A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of relugolix 120 milligrams (mg) orally once daily for 48 weeks on maintaining serum testosterone suppression to castrate levels (< 50 nanograms/deciliter [ng/dL]) in participants with androgen-sensitive advanced prostate cancer.

Detailed Description
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This is a phase 3, multinational, randomized, open-label, parallel group study to evaluate the efficacy and safety of oral daily relugolix 120 mg in participants with androgen-sensitive advanced prostate cancer who require at least 1 year of continuous androgen-deprivation therapy. Relugolix 120 mg orally once daily or leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan based on local labels), every 3 months by subcutaneous injection will be administered to participants. There are 2 analyses for this study, a primary analysis and a final analysis. Primary Analysis: The primary analysis of efficacy and safety has been completed (N=934). Participants were randomized 2:1 to receive relugolix or leuprolide for 48 weeks, followed by a 30-day safety follow-up visit or early termination 30-day safety follow-up. Final Analysis: The final analysis will occur after additional participants with metastatic disease (approximately 130) have been enrolled and randomized from any sites to the study, and have completed the 48-week treatment period. A cohort of participants enrolled in China and Taiwan will be analyzed separately once they have completed treatment to support registration in China. Eligible participants were randomized 2:1 to relugolix or leuprolide arm and will attend visits monthly (every 4 weeks) where serum testosterone and prostate-specific antigen will be assessed. Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, and 12-lead electrocardiograms. Castration resistance-free survival will be assessed up to Week 49, Day 1 of the study and reported as part of the final analysis. The study enrolled 1134 participants, including 139 participants with metastatic advanced prostate cancer to support the analysis of the secondary endpoint of castration resistance-free survival and 93 Chinese participants (enrolled in China and Taiwan) to support registration in China.

Official Title
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HERO: A Multinational Phase 3 Randomized, Open-label, Parallel Group Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Relugolix
* Drug: Leuprolide Acetate


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen deprivation therapy for the management of androgen-sensitive advanced prostate cancer with 1 of the following clinical disease state presentations: Evidence of biochemical (PSA) or clinical relapse following local primary intervention with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency ultrasound and not a candidate for salvage treatment by surgery; or Newly diagnosed androgen-sensitive metastatic disease; or Advanced localized disease unlikely to be cured by local primary intervention with either surgery or radiation with curative intent. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (5.2 nanomoles [nmol]/liter [L]). Has a serum PSA concentration at the Screening visit of > 2.0 ng/milliliter (mL) (2.0 microgram [μg]/L), or, when applicable, post radical prostatectomy of > 0.2 ng/mL (0.2 μg/L) or post radiotherapy, cryotherapy, or high frequency ultrasound > 2.0 ng/mL (2.0 μg/L) above the post interventional nadir. Has an Eastern Cooperative Oncology Group performance status of 0 or 1 at initial screening and at baseline. Key Exclusion Criteria: In the investigator's opinion, is likely to require chemotherapy or surgical therapy for symptomatic disease management within 2 months of initiating androgen deprivation therapy. Previously received gonadotropin-releasing hormone analog or other form of androgen deprivation therapy (estrogen or antiandrogen) for > 18 months total duration. If androgen deprivation therapy was received for ≤ 18 months total duration, then that therapy must have been completed at least 3 months prior to baseline. If the dosing interval of the depot is longer than 3 months, then the prior androgen deprivation therapy must have been completed at least as long as the dosing interval of the depot. Previous systemic cytotoxic treatment for prostate cancer (for example, taxane-based regimen). Metastases to brain per prior clinical evaluation. Participants with myocardial infarction, unstable symptomatic ischemic heart disease, cerebrovascular events, or any significant cardiac condition within the prior 6 months. Active conduction system abnormalities. Uncontrolled hypertension.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relugolix<br>Relugolix for 48 weeks | Drug: Relugolix<br>* Relugolix 120-mg tablet administered orally once daily following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1<br>* Other names: T-1331285;|
