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

This study is an international phase 3 randomized, open-label, parallel group efficacy and
safety study to evaluate oral daily relugolix 120 mg in patients with androgen-sensitive
advanced prostate cancer who require at least 1 year (48 weeks) of continuous androgen
deprivation therapy. Relugolix 120 mg orally once daily or leuprolide acetate depot
suspension, 22.5 mg (or 11.25 mg in some Asian countries), every 3-months (3-M) by
subcutaneous or intramuscular injection will be administered to patients with prostate cancer
who require androgen deprivation therapy.

Approximately 1100 patients will be enrolled in this study, including approximately 390
patients with metastatic advanced prostate cancer to support the analysis of the secondary
endpoint of time to castration-resistance and 138 Chinese patients (enrolled in China and
Taiwan) to support registration in China. The study includes a Screening Period, a Treatment
Period of 48 weeks, and a Follow-up Period. Additionally, unscheduled follow-up visit(s) may
be arranged for patients with study-related safety concerns as needed. Eligible patients
include those with evidence of biochemical relapse (rising PSA) following local primary
intervention with curative intent, newly diagnosed metastatic disease (excluding metastases
to the brain), and/or advanced localized disease.

Following successful completion of the Screening period study participants will be randomized
2:1 to oral relugolix 120 mg once daily or leuprolide acetate 22.5 mg (or 11.25 mg in some
Asian countries) 3-M depot subcutaneous or intramuscular injection and will attend visits
monthly (ie, every 4 weeks) where serum testosterone and PSA 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.

Key Inclusion Criteria:

1. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the
prostate;

2. 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 one of the following clinical disease state presentations:

1. 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

2. Newly diagnosed androgen-sensitive metastatic disease; or

3. Advanced localized disease unlikely to be cured by local primary intervention
with either surgery or radiation with curative intent

Note: Once 915 patients are enrolled worldwide only patients with metastatic advanced
prostate cancer will be eligible for the study in all regions except China, where both
metastatic and non-metastatic patients will continue to be enrolled.

3. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (5.2 nmol/L);

4. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL (2.0 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;

5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at
initial screening and at baseline.

Key Exclusion Criteria:

1. 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;

2. Previously received GnRH 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;

3. Previous systemic cytotoxic treatment for prostate cancer (eg: taxane-based regimen);

4. Metastases to brain per prior clinical evaluation;

5. Scheduled for major surgery after baseline;

6. History of surgical castration.