Abstract
Leuprorelin acetate microspheres, a common gonadotropin-releasing hormone agonist, have certain clinical benefits for prostate cancer (PCa). The present study aimed to compare the efficacy and safety of generic and branded leuprorelin acetate microspheres in patients with PCa. The present retrospective, observational study included 116 patients with PCa who received generic (Boennuokang®; Beijing Biote Pharmaceutical Co., Ltd.) or branded (Enantone®; Takeda Pharmaceutical Company, Ltd.) leuprorelin acetate microspheres via injection (commonly 3.75 mg once every 4 weeks), defined as the test (n=64) and reference (n=52) groups, respectively. The present study showed that testosterone levels at month (M) 3 (P<0.001), M6 (P=0.012) and M12 (P<0.001) were decreased in the test group compared with the reference group. However, prostate-specific antigen (PSA) levels at baseline, M1, M3, M6 and M12 were not significantly different between the test and reference groups (all P>0.05). The median (interquartile range) testosterone and PSA levels at M12 were 15.50 ng/dl (10.00–31.25 ng/dl) and 0.01 ng/ml (0.01–0.10 ng/ml), respectively, in the test group and 28.00 ng/dl (22.00–37.00 ng/dl) and 0.02 ng/ml (0.01–0.16 ng/ml), respectively, in the reference group. No significant differences were observed in the M1-baseline, M3-baseline, M6-baseline and M12-baseline changes of testosterone or PSA levels between the two groups (all P>0.050). Additionally, the incidence of all adverse events was not significantly different between the two groups (all P>0.050). Overall, Boennuokang® leuprorelin acetate microspheres exhibited a similar efficacy for suppression of testosterone and PSA levels with a comparable safety profile compared with Enantone® leuprorelin acetate microspheres in patients with PCa.
Keywords: prostate cancer, Boennuokang®, Enantone®, treatment efficacy, safety profile
Introduction
Prostate cancer (PCa), mainly caused by genetic mutations in basal or luminal prostate epithelial cells, accounts for ~7% of newly diagnosed types of cancer in male patients globally (1,2). In China, the disease burden of PCa is heavy and its age-standardized incidence in male patients has shown an average annual percentage increment of 2.6% from 2008 to 2012 (3,4). Since PCa is a highly androgen-dependent disease, androgen deprivation therapy (ADT), with the goal of reducing circulating androgen levels, is widely applied in PCa management (5). For patients with PCa with lymph node metastasis after extended pelvic lymph node dissection, ADT is recommended as an early adjuvant therapy following radical prostatectomy (6). Furthermore, ADT is the foundational treatment for patients with high-risk stage III and IV PCa (7,8), which may be more prevalently applied in China since the proportion of metastatic PCa is higher in China (25–32%) compared with the United States (19%) and the United Kingdom (18%) (9).
ADT comprises bilateral orchiectomy as well as gonadotropin-releasing hormone (GnRH) agonists, such as leuprorelin, goserelin, histrelin and triptorelin, and antagonists, such as degarelix (10,11). Bilateral orchiectomy has been gradually replaced due to its irreversibility and side effects of psychological trauma (8). However, GnRH agonists, which have become increasingly administered in clinical practice since their development, function to suppress the secretion of testosterone by regulating luteinizing hormone and follicle-stimulating hormone in the hypothalamic-pituitary-gonadal axis (12,13).
