Study to Compare the Effects of Drug Darolutamide and Drug Enzalutamide on Physical Function, Including Balance and Daily Activity, in Patients With Castration-resistant Prostate Cancer (CRPC)

Study Overview
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Brief Summary
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Researchers in this study want to compare the effects of drug darolutamide and drug enzalutamide on physical function, including balance and daily activity, in patients with castration-resistant prostate cancer (CRPC). Both darolutamide and enzalutamide are approved AR inhibitors used for the treatment of patients with CRPC. AR inhibitor is a substance that keeps androgens (male sex hormones) from binding to proteins called androgen receptors, which are found in normal prostate cells, some prostate cancer cells, and in some other cells. Preventing this binding blocks the effects of these hormones in the body and therefore keeps prostate cancer cells from growing. Patients participating this study will receive either darolutamide or enzalutamide tablets. To evaluate the physical function, patients will be asked to make some movements like rising from a chair, walking three meters, etc. Additionally, researchers also want to find out the survival of patients and if patients have fatigue (feeling tired), cognitive (learning and thinking) problems, or other medical problems during the trial. Brand name of darolutamide is Nubeqa; brand name of enzalutamide is Xtandi.

Official Title
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A Randomized, Open-label, Multicenter, Phase 2b Study to Evaluate Physical Function, Including Balance and Daily Activity, in Participants With Castration-resistant Prostate Cancer Treated With Darolutamide or Enzalutamide

Conditions
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Prostatic Cancer, Castration-Resistant

Intervention / Treatment
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* Drug: Darolutamide (Nubeqa, BAY1841788)
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 years of age inclusive or older at the time of signing the informed consent. Participants who have: Histologically or cytologically confirmed adenocarcinoma of prostate, CRPC (Castration-resistant prostate cancer) defined by disease progression despite ADT (Androgen deprivation therapy) and may present as either a confirmed rise in serum PSA (Prostate-specific antigen) levels (as defined by PCWG3 (Prostate Cancer Working Group)), the progression of pre-existing disease, and/or the appearance of new metastases. Metastatic and non-metastatic CRPC patients will be eligible. KPS (Karnofsky Performance Scale) performance status of ≥80 Blood counts at screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1500/μL, platelet count ≥100,000/μL Screening values of serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN), total bilirubin ≤1.5 × ULN, creatinine ≤2.0 × ULN Life expectancy of at least 1 year Sex: Male Exclusion Criteria: Symptomatic local-regional disease that requires medical intervention including moderate/severe urinary obstruction or hydronephrosis with abnormal renal function due to prostate cancer. Participants with visceral metastasis will be excluded. Past (within 6 months before the start of study intervention) or concurrent stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, and/or congestive heart failure (New York Heart Association Class III or IV) Prior malignancy. Adequately treated basal cell or squamous cell carcinoma of the skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e. pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed 3 years before the start of study intervention and from which the participant has been disease free Prior or concurrent central nervous system disease, such as epilepsy, Parkinson's disease, Alzheimer's disease, dementia, or multiple sclerosis Non-ambulatory participants who need a wheelchair. Other assistive devices (e.g., cane or walker) are permitted. Clinically significant limitations in cognitive function and/or physical function, such as >20 seconds in the TUG assessment Prior treatment with any of the following: Second-generation AR inhibitors, such as enzalutamide, apalutamide, or Darolutamide Other investigational AR inhibitors Progression on abiraterone acetate and discontinuation within 6 months before signing the ICF for the study For mCRPC participants: any chemotherapy, and/or >2 prior lines of systemic anticancer treatment. Treatment with an LHRH agonist, LHRH antagonists, or orchidectomy is not counted as systemic treatment with regard to this exclusion criterion. Use of immunotherapy within 28 days before the start of study intervention Treatment with radiotherapy/radiopharmaceuticals within 12 weeks before the start of study intervention Previous participation in other clinical studies within 28 days before the start of study treatment or 5 half-lives of the investigational treatment of the previous study, whichever is longer Diagnostic assessments

