The purpose of the study is to assess if the addition of darolutamide to ADT compared with ADT alone would result in superior clinical efficacy in participants with metastatic hormone-sensitive prostate cancer (mHSPC) by progression-free survival.

The researchers want to learn how long it takes for the cancer to get worse (also known as "progression-free survival") by either increasing symptoms, new metastases, PSA rise or death. All participants will be on treatment and take darolutamide with ADT until their cancer spreads, they have a medical problem, or they leave the study. The results will then be compared with patients' results from another study who received ADT alone (CHAARTED).

This study will also assess safety by gathering adverse event information throughout the duration of the study. An adverse event is any medical problem, related or not to study treatment that a participant has during a study.

The study drug, darolutamide, is already available for doctors to prescribe to patients with prostate cancer that has not yet spread to other parts of the body. It works by blocking a protein called a receptor from attaching to a hormone called androgen that is found in men. This protein can also be found in prostate cancer cells. ADT is a treatment that doctors are currently able to prescribe to patients with mHSPC. ADT is used to lower the amount of the androgen hormone.

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of prostate. Participants may have begun androgen-deprivation therapy (up to 120 days prior to enrollment). Note: Relugolix is not permitted as ADT in this study.

• Metastatic disease and will be stratified by presence of high volume or low volume disease.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2

• Adequate bone marrow, liver and renal function within 4 weeks of enrollment

• At least 4 weeks since prior major surgery and recovered from all toxicity from such surgery prior to enrollment

• Prior adjuvant or neoadjuvant hormonal therapy allowed provided the following criteria are met:

  • Therapy was discontinued ≥ 12 months ago AND there was a clinical state without evidence of disease at least 12 months after completing adjuvant or neoadjuvant hormonal therapy, as defined by 1 of the following:

    • PSA < 0.1 ng/mL after prostatectomy plus hormonal therapy
    • PSA < 0.5 ng/mL and has not doubled above nadir after radiotherapy plus hormonal therapy

  • Therapy lasted no more than 24 months

• Prior palliative radiotherapy allowed for participants, if commenced within 30 days before starting androgen deprivation.

• Bicalutamide, nilutamide or flutamide are allowed as single-agent therapy ≤ 28 days before medical castration to prevent flare.

Exclusion Criteria:

• PSA met criteria for PSA progression
• History of malignancy in the past 5 years, with the exception of basal cell and squamous cell carcinoma of the skin.
• Had any of the following within 6 months before randomization: myocardial infarction, severe/unstable angina pectoris, congestive heart failure, hospitalization for any cardiac event, including conduction abnormalities
• Pathological finding consistent with small cell, or neuroendocrine carcinoma of the prostate
• Known brain/ leptomeningeal metastases
• An active viral hepatitis (defined as Hepatitis B surface antigen [HBsAg] reactive or detectable [qualitative] HBV DNA defined as HCV Ribonucleic Acid [RNA] [qualitative] is detected), known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need of treatment
• Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management
• A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of study drug
• Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the participant and/or his compliance with study procedures or may interfere with the participant's participation in the study or evaluation of the study results.
• Prior hormone therapy in the metastatic setting
• Prior chemotherapy in the adjuvant or neoadjuvant setting
• Concurrent use or previous exposure of 5-alpha reductase inhibitors (within 28 days before the start of darolutamide or 5 half-lives of the drug, whichever is longer)
• Any Prior treatment with second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide, or other investigational AR inhibitors, Cytochrome P17 enzyme inhibitor such as abiraterone acetate or other investigational CYP 17 as antineoplastic treatment for prostate cancer
• Previous (within 28 days before the start of darolutamide or 5 half-lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s).
• Contraindication to both CT and MRI contrast agent
• Hypersensitivity to any of the study treatments, study treatment classes, or excipients in the formulation of the study treatments
• Inability to swallow oral medications

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.