Leuprorelin is a long-acting GnRH agonist that primarily acts on the anterior pituitary, the continuous use of which causes the desensitization of the pituitary and further suppresses circulating gonadotrophins (14). Leuprorelin acetate microspheres were initially developed by Takeda Pharmaceutical Company, Ltd., and have been approved for PCa treatment in China since 2003, with the brand name Enantone® (15). A number of studies have reported the efficacy and safety of Enantone® leuprorelin acetate microspheres in the treatment of PCa (16–20). For example, a previous study demonstrated that after Enantone® leuprorelin acetate microsphere monotherapy, serum testosterone levels decreased over time in patients with PCa, whose mean level at baseline, 3, 6 and 9 months was 460.2, 9.6, 8.7 and 6.8 ng/dl, respectively (16). Furthermore, another study found that Enantone® leuprorelin acetate microsphere ADT treatment resulted in a favorable pathologic response in 21% of patients with high-risk localized PCa (17). Notably, Boennuokang® leuprorelin acetate microspheres, as the first generic and domestic product developed by Beijing Biote Pharmaceutical Co., Ltd., have provided another treatment option for patients with PCa. At present, some studies have reported the favorable efficacy of Boennuokang® leuprorelin acetate microspheres for controlling prostate-specific antigen (PSA) levels, improving voluntary urination and elevating the quality of life in patients with PCa (21–23). Nevertheless, although Boennuokang® and Enantone® leuprorelin acetate microspheres are both commonly used for PCa treatment in China, to the best of our knowledge, their efficacy and safety have not been compared. Therefore, the present study aimed to compare the efficacy and safety profile of Boennuokang® and Enantone® leuprorelin acetate microspheres in patients with PCa.
Materials and methods
Patients
The present retrospective, observational, single-center study included 116 patients with PCa who received leuprorelin acetate microspheres via injection (Boennuokang® or Enantone®) between January 2017 and April 2022. The inclusion criteria were: i) Diagnosed with PCa via pathological examination; ii) treated with Boennuokang® or Enantone®; iii) aged >18 years old; and iv) with a complete medical history. The exclusion criteria were: i) History of surgical castration or pharmacologic endocrine therapy; ii) diagnosed with hematological malignancies or other types of cancer; iii) suffers from dysfunction of organs, such as heart, liver or kidneys; and iv) is missing information on key data, such as testosterone or PSA levels. The present study obtained approval from the Ethics Committee of Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences (approval no. I-23PJ473; Beijing, China), and the committee waived the requirement for informed consent.
Treatment
At Peking Union Medical College Hospital (Beijing, China), generic leuprorelin acetate microspheres (Boennuokang®; Beijing Biote Pharmaceutical Co., Ltd.; 3.75 mg depot formulation) and branded leuprorelin acetate microspheres (Enantone®; Takeda Pharmaceutical Company, Ltd.; 3.75 mg depot formulation) were administered via injection and were used to treat PCa. The common dosage and usage for both Boennuokang® and Enantone® was 3.75 mg once every 4 weeks according to the package insert. Patients who received Boennuokang® were considered to be the test group, while those who received Enantone® were considered to be the reference group. Patients received appropriate therapy (laparoscopic radical prostatectomy, endocrine therapy or radiotherapy) based on their disease status according to the National Comprehensive Cancer Network (NCCN) guideline (24) and other medications were administered as required.
Data collection
Clinical characteristics of patients with PCa were screened from their medical records, which involved demographics and disease information. Data on testosterone and PSA levels at baseline, 1 (M1), 3 (M3), 6 (M6) and 12 months (M12) after treatment were collected to evaluate efficacy, and data on adverse events from baseline to M12 were collected for safety evaluation. In addition, follow-up data including castration-resistant PCa-free survival (CRPC-FS) and overall survival (OS) were retrieved. CRPC-FS was defined as the time in months between the date of diagnosis and the date of occurrence of CRPC or last follow-up. OS was defined as the time in months between the date of diagnosis and the date of any-cause death or last follow-up. The last follow-up date was 7th March, 2024, and the follow-up duration ranged from 1 to 86 months.
