mg (n ¼ 58) 6M depot 30 mg (n ¼ 120)

No. (%) of patients experiencing AE 45 (77.6) 95 (79.2) No. (%) of patients with AE leading to withdrawal 2 (3.4) 5 (4.2)

No. (%) of patients experiencing SAE 7 (12.1) 19 (15.8) No. (%) of patients with SAE leading to withdrawal 2 (3.4) 3 (2.5) No. of deaths 2 4

Abbreviations: AEs, adverse events; SAEs, serious AEs. common adverse drug reactions (adverse drug reactions, data were given for 3.4% of patients in the 3M group and defined as definite, probable, possible or unknown 5.8% of patients in the 6M group. There was no relevant relationship to study drug) is shown in Table 2. The difference between the 3M 11.25 mg depot and the 6M most common adverse drug reaction was flushing. No depot 30 mg in terms of EORTC response criteria. The significant findings or apparent differences between the difference in progression rates was not statistically treatment groups were observed in mean changes from significant between the two groups (P ¼ 0.1570, w2 test). baseline to last value in any haematological, biochem- At final examination at month 12, more than 90% of istry or vital sign variables. patients in both groups had not progressed. The number of injection-site reactions reported and the The Eastern Cooperative Oncology Group/World number of patients experiencing them increased with a Health Organization performance status at final exam- higher dose. Of the total number of injections given, ination revealed that 56.9 and 58.3% in the 3- and 6M injection-site reactions occurred with 4/197 (2%) injec- groups, respectively, were assessed as grade 0, whereas tions in the 3M depot arm and 26/221 (11.8%) injections 36.2 and 28.3% were assessed as grade 1. No difference in the 6M depot arm. None of these events were assessed was observed between the groups with regard to as severe and about two-thirds were considered mild. performance scale at baseline and at final visit. Injection-site indurations were seen in two patients Further efficacy parameters were serum levels of (3.4%) and seven patients (5.8%) with the 3M and the testosterone, LH, follicle-stimulating hormone, PSA and 6M depot groups, respectively. leuprorelin in responders. No relevant differences could The incidence of AEs and serious AEs are shown in be seen between the treatment groups for all parameters. Table 3. The percentage of patients who experienced any The median values of testosterone (Figure 1) ranged from AE was similar in both groups as were the adverse drug 12.0 to 15.0 ng per 100 ml for the 3M depot and from 12.0 reactions. There were no serious AEs with positive causal to 15.0 ng per 100 ml for the 6M depot from months 1 to relationship to the study medication. Overall, the 12 during the treatment course. The response rate by number of patients withdrawing due to AEs was very time point at month 12 was 100% (42/42) for the 3M low at 3.9% (7/178). During the treatment period, two depot and 98% (96/98) for the 6M depot group. If all patients died in the 3M group (n ¼ 58) and four in the 6M measured serum testosterone levels from months 1 to 12 group (n ¼ 120); all deaths were unrelated to the study were taken into account, 96% (1257/1310) of levels were drug. p50 ng per 100 ml in the 6M group and 94% (565/602) in the 3M depot group. Serum testosterone levels p20 ng per 100 ml were achieved in 81 and 90% of the patients at Efficacy analyses month 12 in the 3- and 6M depot groups, respectively. Efficacy analyses were conducted for the intention-to- The observed decrease in PSA was similar in both treat population where 58 and 120 patients were groups (Figure 2). PSA, as a marker for tumour response, evaluable for the 3M and the 6M groups, respectively. showed decreases of 88% in the 3M depot and 89% in the The EORTC response criteria assessed at the final visit 6M depot group at month 12 of the study, with no indicate that complete remission was not seen in either differences observed between the treatment groups. group. Partial remission was seen in 46.6% in the 3M From month 1 to the end of the study, median PSA group and in 50.8% in the 6M group, and objective levels ranged from 1.0 to 0.2 ng mlÀ1 in the 3M group and stabilization in 46.6 and 34.2% in the 3M and the 6M from 1.1 to 0.3 ng mlÀ1 in the 6M group. With regard to groups, respectively. Objective progression was docu- leuprorelin levels, the 6M group showed higher concen- mented in 3.4 and 9.2% in the 3M and the 6M groups, trations due to the higher dosage, with median values respectively, at any point during the study conduct. No ranging from 76.0 to 139.5 pg mlÀ1 for the 3M group and

Prostate Cancer and Prostatic Diseases Leuprorelin acetate 6M depot in prostate cancer UW Tunn and K Wiedey 86 1000 350 3M depot 11.25 mg )

