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Study Overview
Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.
Design. Global, multicenter, randomized, open-label, phase 3 trial.
Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.
Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.
Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.
Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.
Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).
The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.
Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.
Commentary
Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.1 Injection-site reactions remain an issue with this formulation.
Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.2 While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.3 Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.4 The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.
Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.5 Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.3 These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.
In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.
Clinical Implications
The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.
–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS
1. Barkin J, Burton S, Lambert C. Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix. Can J Urol. 2016;23:8179-8183.
2. Higano CS. Cardiovascular disease and androgen axis-targeted drugs for prostate cancer. N Engl J Med. 2020;382:2257-2259.
3. Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565-573.
4. Margel D, Peer A, Ber Y, et al. Cardiovascular morbidity in a randomized trial comparing GnRH agonist and GnRH antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. J Urol. 2019;202:1199-1208.
5. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382:2197-2206.
6. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
7. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235-1246.
Study Overview
Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.
Design. Global, multicenter, randomized, open-label, phase 3 trial.
Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.
Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.
Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.
Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.
Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).
The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.
Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.
Commentary
Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.1 Injection-site reactions remain an issue with this formulation.
Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.2 While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.3 Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.4 The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.
Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.5 Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.3 These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.
In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.
Clinical Implications
The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.
–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS
Study Overview
Objective. To evaluate the safety and efficacy of the highly selective oral gonadotropin-releasing hormone (GnRH) antagonist relugolix in men with advanced prostate cancer.
Design. Global, multicenter, randomized, open-label, phase 3 trial.
Intervention. Patients were randomized in a 2:1 ratio to receive either relugolix 120 mg once daily after receiving a single loading dose of 360 mg, or 22.5 mg of leuprolide acetate every 3 months. Patients in Japan and Taiwan received 11.25 mg of leuprolide. The randomization was stratified by age (> 75 years or ≤ 75 years), metastatic disease status, and geographic region (Asia, Europe, North and South America). The intervention period was 48 weeks.
Setting and participants. 1327 patients were screened, and 934 patients underwent randomization: 622 patients to the relugolix group and 308 to the leuprolide group. Patients had histologically or cytologically confirmed adenocarcinoma of the prostate. All patients had to have 1 of the following: evidence of biochemical or clinical relapse after primary curative therapy, newly diagnosed hormone-sensitive metastatic disease, or advance localized disease unlikely to be cured by local primary intervention. The patients with disease progression or rising prostate-specific antigen (PSA) had the option to receive enzalutamide or docetaxel after the confirmation of progression. Patients were excluded if they had a major cardiovascular event within 6 months of enrollment.
Main outcome measures. The primary endpoint was sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL while on study treatment from week 5 through week 48. Secondary endpoints included noninferiority of relugolix to leuprolide in regard to sustained castration rate. Superiority testing was performed if the noninferiority margin of –10 percentage points was met. Additional secondary endpoints were probability of testosterone suppression to ≤ 50 ng/dL on day 4 and day 15 and the percentage of patients with a > 50% decrease in PSA at day 15 and follicle-stimulating hormone (FSH) levels at the end of week 24.
Main results. The baseline characteristics were well balanced between the treatment groups. Approximately 30% of the patients in each group had metastatic disease. Approximately 50% of patients enrolled had biochemical recurrence following primary treatment for prostate cancer. The mean PSA was 104.2 ng/mL in the relugolix group and 68.6 ng/mL in the leuprolide group. The majority of patients had at least 1 cardiovascular risk factor (ie, tobacco use, obesity, diabetes, hypertension, or a history of a major adverse cardiac event [MACE]). Adherence to oral therapy was reported as 99% in both groups. The median follow-up time was 52 weeks; 90% of patients in the relugolix arm and 89% in the leuprolide arm completed 48 weeks of treatment.
Sustained testosterone suppression to ≤ 50 ng/dL from day 29 through week 48 was seen in 96.7% of patients in the relugolix group and 88.8% in the leuprolide group, which was determined to be noninferior. Additionally, relugolix was also found to be superior to leuprolide in regard to sustained testosterone suppression (P < 0.001). These results were consistent across all subgroups. Relugolix was also found to be superior to leuprolide for all secondary endpoints, including cumulative probability of castration on day 4 (56% vs 0%) and day 15 (98.7% vs 12%) and testosterone suppression to ≤ 20 ng/dL on day 15 (78.4% vs 1%). Confirmed PSA response on day 15 was seen in 79.4% of patients in the relugolix arm and in 19.8% in the leuprolide arm (P < 0.001). FSH suppression was greater in the relugolix arm compared with the leuprolide arm by the end of week 24. An increase of testosterone levels from baseline was noted in the leuprolide patients at day 4, with the level decreasing to castrate level by day 29. In contrast, relugolix patients maintained castrate testosterone levels from day 4 throughout the intervention period. Testosterone recovery at 90 days was seen in 54% of patients in the relugolix group compared with 3% in the leuprolide group (P = 0.002).
The most frequent adverse event seen in both groups was hot flashes (54.3% in the relugolix group and 51.6% in the leuprolide group). The second most common adverse event report was fatigue, which occurred in 21.5% of patients in the relugolix arm and 18.5% in the leuprolide arm. Diarrhea was reported more frequently with relugolix than with leuprolide (12.2% vs 6.8%); however, diarrhea did not lead to discontinuation of therapy in any patient. Fatal events were reported more frequently in the leuprolide group (2.9%) compared with the relugolix group (1.1%). MACE were defined as nonfatal myocardial infarction, stroke, and death from any cause. After completing the intervention period of 48 weeks, the relugolix group had a 2.9% incidence of major cardiovascular events, compared with 6.2% in the leuprolide group. In patients having a medical history of cardiovascular events, the adverse event rate during the trial period was 3.6% in the relugolix group and 17.8% in leuprolide group. This translated into a 54% lower risk of MACE in the relugolix arm compared with the leuprolide arm.