Statistical analysis
SPSS v.26.0 (IBM Corp.) was used for data analysis and GraphPad Prism 7.01 (Dotmatics) was used for figure construction. The Kolmogorov-Smirnov test was used to test the normality of continuous variables. Continuous variables that did not follow a normal distribution are presented as the median [interquartile range (IQR)], while those following a normal distribution are presented as the mean ± standard deviation. Categorical variables are presented as the number (percentage). A Wilcoxon rank-sum test, unpaired Student's t-test, χ2 test or Fisher's exact test was used for comparisons between groups. Specifically, the Wilcoxon rank-sum test was used to compare non-normally distributed variables between groups. Student's t-test was used to compare normally distributed variables between groups. The χ2 test or Fisher's exact test was used to compare categorical variables between groups. Kaplan-Meier curves were generated to show CRPC-FS or OS rates, and the log-rank test was used to compare the rates between groups. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient selection
A total of 494 patients with PCa receiving Boennuokang® or Enantone® leuprorelin acetate microspheres for treatment were assessed. Among them, 271 patients who did not use Boennuokang® or Enantone® leuprorelin acetate microspheres as the initial ADT drugs, 46 patients who lacked data on testosterone levels at baseline, 29 patients who changed ADT drugs during the first year of observation and 32 patients whose testosterone level detection time interval did not meet the requirements were excluded. Finally, 116 patients with PCa were included in the analysis, and the process of patient selection with inclusion and exclusion data is shown in Fig. 1.
Figure 1.
Flow chart of patient selection. PCa, prostate cancer; ADT, androgen deprivation therapy.
Clinical characteristics of the test and reference groups
The mean age of the test and reference groups was 74.2±8.8 years (ranging from 49 to 90 years) and 74.1±8.1 years (ranging from 57 to 90 years), respectively. The mean Gleason score was 7.6±1.2 and 7.7±0.9 in the test and reference group, respectively. With respect to the tumor grade, 8 (12.5%), 10 (15.6%), 10 (15.6%), 7 (10.9%) and 13 (20.3%) patients in the test group were evaluated as having International Society of Urological Pathology (ISUP) (25) grade 1, 2, 3, 4 and 5, respectively, and the ISUP grade for the remaining 16 (25.0%) patients was unavailable. In the reference group, there were 2 (3.8%), 6 (11.5%), 9 (17.3%), 11 (21.2%) and 8 (15.4%) patients that were identified as having ISUP grade 1, 2, 3, 4 and 5, respectively. The ISUP grade was unknown in the remaining 16 (30.8%) patients. The percentage of patients with ISUP grade 1 and 2 was not different between the test group and the reference group (28.1 vs. 15.3%; P=0.102). Notably, clinical characteristics, including age, Gleason score, ISUP grade, tumor node metastasis stage, treatment regimens, baseline testosterone levels and baseline PSA levels, did not vary between the test group and the reference group (all P>0.05; Table I).
Table I.
Clinical characteristics of patients with prostate cancer.
| Characteristics | Test group (n=64) | Reference group (n=52) | P-value |
|---|---|---|---|
| Age (years), mean ± SD | 74.2±8.8 | 74.1±8.1 | 0.970a |
| Gleason score, mean ± SD | 7.6±1.2 | 7.7±0.9 | 0.638a |
| ISUP grade, n (%) | 0.369b | ||
| 1 | 8 (12.5) | 2 (3.8) | |
| 2 | 10 (15.6) | 6 (11.5) | |
| 3 | 10 (15.6) | 9 (17.3) | |
| 4 | 7 (10.9) | 11 (21.2) | |
| 5 | 13 (20.3) | 8 (15.4) | |
| NA | 16 (25.0) | 16 (30.8) | |
| ISUP grade 1&2, n (%) | 18 (28.1) | 8 (15.3) | 0.102c |
| TNM stage, n (%) | 0.100c | ||
| II | 21 (32.8) | 7 (13.5) | |
| III | 16 (25.0) | 18 (34.6) | |
| IV | 11 (17.2) | 13 (25.0) | |
| NA | 16 (25.0) | 14 (26.9) | |
| Treatment regimens, n (%) | |||
| Endocrine therapy only | 34 (53.1) | 21 (40.4) | 0.172c |
| Radiotherapy combined with endocrine therapy | 20 (31.3) | 23 (44.2) | 0.150c |
| Laparoscopic radical prostatectomy combined with endocrine therapy | 10 (15.6) | 8 (15.4) | 0.972c |
P-value calculated using a
Student's t-test,
Fisher's exact test, and
χ2 test. ISUP, International Society of Urological Pathology; IQR, interquartile range; PSA, prostate-specific antigen; NA, relevant data were missing or unavailable.
