This study evaluated the efficacy and safety of a new 6-month depot formulation of leuprolide acetate and demonstrated that testosterone suppression to and below castration levels (
) was rapid and sustained throughout the 12-month (48-week) treatment period; 93.4% of subjects had castrate levels of serum testosterone from week 4 through week 48. None of the escapes from testosterone suppression were associated with increases in PSA.
The suppression of testosterone achieved with this leuprolide acetate 6-month depot formulation is consistent with that achieved with the leuprolide acetate 3- and 4-month depot formulations.6, 7
A cross-study comparison, using the simple percentage of subjects who did not achieve testosterone suppression to
by week 4 or escaped from suppression on or before week 48, indicated that the leuprolide acetate 6-month depot formulation is at least as efficacious as the marketed 3- and 4-month depot formulations (failure rates of 6.0, 10.3 and 10.9% for 6-month, 3-month and 4-month formulations, respectively).6, 7
Overall, subgroup analyses indicate that leuprolide acetate 6-month depot was effective for testosterone suppression regardless of prostate cancer stage, body mass index or race. In the total population, treatment with leuprolide acetate 6-month depot elicited a statistically significantly higher rate of response in the patients with the most advanced disease (P=0.003, stage IV vs stage II). However, while not statistically significant, there was a numerical difference in the percentage of African-American men with testosterone suppression (86.5%) compared with Caucasian men (95.4%). The reasons for this difference are unclear.
With leuprolide acetate 6-month depot treatment, mean testosterone levels after week 4 were suppressed below 15
for the remainder of the 48-week treatment period and were
at the end of each treatment cycle. In this study, the use of anti-androgens was excluded per protocol because use of these drugs would interfere with assessment of hormonal response (such as the primary end point) and potentially with the effects of leuprolide acetate on testosterone suppression during the initial phase of treatment. In our study, mean testosterone increases were not observed with the second leuprolide acetate injection. Small mean decreases in testosterone were observed from before the second injection to serial time points after the injection, and only three individual subjects experienced increases above 50
, indicating that suppression of testosterone remained stable even after repeated exposure to leuprolide acetate 6-month depot in the vast majority of patients. In addition, PSA levels, which are used as a surrogate marker for prostate cancer progression, paralleled the decreases in testosterone concentrations, and only 4.6% of subjects experienced PSA recurrence, which occurred without an increase in serum testosterone.
Leuprolide acetate 6-month depot was well tolerated, and the type and incidence of AEs and laboratory findings reported were consistent with the safety profiles of the marketed leuprolide acetate intramuscular 3- and 4-month depot formulations6, 7
and a marketed subcutaneous 6-month depot formulation,8
as expected for this patient population.7, 8, 9
Overall, the incidence of injection site reactions was 24.5%, which is higher than reported in other studies with 6-month depot formulations of GnRHa.8, 10, 11
The rigorous monitoring for injection site reactions may have increased the frequency of adverse reaction reporting in our study population. The relatively low incidence of sexual side effects, which were collected as AEs, might be due to under reporting of these events in this study.
The mean changes in glucose and hemoglobin observed in this study were consistent with the mean changes observed for the marketed leuprolide acetate 3- and 4-month depot formulations.7, 9
Androgen deprivation therapy has been shown to increase insulin resistance and increase the risk of new onset diabetes.12, 13, 14, 15
Notably, there was only one potentially significant increase in glucose in a subject with established diabetes and only one report of new onset diabetes during this study. Reductions in hemoglobin are known to occur after orchiectomy and GnRHa therapy as a result of loss of androgen stimulation of the hematopoietic system.16, 17, 18
This study demonstrates the efficacy and safety of the leuprolide acetate 6-month depot formulation for sustained reduction of serum testosterone to castrate levels in men with locally advanced and advanced prostate cancer. The availability of a leuprolide acetate 6-month depot formulation will limit the number of injections needed per year to two, and better align with the treatment schedules of prostate cancer patients, which may improve patient compliance and outcomes.