| Active Comparator: Leuprolide Acetate<br>Leuprolide acetate for 48 weeks | Drug: Leuprolide Acetate<br>* Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), every 3 months by subcutaneous injection<br>* Other names: Leuprolide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Castration Rate | Sustained castration rate defined as the cumulative probability of testosterone suppression to < 50 nanogram (ng)/deciliter (dL). The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. The lower bound of the 95% confidence interval (CI) for the cumulative probability of sustained testosterone suppression in the relugolix treatment group must have been ≥ 90% to meet evaluation criteria for efficacy. | From Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Castration Rate At Week 1 Day 4 | Castration rate was defined as the cumulative probability of testosterone suppression to < 50 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | Week 1 Day 4 (Day 4) | 
| Castration Rate At Week 3 Day 1 | Castration rate was defined as the cumulative probability of testosterone suppression to < 50 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | Week 3 Day 1 (Day 15) | 
| Confirmed Prostate-specific Antigen (PSA) Response Rate | Confirmed PSA response defined as > 50% reduction in PSA from baseline at Week 3 Day 1 followed with confirmation at Week 5 Day 1. | Week 3 Day 1 (Day 15) and Week 5 Day 1 (Day 29) | 
| Profound Castration Rate At Week 3 Day 1 (Day 15) | Castration rate defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | Week 3 Day 1 (Day 15) | 
| Follicle-stimulating Hormone (FSH) Level | To evaluate the effect of relugolix and leuprolide acetate on FSH suppression. | Week 25 Day 1 (Day 169) | 
| PSA Response Rate At Week 3 Day 1 | PSA response defined as > 50% reduction in PSA from baseline. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | Week 3 Day 1 (Day 15) | 
| PSA Response Rate At Week 5 Day 1 | PSA response defined as > 50% reduction in PSA from baseline. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | Week 5 Day 1 (Day 29) | 
| Testosterone Recovery Rate | The cumulative probability of testosterone recovery back to > 280 ng/dL (lower limit of the normal range), back to ≥ 50 ng/dL (definition of castration), and back to > 280 ng/dL or baseline at 90 days after drug discontinuation was assessed. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | Day 90 follow-up | 
| Sustained Profound Castration Rate From Week 5 Day 1 Through Week 49 Day 1 | Sustained profound castration rate was defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated by the Kaplan-Meier method and reported as percentage of participants. | Week 5 Day 1 (Day 29) through Week 49 Day 1 (Day 337) | 
| Profound Castration Rate At Week 1 Day 4 (Day 4) | Castration rate defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. | At Week 1 Day 4 (Day 4) | 
| Sustained Profound Castration Rate From Week 25 Day 1 Through Week 49 Day 1 | Sustained profound castration rate was defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated by the Kaplan-Meier method and reported as percentage of participants. | Week 25 Day 1 (Day 169) through Week 49 Day 1 (Day 337) | 
| Undetectable PSA Rate | Defined as the proportion of participants with PSA concentration < 0.02 ng/milliliter (mL).The rate was estimated by the Kaplan-Meier method and reported as percentage of participants. | Week 25 Day 1 (Day 169) | 
| Rate Of PSA Progression-free Survival | PSA progression was defined as the first increase in PSA of 25% or greater and 2 ng/mL or greater above the nadir with confirmation by a second consecutive PSA measurement at least 3 weeks later. For participants without declining PSA from baseline, a PSA increase of ≥ 25% and ≥ 2 ng/mL from baseline beyond 12 weeks was considered PSA progression. The rate of progression-free survival was estimated using the Kaplan-Meier method and reported as percentage of participants. | Week 49 Day 1 (Day 337) | 
| Change From Baseline In Quality Of Life (QoL) Total Score As Assessed By The Global Health Domain Of The European Organisation Of Research And Treatment Of Cancer (EORTC)-Quality Of Life Questionnaire (QLQ)-C30 | The EORTC QLQ-C30 core measurement was used to capture distal outcomes, including physical, social functioning, and overall health-related quality of life. The questionnaire incorporates 30 questions comprising nine multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality of life scale. All raw domain scores are linearly transformed to a 0-100 scale. The global health and quality of life domain is presented. An increase in activity or functioning scores indicates improvement (higher/healthier level of functioning) and a decrease in symptom scores indicates improvement (lower level of symptoms/problems). | Baseline, Week 49 Day 1 (Day 337) | 
| Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 | The EORTC QLQ-C30 core measurement was used to capture distal outcomes, including physical, social functioning, and overall health-related quality of life. The questionnaire incorporates 30 questions comprising nine multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality of life scale. All raw domain scores are linearly transformed to a 0-100 scale. All domains except for the global health and quality are presented. An increase in activity or functioning scores indicates improvement (higher/healthier level of functioning) and a decrease in symptom scores indicates improvement (lower level of symptoms/problems). | Baseline, Week 49 Day 1 (Day 337) | 
| Change From Baseline In QoL Total Score As Assessed By The EORTC-QLQ-PR25 Sexual Activity And Functioning And Hormonal-Treatment-Related Symptom Subdomains | Subscales for assessment of hormonal treatment-related symptoms (6 items) and sexual activity and function (6 items) from the EORTC-QLQ-PR25 25-item prostate cancer module of the EORTC are presented. Questions used 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale. An increase in activity or functioning scores indicates improvement (higher/healthier level of functioning) and a decrease in symptom scores indicates improvement (lower level of symptoms/problems). | Baseline, Week 49 Day 1 (Day 337) | 
| Change From Baseline In QoL Total Score For Urinary And Bowel Symptoms Domains As Assessed By The EORTC-QLQ-PR25 | Subscale assessments of urinary symptoms (9 items) and bowel symptoms (4 items) from the EORTC-QLQ-PR25 25-item prostate cancer module of the EORTC are presented. Questions used 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale. A decrease in symptom scores indicates improvement (lower level of symptoms/problems). | Baseline, Week 49 Day 1 (Day 337) | 
| Change From Baseline In QoL Total Score As Assessed By The European Quality Of Life 5-Dimension 5-Level Questionnaire (EuroQoL EQ-5D-5L) | The EuroQoL EQ-5D-5L comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 levels: no problems (1 as numerical score), slight problems (2 as numerical score), moderate problems (3 as numerical score), severe problems (4 as numerical score), and extreme problems (5 as numerical score). The total score ranges from 0 to 100. A decrease in score indicates improvement. | Baseline, Week 49 Day 1 (Day 337) | 
| Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone | Blood samples were collected from participants for hormonal measurements. | Week 1 Day 4 (Day 4), Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337) | 
| Percent Change From Baseline In Serum Concentrations Of FSH | Blood samples were collected from participants for hormonal measurements. | Week 1 Day 4 (Day 4), Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337) | 
| Percent Change From Baseline In Serum Concentrations Of Dihydrotestosterone | Blood samples were collected from participants for hormonal measurements. | Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337) | 
| Percent Change From Baseline In Serum Concentrations Of Sex Hormone-Binding Globulin | Blood samples were collected from participants for hormonal measurements. | Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337) | 
| Maximum Observed Plasma Concentration (Cmax) Of Relugolix | The Cmax of relugolix was determined for single and repeat doses in subsets of participants from Japan. Single dose pharmacokinetics (PK) was assessed on Day 1 following an initial 360 mg dose of relugolix. Repeat dose PK was assessed following repeat dosing of relugolix 120 mg once daily for 2 weeks. | Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2 | 
| Area Under The Concentration-Time Curve (AUC0-τ) Of Relugolix | The AUC0-τ of relugolix was determined for single and repeat doses in subsets of participants from Japan. Single dose PK was assessed on Day 1 following an initial 360 mg dose of relugolix. Repeat dose PK was assessed following repeat dosing of relugolix 120 mg once daily for 2 weeks. | Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2 | 
| Time To Maximum Observed Plasma Concentration (Tmax) Of Relugolix | The Tmax of relugolix was determined for single and repeat doses in subsets of participants from Japan. Single dose PK was assessed on Day 1 following an initial 360 mg dose of relugolix. Repeat dose PK was assessed following repeat dosing of relugolix 120 mg once daily for 2 weeks. | Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2 |