Comparison of testosterone and PSA levels between the test and reference groups
Testosterone levels at M3 (P<0.001), M6 (P=0.012) and M12 (P<0.001) were decreased in the test group compared with the reference group, but testosterone levels at baseline (P=0.635) and M1 (P=0.076) were not significantly different. The detailed testosterone levels at different timepoints in the two groups are listed in Table II.
Table II.
Testosterone and PSA levels of patients with prostate cancer at different time points.
| Item | Test group | Reference group | P-value |
|---|---|---|---|
| Testosterone levels (ng/dl) | |||
| Baseline | |||
| Number of assessed patients | 64 | 52 | |
| Median (IQR) | 324.00 (264.50–417.50) | 319.00 (256.50–421.00) | 0.635a |
| M1 | |||
| Number of assessed patients | 61 | 51 | |
| Median (IQR) | 32.00 (17.00–45.00) | 37.00 (26.00–47.00) | 0.076a |
| M3 | |||
| Number of assessed patients | 63 | 49 | |
| Median (IQR) | 22.00 (10.00–29.00) | 31.00 (23.50–37.00) | <0.001a |
| M6 | |||
| Number of assessed patients | 63 | 51 | |
| Median (IQR) | 21.00 (10.00–33.00) | 31.00 (19.00–37.00) | 0.012a |
| M12 | |||
| Number of assessed patients | 62 | 51 | |
| Median (IQR) | 15.50 (10.00–31.25) | 28.00 (22.00–37.00) | <0.001a |
| PSA levels (ng/ml) | |||
| Baseline | |||
| Number of assessed patients | 64 | 52 | |
| Median (IQR) | 11.70 (8.08–35.54) | 17.43 (10.39–42.77) | 0.145a |
| M1 | |||
| Number of assessed patients | 57 | 48 | |
| Median (IQR) | 2.35 (0.86–4.34) | 2.62 (0.58–8.35) | 0.489a |
| M3 | |||
| Number of assessed patients | 61 | 47 | |
| Median (IQR) | 0.17 (0.06–0.44) | 0.24 (0.04–0.96) | 0.712a |
| M6 | |||
| Number of assessed patients | 60 | 47 | |
| Median (IQR) | 0.03 (0.01–0.14) | 0.04 (0.01–0.38) | 0.590a |
| M12 | |||
| Number of assessed patients | 59 | 47 | |
| Median (IQR) | 0.01 (0.01–0.10) | 0.02 (0.01–0.16) | 0.444a |
P-value calculated using the Wilcoxon rank sum test. PSA, prostate-specific antigen; IQR, interquartile range; M1, 1st month after treatment; M3, 3rd month after treatment; M6, 6th month after treatment; M12, 12th month after treatment.
PSA levels at baseline (P=0.145), M1 (P=0.489), M3 (P=0.712), M6 (P=0.590) and M12 (P=0.444) did not vary between the test and reference groups. The detailed PSA levels at different timepoints in the two groups are shown in Table II.
Comparison of changes in testosterone levels between the test and reference groups
Following treatment, testosterone levels decreased in both groups and no difference was seen in M1-baseline (P=0.441), M3-baseline (P=0.463), M6-baseline (P=0.598) or M12-baseline (P=0.520) changes in testosterone levels between the test and reference groups. Specifically, the median (IQR) M1-baseline, M3-baseline, M6-baseline and M12-baseline changes in testosterone levels were −292.00 ng/dl (−387.50 to −239.50 ng/dl), −303.00 ng/dl (−391.00 to −245.00 ng/dl), −306.00 ng/dl (−391.00 to −247.00 ng/dl) and −305.50 ng/dl (−388.00 to −241.75 ng/dl), respectively, in the test group. The median (IQR) M1-baseline, M3-baseline, M6-baseline and M12-baseline changes in testosterone levels were −290.00 ng/dl (−389.00 to −215.00 ng/dl), −288.00 ng/dl (−385.00 to −219.50 ng/dl), −296.00 ng/dl (−388.00 to −227.00 ng/dl) and −293.00 ng/dl (−391.00 to −225.00 ng/dl), respectively, in the reference group (Table III).
