BAY1841788

Metastasis-free survival (MFS) is defined as the time interval from randomization to the date of the appearance of metastasis (on next generation imaging) or death (from any cause), whichever occurs first.

Rate of grade 3-5 AEs, followed by rate of neutropenia grade 3/4 + grade 5 AEs t

The failure-free survival is defined as the time from the date of randomization to clinical (new cancer-related symptoms), biochemical (PSA rising) or radiological (local relapse or new metastases) progression, death, end of 3-year follow-up period or lost to follow-up, whichever occurs first.

rPFS used conventional imaging method (99mTc-phosphonate bone scan, CT/MRI scan). rPFS was defined as the time from the date of randomization to the date of progressive disease in malignant soft tissue lesions, progressive disease in malignant bone lesions, or death due to any cause, whichever occurs first. Malignant soft tissue lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and malignant bone lesions were assessed by Prostate Cancer Clinical Trials Working Group (PCWG3) criteria.

Overall survival (OS) was defined as the time from the date of randomization until death from any cause. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. Long-term (Survival) follow-up period: After Active follow-up, patients continued to be contacted approximately every 12 weeks by phone. The end of the Survival follow-up period was defined as when the patient died, was lost to follow-up, withdrew consent, or at the end-of-study.

Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. Long-term (Survival) follow-up period: After Active follow-up, patients continued to be contacted approximately every 12 weeks by phone. The end of the Survival follow-up period was defined as when the patient died, was lost to follow-up, withdrew consent, or at the end-of-study. Median, percentile and other 95% CIs were computed using Kaplan-Meier estimates. NA = Value cannot be estimated due to censored data

Radiographic progression-free survival (rPFS) is defined as the time from randomization to radiographic disease progression or death from any cause, whichever occurs first. Progression is assessed using RECIST 1.1 for soft tissue and PCWG3 criteria for bone lesions. The 3-year rPFS rate will be estimated using the Kaplan-Meier method.

pRR is defined as the proportion of participants with either condition of pCR or MRD at week 12 or 24 in corresponding arm. Proportion of participants with pCR is defined as the proportion of participants with no residual tumor detected in radical prostatectomy (RP) specimens following 12 or 24 weeks of neoadjuvant treatment of darolutamide and ADT per randomization. Proportion of participants with MRD is defined as the proportion of participants that have residual cancer burden (RCB) ≤0.25 cm\^3 in the RP specimens.

Percent of subjects are free of clinical or radiographic progression at 24 months from initiation of treatment

The primary outcome is the association between the pre-treatment PCAI ImmunoScore and the occurrence of minimal residual disease (MRD) after 90-120 days of neoadjuvant Darolutamide treatment. MRD is defined as \< 0.05 cm3 residual tumour on final pathology after prostatectomy. The study endpoint MRD will be dichotomized into responder (if MRD is met) or non-responder (if MRD is not met) as input for the statistical data analysis. This classification (ground truth) will be tested in AUROC analysis against the calculated PCAI ImmunoScore-based probability p (0\<p\<1) of Darolutamide response. PCAI ImmunScore is calculated from RNA sequencing of tumor material from diagnostic (pre-treatment) biopsies. The collection of RNA and calculation of PCAI ImmunoScore will take place after the recruitment period. Sequencing will be performed in bulk once all samples have been collected. The objective is to assess the predictive value of the pre-treatment genomic biomarker for pathological response.

Recurrence Free Survival (RFS), with recurrence event defined as (whichever occurs first): * Biochemical failure defined as per Phoenix criteria (i.e., a rise in PSA by 2 ng/mL or more above the nadir PSA, confirmed by a second PSA measurement) * Clinical, radiographic, or pathological evidence of local, regional, or distant recurrence/metastasis * Initiation of salvage hormonal therapy * Death from any cause.

PSA response rate of ≥50% decline is defined as the proportion of participants who have achieved a decline of 50% or more from baseline during treatment at any time.