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants treated with darolutamide<br> | Drug: Darolutamide (Nubeqa, BAY1841788)<br>* 600mg, twice daily<br>|
| Experimental: Participants treated with enzalutamide<br> | Drug: Enzalutamide<br>* 160mg, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Worsening in TUG Time During the 24- Week Period. | TUG: Timed Up & Go. Worsening is defined as an increase of at least 1 second in TUG time from baseline. (The minimum clinically important difference [MCID] in TUG time is 1 second | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Increase of at Least 1 Second in TUG Time at 12 and 24 Weeks and During the 52 Weeks. | Worsening was defined as an increase of at least 1 second in TUG time from baseline. Improved was defined at least 1 second decrease from baseline. Stable was defined as change from baseline between less than 1 second increase and less than 1 second decrease. | At 12 week, 24 week and 52 week. | 
| Time to Worsening (Increase of at Least 1 Second) in TUG Time | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | From randomization to the first date a participant had a worsening. | 
| Number of Participants With a Worsening in SPPB Total Score at 12 and 24 Weeks and During the 24 Weeks and 52 Weeks From Baseline. | The SPPB is a group of measures that combines the results of the gait speed, chair stand and balance tests. The composite SPPB score ranges from 0 (worst performance) to 12 (best performance) | At 12 and 24 weeks and during the 24 weeks and 52 weeks from baseline | 
| Mean Change From Baseline in Daily Physical Activity as Assessed by CPM, at 12 and 24 Weeks, and During the 24 Weeks and 52 Weeks From Baseline. | Participants required at least 2 valid days to be included in the analysis at each visit. 'Valid' is defined as at least 10 awake wear hours. CPM for each valid day is defined as 'awake wear-filtered total vector magnitude counts' divided by 'awake wear minutes''. A participant's CPM at each visit is the average of daily CPM. | At 12 week, 24 week and 52 week | 
| Mean Change From Baseline in Accelerometer-assessed Proportion of Time Spent in Light to Vigorous Physical Activity Based on a Threshold of >100 Activity Counts Per Minute. | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | At 12, 24, and 52 weeks for the randomization phase | 
| Number of Participants With a Decline in Cognitive Function During the 24 Weeks and 52 Weeks From Baseline, as Assessed by HVLT-R. | The HVLT-R is a learning and memory test, in which the participant is asked to learn and recall a list of 12 words over three trials. The HVLT-R TR (total score) score ranges from 0 to 36, where higher scores indicated greater verbal learning and recall. The HVLT-R DR (delayed recall) score ranges from 0 to 12, where higher scores indicated greater verbal learning and recall. The HVLT-R RECOG (Delayed Recognition) score ranges from -12 to 12, where higher scores indicated better performance. | During the 24 weeks and 52 weeks from baseline. | 
| Number of Participants With a Decline in Cognitive Function During the 24 Weeks and 52 Weeks From Baseline, as Assessed by TMT. | TMT Part A (TMTA) is timed up to a maximum of 3 minutes, and TMT Part B (TMTB) is timed up to a maximum of 5 minutes. The lower score indicated the better performance. | During the 24 weeks and 52 weeks from baseline. | 
| Number of Participants With a Decline in Cognitive Function During the 24 Weeks and 52 Weeks From Baseline, as Assessed by COWA. | The COWA test assessed lexical fluency. Given a specific letter of the alphabet, participants were required to produce as many words as possible that begin with that letter. There were two alternate forms of the COWA, each with three unique letter exemplars. The lowest possible score is zero, meaning no words could be produced. There is no limit to the higher end of the scale given that participants can produce as many words as possible for each of the three letters. Higher scores indicate greater word retrieval and better cognitive function. | During the 24 weeks and 52 weeks from baseline. | 
| Number of Participants With a Decline Using a Selected Domain of Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog). | FACT-Cog with a range of 0-28 points, higher score is better. Decline was defined as a decrease of >10 points during the 24 weeks and 52 weeks from baseline. | During the 24 weeks and 52 weeks from baseline. | 
| Number of Participants With a Worsening of Fatigue During the 24 Weeks and 52 Weeks. | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | Up to 52 weeks in randomization phase. | 
| Number of Participants With an Increase of at Least 1 Point in Fatigue Interference by 24 Weeks and 52 Weeks From Baseline (Based on Items 4A-F of the BFI) | Fatigue Interference decline is defined as an increase of at least 1 point in any Fatigue Interference from baseline. BFI: Brief Fatigue Inventory. BFI is a 5 minute self-assessment tool that identifies fatigue in cancer participants over a 24-hour period. | At 24 weeks and 52 weeks | 
| Number of Participants With a Worsening in Scores in the PHQ-9 During the 24 Weeks and 52 Weeks From Baseline. | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | Up to 52 weeks in randomization phase | 
| Number of Participants With Treatment Emergent AEs, SAEs, and AEs Leading to Study Intervention Discontinuation | Treatment-Emergent Adverse Events (TEAEs) were defined as any events arising or worsening after the first dose of study drug until 30 days after last dose. SAEs: Serious adverse events | Up to 52 weeks | 
| Number of Participants With AEs of Interest, Including Falls, Fractures, and Hypothyroidism | AEs of interest were followed up regardless of causality or relationship to study intervention. | Up to 52 weeks | 
| Time to Deterioration of Karnofsky Performance Scale (KPS) Defined as at Least a 10 Point Decline From Baseline. | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | From randomization to the first date the participant had had a decline in KPS of at least 10 points. | 
| Number of Participants With Treatment Exposure of the Study Intervention Including Time on Treatment | A total of 30 participants received treatment with darolutamide 600 mg twice daily in the lead-in phase of the study, comprising the safety evaluable population. No participant received either darolutamide or enzalutamide in the randomized phase of the study as the study was terminated prematurely prior to the initiation of the randomized phase of the study. | Up to 52 weeks | 
| Number of Participants With Dose Reductions of Study Intervention | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | Up to 52 weeks in randomization phase | 
| Time to Prostate-specific Antigen (PSA) Progression (as Per Prostate Cancer Working Group [PCWG3] Criteria) | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | From randomization to the time when the criteria for PSA progression (according to PCWG3) was met, up to 52 weeks. | 
| Survival Status | At the end of the lead-in phase, the overall feasibility of the study execution was assessed and decided not to proceed with the randomized phase. Therefore, data on this outcome which needed to be collected in the randomized phase was unavailable. | Up to 52 weeks in randomization phase |