Table III.
Changes in testosterone levels of patients with prostate cancer.
| Item | Test group | Reference group | P-value |
|---|---|---|---|
| M1-baseline | |||
| Number of assessed patients | 61 | 51 | |
| Median (IQR), ng/dl | −292.00 (−387.50 to −239.50) | −290.00 (−389.00 to −215.00) | 0.441a |
| M3-baseline | |||
| Number of assessed patients | 63 | 49 | |
| Median (IQR), ng/dl | −303.00 (−391.00 to −245.00) | −288.00 (−385.00 to −219.50) | 0.463a |
| M6-baseline | |||
| Number of assessed patients | 63 | 51 | |
| Median (IQR), ng/dl | −306.00 (−391.00 to −247.00) | −296.00 (−388.00 to −227.00) | 0.598a |
| M12-baseline | |||
| Number of assessed patients | 62 | 51 | |
| Median (IQR), ng/dl | −305.50 (−388.00 to −241.75) | −293.00 (−391.00 to −225.00) | 0.520a |
P-value calculated using the Wilcoxon rank sum test. M1, 1st month after treatment; IQR, interquartile range; M3, 3rd month after treatment; M6, 6th month after treatment; M12, 12th month after treatment.
Comparison of changes in PSA levels between the test and reference groups
The test and reference groups both exhibited decreased PSA levels after treatment, but the M1-baseline (P=0.286), M3-baseline (P=0.144), M6-baseline (P=0.158) and M12-baseline (P=0.270) PSA changes were not significantly different between the test and reference groups. Specifically, the median (IQR) M1-baseline, M3-baseline, M6-baseline and M12-baseline changes in PSA levels in the test group were −10.00 ng/ml (−28.53 to −5.13 ng/ml), −11.60 ng/ml (−32.10 to −7.90 ng/ml), −11.78 ng/ml (−36.70 to −8.00 ng/ml) and −11.89 ng/ml (−37.16 to −8.09 ng/ml), respectively. Meanwhile, in the reference group, the median (IQR) PSA changes at these time points were −14.13 ng/ml (−34.53 to −9.04 ng/ml), −16.86 ng/ml (−42.90 to −10.10 ng/ml), −16.89 ng/ml (−43.62 to −10.11 ng/ml) and −17.14 ng/ml (−43.79 to −10.07 ng/ml), respectively (Table IV).
Table IV.
Changes in prostate-specific antigen levels of patients with prostate cancer.
| Item | Test group | Reference group | P-value |
|---|---|---|---|
| M1-baseline | |||
| Number of assessed patients | 57 | 48 | |
| Median (IQR), ng/ml | −10.00 (−28.53 to −5.13) | −14.13 (−34.53 to −9.04) | 0.286a |
| M3-baseline | |||
| Number of assessed patients | 61 | 47 | |
| Median (IQR), ng/ml | −11.60 (−32.10 to −7.90) | −16.86 (−42.90 to −10.10) | 0.144a |
| M6-baseline | |||
| Number of assessed patients | 60 | 47 | |
| Median (IQR), ng/ml | −11.78 (−36.70 to −8.00) | −16.89 (−43.62 to −10.11) | 0.158a |
| M12-baseline | |||
| Number of assessed patients | 59 | 47 | |
| Median (IQR), ng/ml | −11.89 (−37.16 to −8.09) | −17.14 (−43.79 to −10.07) | 0.270a |
P-value calculated using the Wilcoxon rank sum test. M1, 1st month after treatment; IQR, interquartile range; M3, 3rd month after treatment; M6, 6th month after treatment; M12, 12th month after treatment.