Time interval from enrollment to PSA progression, clinical progression or death, whichever occurs first. PSA progression is defined as when the PSA demonstrates an increase that is more than 50% of nadir, taking as reference the lowest recorded PSA level since starting androgen deprivation therapy (ADT). Clinical progression is defined as increasing symptomatic bone metastases, radiographic progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria (v. 1.1) for soft tissue metastases and PCWG3 criteria for bone metastases, or clinical deterioration due to cancer per investigator's opinion.

To compare the effects of treatment with enzalutamide (ENZ) versus darolutamide (DARO) on the cognitive function of men with non-metastatic and metastatic castration-resistant prostate cancer by comparing the change in the maximally changed cognitive domain utilizing Cambridge Neuropsychological Test Automated Battery \[CANTAB\] cognitive tests from baseline in patients in each study arm. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual. CANTAB is the max score from 5 subscores Paired Associates Learning (0-20, Higher scores = better performance), Spatial Working Memory (0-63, Higher scores = worse performance), Rapid Visual Information Processing (0-1, Higher scores = better performance), Spatial Span (2-9, Higher scores = better performance), and One Touch Stockings of Cambridge (1-7, Higher scores = worse performance).

Defined as (at least one of the 3 criteria below): * Bone progression according to the Prostate Cancer Working Group 3 (PCWG3): * The first bone scan with ≥2 new lesions compared to baseline is observed \<12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline); * The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks from randomization and the new lesions are verified on the next bone scan ≥6 weeks later (a total of ≥2 new lesions compared to baseline). * Progression of soft tissue lesions measured by CT or MRI as defined in modified RECIST criteria. * •Death from any cause. The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks from randomization and the new lesions are verified on the next bone scan ≥6 weeks later (a total of ≥2 new lesions compared to baseline).

The proportion of patients with confirmed tumor response of complete response (CR) or partial response (PR) per RECIST 1.1, as assessed by investigators

The proportion of patients with confirmed tumor response of CR or PR per RECIST 1.1, as assessed by an independent review committee

Obtained by comparing whole brain grey matter quantitative voxel-by-voxel maps of cerebral blood flow/ perfusion (mL per 100g tissue per min) of enzalutamide to placebo. Measured in grey matter voxels with arterial spin labeling magnetic resonance imaging (ASL-MRI).

Obtained by comparing whole brain grey matter quantitative voxel-by-voxel maps of cerebral blood flow/ perfusion (mL per 100g tissue per min) of darolutamide to placebo. Measured in grey matter voxels with ASL-MRI.

Obtained by comparing whole brain grey matter quantitative voxel-by-voxel maps of cerebral blood flow/ perfusion (mL per 100g tissue per min) of enzalutamide to darolutamide. Measured in grey matter voxels with ASL-MRI.

Exposure of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose AUC(0-tlast): AUC from time 0 to the last data point \> LLOQ

Maximum plasma concentration of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate Cmax: maximum observed drug concentration in measured matrix after single dose administration

Exposure of midazolam in plasma following a single administration of midazolam

Maximum plasma concentration of midazolam in plasma following a single administration of midazolam

National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE)

Cmax: maximum drug concentration in plasma after single dose administration

tmax: time to reach maximum drug concentration in plasma after single (first) dose

AUC(0-12):AUC from time 0 to 12 hours after administration

Cmax: maximum drug concentration in plasma after single dose administration

tmax: time to reach maximum drug concentration in plasma after single (first) dose

AUC(0-12):AUC from time 0 to 12 hours after administration

Cmax: maximum drug concentration in plasma after single dose administration

tmax: time to reach maximum drug concentration in plasma after single (first) dose

AUC(0-12):AUC from time 0 to 12 hours after administration

Cmax: maximum drug concentration in plasma after single dose administration

Day -5 {pre dose, 0.5,1,1.5,3,5 ,8,12,24,36,48},Day -2 {before morning dose, 0.5,1,1.5,3,5,8, 12, 24, 36 and 48 h} ,Day 7 {before morning dose, 0.5, 1, 1.5,3,5,8,12 h (before evening dose)}

AUC(0-12):AUC from time 0 to 12 hours after administration