Leuprolide, goserelin, and triptorelin are luteinizing hormone-releasing hormone (LHRH) agonists used for the treatment of prostate cancer. The latest National Comprehensive Care Network (NCCN) guidelines for prostate cancer list the three agents as an option for androgen deprivation therapy (ADT), which includes localized and regional disease states along with castrate-sensitive metastatic cancer. A formal comparison between the three agents was not provided by the guidelines. [1]
A 2022 systematic review investigated the comparative efficacy and safety between different gonadotropin-releasing hormone (GnRH) agonists, including triptorelin, leuprolide, and goserelin, for prostate cancer. Overall, the findings suggest a similar safety and efficacy profile between the GnRH agonists, with goserelin being the most studied. Various intensities of castration suppression based on T levels were explored. Overall, 90%-100% of investigated patients are reported to have T level suppression of 50 ng/dL or lower with leuprorelin, triptorelin, and goserelin, at varying doses and formulations. The study by Shim et al. compares the three agents, demonstrating similar efficacy rates (see Table 1). [2]
For prostate-specific antigen (PSA) levels, goserelin demonstrated the highest rate of suppression to desired levels, followed by triptorelin. The data is less clear for leuprorelin. Goserelin also exhibits the most robust long-term data, demonstrating a 10-year overall survival (OS) rate of 87%, while triptorelin reports an 8-year OS of 84.6% (data for leuprolide unavailable). Adverse events appear to be comparable between GnRH agonists. Goserelin and leuprolide are available as ready-to-use prefilled syringes, while triptorelin is only available as a powder ready for reconstitution. In conclusion, the authors did not observe any novel data that alters the conclusive comparison between the three agents. While goserelin is the most investigated agent, there is no clear superiority established compared to the other two GnRH agonists. [2]
A 2018 comprehensive systematic review included direct comparative studies (N= 16) of GnRH agonists triptorelin, leuprorelin, and goserelin for the treatment of prostate cancer to evaluate meaningful clinical differences between these agents. Twelve out of 16 studies reported efficacy outcomes, whereas four studies evaluated safety, and five studies reported on the convenience of administration. Studies reporting on efficacy endpoints did not reveal significant differences in the ability of GnRH agonists to reduce levels of testosterone or prostate-specific antigen. Overall, in the absence of direct comparative data regarding the effects of all three agents on PSA levels and limited survival data, drawing a differential conclusion seems to be difficult. Several studies suggested differences in short- or long-term testosterone control, the rate of injection site adverse events, and patient/healthcare professional perceptions. However, given the notable limitations of available studies, such as small sample sizes, open-label designs, and various formulations and measured endpoints, a definitive decision regarding the preference of one GnRH agonist over another can not be made from the existing evidence. [3]
A 2014 randomized clinical trial evaluated the side effects and hormonal changes associated with leuprorelin and triptorelin in Chinese women following conservative laparoscopic surgery for ovarian endometriosis. The study included 302 women with revised American Society for Reproductive Medicine (rASRM) stage III or IV ovarian endometriomas who underwent laparoscopic excision. Patients were randomized to receive either leuprorelin (n=151; group A) or triptorelin (n=151; group B), each administered intramuscularly at a dose of 3.75 mg on postoperative days 1-3 and then every 28-30 days for a total of three doses. Twenty-two patients dropped out, leaving 142 patients in the leuprorelin group and 138 in the triptorelin group who completed the study. Menopausal symptoms were assessed through a questionnaire, and serum sex hormone levels were measured throughout the study. At week 4 of treatment, most patients in the leuprorelin group reported no significant side effects. However, by week 9, common symptoms such as bone pain, hot flashes, sweating, and irregular bleeding were observed in both groups, with no significant differences between them. Notably, anxiety, depression, vaginal dryness, headache, and acne occurred at significantly higher rates in the triptorelin group compared to the leuprorelin group. At day 21, significant differences in hormonal levels were observed between the two groups: follicle-stimulating hormone (FSH; p= 0.003), luteinizing hormone (LH; p= 0.026), and estradiol (E2; p = 0.002) levels were all lower in the triptorelin group. At six weeks, FSH (p= 0.021) and E2 (p= 0.033) levels remained significantly higher in the leuprorelin group, while the difference in LH levels (p= 0.917) was no longer statistically significant. The authors concluded that leuprorelin results in a more gradual suppression of pituitary-ovarian function compared to triptorelin. This slower hormonal decline may account for the lower incidence of menopausal symptoms in the leuprorelin group. Therefore, leuprorelin acetate may be better tolerated than triptorelin in this patient population. [4]
Lastly, a prospective, double-blind crossover trial, published in 2000, compared the potency, side effects, and duration of action of triptorelin and leuprorelin acetate in treating pelvic endometriosis. The study included 54 patients, of which 6 were excluded from the final analysis due to various reasons (e.g., pregnancy, carcinoma diagnosis, or patient refusal). The remaining 27 patients were in the triptorelin-leuprorelin acetate (T-L) group, and 21 were in the leuprorelin acetate-triptorelin (L-T) group. Each patient received three doses of either 3.75 mg of triptorelin or 3.75 mg of leuprorelin acetate by intramuscular injection at 4-week intervals. The main outcomes assessed included menopausal symptoms, serum hormone levels (estradiol, FSH, LH), lipid profiles, and liver function tests. The potencies of the two drugs in lowering estradiol, FSH, and LH levels were comparable. Specifically, 70%-90% of patients in both groups had estradiol levels below the endometrial threshold before and after the crossover. In the T-L group, 53.9% of patients had FSH levels greater than 4 IU/L after three doses of leuprorelin acetate, compared to 27.0% after three doses of triptorelin (p<0.02). Liver function and lipid changes were also measured 4 weeks after the third dose of GnRH-a. Four parameters (total bilirubin, LDL-C, apo A-I, and apo B) showed significant increases after three doses of leuprorelin acetate in the L-T group, though all changes remained within normal ranges. The increase in total bilirubin was significantly higher in the L-T group (3.00 ± 3.58 mmol/L) compared to the T-L group (0.61 ± 2.08 mmol/L; p= 0.025). [5]
Regarding menopausal symptoms, no significant difference was noted between the two groups after the first three doses. The Kuppermann index, which measures menopausal symptom severity, increased similarly in both groups. In the first 4 weeks after the first dose of GnRH-a, 33.3% of patients in the T-L group and 42.9% in the L-T group experienced significant vaginal bleeding (requiring more than two pads per day), though this difference was not statistically significant. The return of ovarian activity was assessed by measuring serum estradiol, FSH, and LH levels, and the time taken for menstruation to return. Eight weeks after the last dose, 80.0% of patients in the L-T group had serum estradiol levels below the endometrial threshold, compared to 51.9% in the T-L group (p= 0.047). Additionally, 100% of patients in the L-T group had LH levels below 0.5 IU/L, compared to only 30% in the T-L group (p<0.01). Overall, the study found that while both drugs were equally potent in suppressing pituitary-ovarian function, triptorelin had a longer duration of action, allowing for less frequent administration. Leuprorelin acetate, however, led to a quicker recovery of ovarian activity, with earlier return of menstruation. Both drugs demonstrated comparable side effect profiles, though leuprorelin acetate was associated with more noticeable changes in liver function and lipid profiles. [5]