Comparison of long-term outcomes between the test and reference groups
CRPC-FS did not differ between the test group and the reference group (P=0.550). In detail, the 1-, 3- and 5-year CRPC-FS rates in the test group were 90.2, 78.6 and 78.6%, and these were 90.7, 76.2 and 64.3% in the reference group (Fig. S1A). OS did not vary between the test and reference groups (P=0.437). Specifically, the 1-, 3- and 5-year OS rates in the test group were 98.4, 95.0 and 95.0%, and these were 97.1, 89.9 and 81.7% in the reference group (Fig. S1B).
Comparison of adverse events between the test and reference groups
Generally, the adverse events were controllable in both the test and reference groups. The most common adverse events in the test group were fatigue (20.3%), weight gain (17.2%) and sweating (15.6%). Similarly, the most common adverse events in the reference group were sweating (21.2%), weight gain (19.2%) and fatigue (17.3%). Notably, no significant difference was observed in the frequency of each adverse event, including fatigue (P=0.681), weight gain (P=0.776), sweating (P=0.442), elevated blood lipids (P=0.478), lower urinary tract symptoms (P=0.690), elevated blood glucose levels (P=0.699), elevated transaminase levels (P>0.999), tachycardia (P>0.999) and bloody stool (P=0.448), between the test and reference groups. Furthermore, 1 patient in the reference group experienced bloody stool, which was induced by radiation enteritis (Table V).
Table V.
Adverse events.
| Events | Test group, n (%) (n=64) | Reference group, n (%) (n=52) | P-value |
|---|---|---|---|
| Fatigue | 13 (20.3) | 9 (17.3) | 0.681a |
| Weight gain | 11 (17.2) | 10 (19.2) | 0.776a |
| Sweating | 10 (15.6) | 11 (21.2) | 0.442a |
| Elevated blood lipid | 7 (10.9) | 8 (15.4) | 0.478a |
| LUTS | 4 (6.3) | 2 (3.8) | 0.690b |
| Elevated blood glucose | 3 (4.7) | 4 (7.7) | 0.699b |
| Elevated transaminase | 2 (3.1) | 1 (1.9) | >0.999b |
| Tachycardia | 1 (1.6) | 1 (1.9) | >0.999b |
| Bloody stool | 0 (0.0) | 1 (1.9) | 0.448b |
P-value calculated using the
χ2 test and
Fisher's exact test. LUTS, lower urinary tract symptoms.
Subgroup analysis
Further subgroup analysis was conducted in patients receiving different treatment regimens, which showed that, in patients with PCa treated with endocrine therapy only and patients who received laparoscopic radical prostatectomy combined with endocrine therapy, PSA levels at baseline, M1, M3, M6 and M12 were not significantly different between the test and reference groups (all P>0.050). In patients receiving radiotherapy combined with endocrine therapy, PSA levels at baseline (P<0.001) and M1 (P=0.004) were decreased in the test group compared with the reference group, but there was no difference in PSA levels between the two groups at M3, M6 and M12 (Table VI).
Table VI.
Subgroup analysis of prostate-specific antigen levels.
