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according to investigators from the phase 3 HERO trial.
Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.
“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.
LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
Study details
In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.
About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.
Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.
The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.
“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
Efficacy
Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.
The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).
Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.
Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):
- Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
- Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
- Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
- Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).
Safety
Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.
At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.
The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
Antagonists vs. agonists
Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.
“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.
Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.
“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.
“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.
“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.
The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.
SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.
according to investigators from the phase 3 HERO trial.
Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.
“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.
LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
Study details
In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.
About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.
Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.
The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.
“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
Efficacy
Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.
The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).
Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.
Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):
- Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
- Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
- Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
- Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).
Safety
Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.
At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.
The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
Antagonists vs. agonists
Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.
“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.
Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.
“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.
“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.
“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.
The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.
SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.
according to investigators from the phase 3 HERO trial.
Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.
“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.
LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
Study details
In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.
About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.
Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.
The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.
“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
Efficacy
Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.
The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).
Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.
Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):
- Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
- Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
- Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
- Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).
Safety
Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.
At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.
The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
Antagonists vs. agonists
Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.
“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.
Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.
“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.
“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.
“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.
The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.
SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.
FROM ASCO 2020