Conclusion. The use of relugolix in advanced prostate cancer led to rapid, sustained suppression and faster recovery of testosterone level compared with leuprolide. Relugolix appeared safer to use for men with a medical history of cardiovascular events and showed a 54% lower risk of MACE than leuprolide.
Commentary
Relugolix is a highly selective oral GnRH antagonist that rapidly inhibits pituitary release of luteinizing hormone and FSH. The current phase 3 HERO trial highlights the efficacy of relugolix in regard to testosterone suppression, adding to potential therapeutic options for these men. Relugolix yielded superior sustained testosterone suppression to less than 50 ng/dL throughout the 48-week study period, meeting its primary endpoint. Additionally, relugolix showed superiority in all secondary endpoints across all subgroups of patients. To date, the only GnRH antagonist on the market is degarelix, which is given as a monthly subcutaneous injection.1 Injection-site reactions remain an issue with this formulation.
Cardiovascular disease is the leading cause of death in the United States, and it is known that men with prostate cancer have a higher incidence of cardiovascular disease.2 While data regarding adverse cardiac outcomes with androgen deprivation therapy have been mixed, it is thought that this therapy increases the risk for MACE. There is mounting evidence that GnRH antagonists may have a less detrimental effect on cardiovascular outcomes compared with GnRH agonists. For example, a pooled analysis of 6 phase 3 trials showed a lower incidence of cardiovascular events in men with preexisting cardiovascular disease using the GnRH antagonist degarelix compared with GnRH agonists after 12 months of treatment.3 Furthermore, a more recent phase 2 randomized trial showed that 20% of patients treated with a GnRH agonist developed cardiovascular events, compared to 3% in the GnRH antagonist group. The absolute risk reduction of cardiovascular events at 12 months was 18%.4 The results of the current trial support such findings, showing a 54% reduction in MACE after 48 weeks of therapy when compared with leuprolide (2.9% in relugolix arm vs 6.2% in leuprolide arm). More importantly perhaps, in the subgroup of men with preexisting cardiovascular disease, the benefit was even greater, with a MACE incidence of 3.6% with relugolix compared with 17.8% with leuprolide.
Studies have also shown that second-generation antiandrogens such as enzalutamide are associated with an increased risk of death from cardiovascular causes. For example, data from the recently updated PROSPER trial, which evaluated the use of enzalutamide in men with nonmetastatic, castration-resistant prostate cancer, showed an increased risk of adverse events, including falls, fatigue, hypertension, and death from cardiovascular events.5 Furthermore, adding second-generation antiandrogens to GnRH-agonist therapy is associated with a high risk of cardiovascular events in men with preexisting cardiovascular disease.3 These results were noted in all of the trials of second-generation antiandrogens, including enzalutamide, apalutamide, and darolutamide, in combination with GnRH agonists.6-8 Taken together, one might consider whether the use of a GnRH antagonist would result in improved cardiovascular outcomes in high-risk patients.
In light of the efficacy of relugolix in regard to testosterone suppression highlighted in the current trial, it is likely that its efficacy in regard to cancer outcomes will be similar; however, to date there is no level 1 evidence to support this. Nevertheless, there is a clear association of adverse cardiovascular outcomes in men treated with GnRH agonists, and the notable 54% risk reduction seen in the current trial certainly would support considering the use of a GnRH antagonist for the subgroup of patients with preexisting cardiovascular disease or those at high risk for MACE. Further work is needed to define the role of GnRH antagonists in conjunction with second-generation antiandrogens to help mitigate cardiovascular toxicities.
Clinical Implications
The use of GnRH antagonists should be considered in men with advanced prostate cancer who have underlying cardiovascular disease to help mitigate the risk of MACE. Currently, degarelix is the only commercially available agent; however, pending regulatory approval, oral relugolix may be considered an appropriate oral option in such patients, with data supporting superior testosterone suppressive effects. Further follow-up will be needed.
–Saud Alsubait, MD, Michigan State University, East Lansing, MI
–Daniel Isaac, MD, MS
1. Barkin J, Burton S, Lambert C. Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix. Can J Urol. 2016;23:8179-8183.
2. Higano CS. Cardiovascular disease and androgen axis-targeted drugs for prostate cancer. N Engl J Med. 2020;382:2257-2259.
3. Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565-573.
4. Margel D, Peer A, Ber Y, et al. Cardiovascular morbidity in a randomized trial comparing GnRH agonist and GnRH antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. J Urol. 2019;202:1199-1208.
5. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382:2197-2206.
6. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
7. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235-1246.
1. Barkin J, Burton S, Lambert C. Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix. Can J Urol. 2016;23:8179-8183.
2. Higano CS. Cardiovascular disease and androgen axis-targeted drugs for prostate cancer. N Engl J Med. 2020;382:2257-2259.
3. Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565-573.
4. Margel D, Peer A, Ber Y, et al. Cardiovascular morbidity in a randomized trial comparing GnRH agonist and GnRH antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. J Urol. 2019;202:1199-1208.
5. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382:2197-2206.
6. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
7. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235-1246.