| Subgroup | Test group | Reference group | P-value |
|---|---|---|---|
| Endocrine therapy only | |||
| Number of assessed patients | 34 | 21 | |
| Baseline, median (IQR), ng/ml | 24.93 (8.52–80.05) | 14.85 (5.60–171.00) | 0.872a |
| M1, median (IQR), ng/ml | 2.86 (0.69–6.43) | 1.45 (0.35–13.85) | 0.420a |
| M3, median (IQR), ng/ml | 0.22 (0.09–1.14) | 0.11 (0.03–0.96) | 0.409a |
| M6, median (IQR), ng/ml | 0.06 (0.02–0.53) | 0.05 (0.01–0.80) | 0.812a |
| M12, median (IQR), ng/ml | 0.04 (0.01–0.23) | 0.10 (0.01–1.18) | 0.784a |
| Radiotherapy combined with endocrine therapy | |||
| Number of assessed patients | 20 | 23 | |
| Baseline, median (IQR), ng/ml | 9.27 (6.39–15.83) | 19.23 (14.10–32.60) | <0.001a |
| M1, median (IQR), ng/ml | 2.08 (1.05–3.17) | 3.60 (2.50–8.40) | 0.004a |
| M3, median (IQR), ng/ml | 0.18 (0.03–0.59) | 0.43 (0.08–1.43) | 0.054a |
| M6, median (IQR), ng/ml | 0.01 (0.01–0.09) | 0.04 (0.01–0.38) | 0.074a |
| M12, median (IQR), ng/ml | 0.01 (0.01–0.06) | 0.02 (0.01–0.12) | 0.174a |
| Laparoscopic radical prostatectomy combined with endocrine therapy | |||
| Number of assessed patients | 10 | 8 | |
| Baseline, median (IQR), ng/ml | 10.10 (8.10–30.08) | 7.83 (3.32–50.90) | 0.570a |
| M1, median (IQR), ng/ml | 2.49 (1.05–3.29) | 1.09 (0.15–3.40) | 0.570a |
| M3, median (IQR), ng/ml | 0.06 (0.01–0.14) | 0.01 (0.01–0.04) | 0.100a |
| M6, median (IQR), ng/ml | 0.01 (0.00–0.02) | 0.01 (0.01–0.01) | 0.785a |
| M12, median (IQR), ng/ml | 0.01 (0.00–0.01) | 0.01 (0.01–0.80) | 0.525a |
P-value calculated using the Wilcoxon rank-sum test. M1, 1st month after treatment; IQR, interquartile range; M3, 3rd month after treatment; M6, 6th month after treatment; M12, 12th month after treatment.
Discussion
At present, there are few clinical reports describing Boennuokang® leuprorelin acetate microspheres in the treatment of PCa, and their use has been reported in only three previous studies (21–23). As reported in one randomized, controlled study, patients with PCa treated with Boennuokang® leuprorelin acetate microspheres plus bicalutamide and radiotherapy had decreased PSA levels compared with those treated with radiotherapy alone, with a mean PSA level of 15.69±3.57 and 22.38±5.24 ng/ml, respectively, at M2 after treatment (21). Similarly, another study noted that the combination of Boennuokang® leuprorelin acetate microspheres and intensity-modulated radiotherapy resulted in an improved PSA suppression effect and elevated 1/2-year survival rates compared with intensity-modulated radiotherapy alone in patients with PCa (22). Furthermore, a previous study examined administration of Boennuokang® leuprorelin acetate microspheres in patients with PCa complicated with urinary retention. After 16 weeks of treatment, the maximum urinary flow rate was improved and the prostate volume was reduced in these patients (23). The aforementioned studies indicate the positive clinical efficacy of Boennuokang® leuprorelin acetate microspheres in PCa treatment (21–23). In the current study, both testosterone and PSA levels were reduced after Boennuokang® leuprorelin acetate microsphere treatment in patients with PCa, and the median (IQR) M12-baseline testosterone and PSA changes reached −305.50 ng/dl (−388.00 to −241.75 ng/dl) and −11.89 ng/ml (−37.16 to −8.09 ng/ml), respectively. This positive performance could be explained by leuprorelin acetate microspheres possessing a resistance to proteolytic enzymes and a high affinity to the GnRH receptor, and therefore leuprorelin acetate microspheres effectively inhibits the pituitary-gonadal system (15).
Concerning the application of Enantone® leuprorelin acetate microspheres in patients with PCa, one case report described a patient with PCa with lung metastases receiving Enantone® leuprorelin acetate microsphere injection and oral bicalutamide as the first-line therapy, who achieved a stable disease state during the 3-year follow-up (26). Furthermore, another study reported that the administration of Enantone® leuprorelin acetate microspheres plus flutamide once a month resulted in a decreased testosterone concentration and PSA levels in 16 patients with PCa (27). Similarly, the present study revealed that treatment with Enantone® leuprorelin acetate microspheres resulted in decreased testosterone and PSA levels in patients with PCa. Specifically, the median (IQR) M12-baseline testosterone and PSA changes were −293.00 ng/dl (−391.00 to −225.00 ng/dl) and −17.14 ng/ml (−43.79 to −10.07 ng/ml), respectively. This could also be explained by the drug acting as a GnRH agonist (with a strong inhibiting role against gonadotropin secretion) as aforementioned (14).