3M depot 11.25 mg 1 – 6M depot 30 mg 6M depot 30 mg 300

250

200 100 150 Castration level

level (ng per 100 ml) 100

Log median serum testosterone 50 Median serum leuprorelin level (pg ml 10 0 0123456789101112 0 135791112246810 Months Months –1 month–7days Figure 3 Median serum leuprorelin acetate levels in responders Figure 1 Change in log median testosterone values in responders with newly diagnosed prostate cancer or prostate-specific antigen with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or radical prostatectomy treated over a relapse after radiotherapy or radical prostatectomy treated over a 12-month period with either a 3-month (3M) depot formulation 12-month period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing 30 mg leuprorelin acetate. The 3M depot was adminis- containing 30 mg leuprorelin acetate. The 3M depot was administered at baseline and months 3, 6 and 9, and the 6M depot at tered at baseline and months 3, 6 and 9, and the 6M depot at baseline and month 6. baseline and month 6. observed difference in terms of safety between the 6M depot and the well-established 3M depot except for local 1.6 reactions of which none was assessed as severe and 3M depot 11.25 mg about two-thirds were assessed as mild in severity and 1.4 were considered not clinically relevant. Injection-site 6M depot 30 mg reactions occurred in 11.8% of all injections in patients 1.2 treated with the 6M depot formulation, which is within the range described in other studies with long-acting

) 3,5 1 1.0 – preparations of LHRHas. Hot flushes were the most commonly reported AEs and these are due to effective 0.8 suppression of testosterone and directly related to the mechanism of action of LHRHas. 0.6 level (ng ml Objective response described by the established EORTC criteria did not show relevant differences 0.4 between the treatment groups. Partial remission and

Median prostate-specific antigen objective stabilization of the disease as indicators of 0.2 success of treatment were seen in 93% of patients in the 0 3M depot group and in 85% of patients in the 6M depot group. These results are consistent with other study 02468101 3 5 7 9 11 12 results published with the well-established 3M depot of Months leuprorelin acetate showing clinical response rates of 76, Figure 2 Median prostate-specific antigen (PSA) levels in respon- 72, 84 and 85%.3,6–8 Objective progression rate at any ders with newly diagnosed prostate cancer or PSA relapse after time point during the study was slightly higher, but not radiotherapy or radical prostatectomy treated over a 12-month statistically significant, in the 6M depot group, which period with either a 3-month (3M) depot formulation containing 11.25 mg leuprorelin acetate or a 6-month (6M) depot containing may be due to more advanced tumour stages in this 30 mg leuprorelin acetate. The 3M depot was administered at group, that is more distant metastases, more lymph node baseline and months 3, 6 and 9, and the 6M depot at baseline and involvement, higher tumour grade, higher Gleason month 6. Scores and longer time since first diagnosis. By final examination at month 12, more than 90% of patients in from 186.5 to 124.0 pg mlÀ1 for the 6M group from both groups showed no progression. months 1 to 12 (Figure 3). 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 Discussion at month 12 was comparable between the 3M depot and the 6M depot groups, 100% (42/42) and 98% (96/98), The study showed good tolerance of the new leuprorelin respectively. Non-responders are described for all mar- acetate 6M depot by the patients. Overall, there was no keted LHRHas.9

Prostate Cancer and Prostatic Diseases Leuprorelin acetate 6M depot in prostate cancer UW Tunn and K Wiedey 87 Prostate-specific antigen as a marker for tumour releasing hormone agonist treatment with the single-sphere depot response showed decreases of 88% and more during system for prostate cancer. BJU Int 2007; 100 (Suppl 1): the course of the study, with no differences observed 1–5. between the treatment groups in those patients with 3 Wechsel HW, Zerbib M, Pagano F, Coptcoat MJ. Randomized adequate testosterone suppression. Leuprorelin serum open labelled comparative study of the efficacy, safety and levels were higher with the 6M depot, inferring at least a tolerability of leuprorelin acetate 1M and 3M depot in patients with advanced prostatic cancer. Eur Urol 1996; 30 (Suppl 1): 7–14. similar reliability as with the 3M depot but with the 4 Data on file, Takeda. added benefit of fewer injections per year and a 5 Khan MS, O’Brien A. An evaluation of pharmacokinetics and potentially more convenient treatment option for certain pharmacodynamics of leuprorelin acetate 3M-depot in patients patients. with advanced and metastatic carcinoma of the prostate. Urol Int 1998; 60: 33–40. 6 Jocham D. Leuprorelin three-month depot in the treatment of Conclusion advanced and metastatic prostate cancer: long-term follow-up results. Urol Int 1998; 60 (Suppl 2): 18–24. A 6M 30 mg depot formulation of leuprorelin acetate has 7 Kienle E, Lu¨ bben G. Efficacy and safety of leuprorelin acetate been shown to be as safe and effective as the established depot for prostate cancer. The German Leuprorelin Study Group. Urol Int 1996; 56 (Suppl 1): 23–30. 3M 11.25 mg depot. This new formulation is expected to 8 Tunn UW, Bargelloni U, Cosciani S, Fiaccavento G, Guazzieri S, broaden patient options for treatment of prostate cancer. 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; References 60 (Suppl 1): 9–16. 9 Oefelein MG, Cornum R. Failure to achieve castrate levels of 1 EAU Guidelines on prostate cancer. 2007. www.uroweb.org. testosterone during luteinizing hormone releasing hormone 2 Schulman C, Alcaraz A, Berges R, Montorsi F, Teillac P, agonist therapy: the case for monitoring serum testosterone and Tombal B. Expert opinion on 6-monthly luteinizing hormone- a treatment decision algorithm. J Urol 2000; 164: 726–729.

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