Introduction

Relugolix  is a  gonadotropin-releasing hormone (GnRH) antagonist administered once daily with an effective half-life of 25 hours. It  rapidly inhibits pituitary release of luteinizing hormone and FSH and shown to lower testosterone levels.

Aim

HERO trial evaluated the efficacy and safety of oral relugolix (at a dose of 120 mg once daily) as compared with leuprolide in men with advanced prostate cancer.

Patient Profile

Patients with advanced prostate cancer

Methods

• The HERO trial is a multinational, randomized, open-label, phase 3 trial.

Study Endpoint

Primary end point: Sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks

Secondary end point: Noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.

Results

• Sustained castration rate in the relugolix group was noninferior to that in the leuprolide group (between group difference, 7.9 percentage points) through 48 weeks of treatment (Figure1)

  Figure 1: Primary endpoint result: Sustained castration rate in the relugolix and leuprolide groups at week 48

  

• The relugolix group showed superior secondary outcomes compared to leuprolide (P<0.001)

Table 2 : Secondary endpoints

Secondary End Point	Relugolix (N = 622)	Leuprolide (N = 308)	P Value
Noninferiority analysis for sustained castration rates — %*	96.7	88.8	<0.001†
Cumulative probability of testosterone suppression to <50 ng/dl on day 4 — %	56.0	0	<0.001
Cumulative probability of testosterone suppression to <50 ng/dl on day 15 — %	98.7	12.0	<0.001
PSA response at day 15 followed by confirmation at day 29 — %‡	79.4	19.8	<0.001
Cumulative probability of profound testosterone suppression to<20 ng/dl on day 15 — %	78.4	1.0	<0.001
Mean FSH level at end of wk. 24 (IU/liter)	1.72	5.95	<0.001

• * The sustained castration rate was defined as the cumulative probability of testosterone suppression to less than 50 ng per deciliter through 48 weeks.

 

• ^† The between-group difference was 7.9 percentage points (95% confidence interval, 4.1 to 11.8). Because the lower boundary of the 95% confidence interval (4.1 percentage points) was higher than the noninferiority margin of −10 per-centage points, noninferiority of relugolix as compared with leuprolide was shown. The P value is for the test of superiority of relugolix to leuprolide.

^‡ A PSA response was defined as a decrease of more than 50% in the PSA level

• In the subgroup analysis patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group.

Safety

• The overall adverse events rates were consistent across treatment groups.
• The incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46)

Table 3 : Safety outcomes

Event	Relugolix (N = 622)		Leuprolide (N = 308)
	Any Grade	Grade 3 or 4	Any Grade	Grade 3 or 4
Any adverse event — (%)	92.9	18.0	93.5	20.5
Serious adverse event — (%)	12.2	9.8	15.3	11.4
Fatal adverse event — (%)	1.1	—	2.9	—
MACE — (%) †	2.9	1.3	6.2	1.3
Without a history of MACE (%)	2.8	—	4.2	—
With a history of MACE (%)	3.6	—	17.8	—
Adverse events that occurred in >10% of patients in either group — %
Hot flash	54.3	0.6	51.6	0
Fatigue	21.5	0.3	18.5	0
Constipation	12.2	0	9.7	0
Diarrhea	12.2	0	6.8	0
Arthralgia	12.1	0.3	9.1	0
Hypertension	7.9	1.6	11.7	0.6

 

Conclusion

The HERO trial demonstrated that in men with advanced prostate cancer, relugolix achieved  superior, rapid, and  sustained testosterone suppression compared to leuprolide . Additionally, it lowered the risk of major adverse cardiovascular events by 54% than with leuprolide.

Reference

N Engl J Med 2020;382:2187-96.