To the best of our knowledge, the present study was the first to compare the treatment efficacy of Boennuokang® and Enantone® leuprorelin acetate microspheres in patients with PCa. It was observed that M1-baseline, M3-baseline, M6-baseline or M12-baseline testosterone and PSA changes were not varied between the two groups. This may have been due to Boennuokang® and Enantone® leuprorelin acetate microspheres sharing similar components, including the active substance leuprorelin acetate and polymers of lactic acids, resulting in their similar treatment efficacy (15). Furthermore, it was noted that testosterone levels at M3, M6 and M12 were decreased in patients with PCa who received Boennuokang® leuprorelin acetate microspheres compared with those who received Enantone® leuprorelin acetate microspheres. These findings may be affected by the more advanced microsphere preparation process, as Boennuokang® was launched later, or by the relatively small sample size. Therefore, further studies with a larger sample size are required for validation.
The reliable safety profile of leuprorelin acetate microspheres has been previously reported (28–31); fatigue, weight gain, hot flushes and sweating are the common adverse events recorded in patients with PCa who receive leuprorelin acetate microsphere treatment (28–31). The present study also showed good tolerance of Boennuokang® and Enantone® leuprorelin acetate microspheres in patients with PCa, and the most common adverse events, including fatigue, weight gain and sweating, were consistent with previous studies (28,29), while hot flushes were not observed in this study, which may be explained as follows: It was a retrospective observational study and the adverse events may be underestimated. Furthermore, the incidence of adverse events was not statistically different between the Boennuokang® and Enantone® leuprorelin acetate microsphere groups, indicating that they had a similar safety profile in patients with PCa.
The present study has some limitations. First, it was a retrospective, observational, single-center study, and the comparable treatment efficacy of Boennuokang® and Enantone® leuprorelin acetate microspheres should be validated in further multicenter, randomized, controlled studies. Second, the adverse events were only collected within a short-term follow-up period, and the long-term side effects of both Boennuokang® and Enantone® leuprorelin acetate microspheres were hard to monitor. Given that ADT can be continuously used for maintenance in patients with PCa (12), the long-term side effects should be investigated in further studies. Third, given that the dosage of leuprorelin acetate microspheres was fixed, data on drug concentrations and metabolism were not collected in the present study, and these require further investigation. Fourth, the percentage of patients with ISUP grade 1 and 2 in the test group was numerically higher than that in the reference group (without statistical significance), which could potentially lead to relatively better clinical outcomes in the test group compared to the reference group.
In conclusion, Boennuokang® leuprorelin acetate microspheres may have a comparable efficacy for testosterone and PSA suppression with similar tolerance compared with Enantone® leuprorelin acetate microspheres in patients with PCa. However, the findings need further validation through a randomized controlled study with a larger sample size and longer follow-up duration.
Supplementary Material
Acknowledgements
Not applicable.
Funding Statement
The present study was supported by National High Level Hospital Clinical Research Funding (grant nos. 2022-PUMCH-B-009 and 2022-PUMCH-A-063).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
ZZ, YZ, WY, TF and ZL contributed to the study conception and design. Material preparation, and data collection and analysis were performed by ZZ, YZ and WY. ZZ, YZ, WY, TF and ZL contributed to the first draft of the manuscript and commented on previous versions of the manuscript. TF and ZL confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The present study obtained approval from the Ethics Committee of Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences (approval no. I-23PJ473; Beijing, China), and the committee waived the requirement for informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data generated in the present study may be requested from the corresponding author.