Step Counts to Monitor Changes in Physical Activity in Vulnerable Patients with Metastatic Hormone-Sensitive Prostate Cancer on Darolutamide and Androgen Deprivation Therapy, DaroStep Trial

Inclusion Criteria

• Patients must be aged ≥ 18 years
• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 3
• Patients must screen positive for frailty by meeting at least one of the following: * Katz Activities of Daily Living (ADL) Assessment score 3 or 4 out of 6 e.g., requiring assistance with ≥ 1 basic activity such as bathing, dressing, toileting, transferring, or feeding * 4-Instrumental activities of daily living (4-IADL) assessment score 2 or 3 out of 4 e.g., requiring assistance with tasks such as medication management, transportation, telephone use, or financial management * At least one grade 3 event on the Cumulative Illness Score Rating-Geriatrics (CIRS-G) questionnaire (excluding prostate cancer) e.g., prior myocardial infarction within 5 years or prior coronary revascularization; symptomatic atherosclerotic vascular disease affecting ≥ 2 vascular territories; chronic lung disease with limited ambulation or requiring oral steroids; advanced chronic kidney disease (serum creatinine > 3.0 mg/dL or > 1.5 mg/dL on antihypertensive or diuretic therapy); prior stroke with residual functional deficit or moderate (but not severe) neurodegenerative disease; severe arthritis or osteoporotic vertebral compression fractures limiting activities of daily living; or moderate (but not severe) dementia or major depressive disorder meeting Diagnostic and Statistical Manual of Mental disorders (DSM) criteria * Body mass index (BMI) ≤ 21 kg/m^2 and/or > 10% weight loss in the last 6 months
• Patients must have a diagnosis of metastatic hormone-sensitive prostate cancer (mHSPC), also referred to as metastatic castration-sensitive prostate cancer (mCSPC), for the current metastatic episode, with no prior evidence of castration-resistant prostate cancer before day 0
• Patients must have at least one metastatic lymph node, bone and/or soft tissue/visceral lesion documented for the current metastatic episode by conventional imaging and/or prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) before day 0. Imaging obtained before ADT initiation is acceptable if it was used to diagnose the current metastatic episode and ADT was initiated ≤ 12 weeks before day 0: * Metastatic disease to the bone (in any distribution) visible on technetium Tc 99 muramyl dipeptide (99Tc-MDP) bone scintigraphy or PSMA-PET on imaging performed for the current metastatic episode; and/or * Lymph node metastases of any size or distribution, defined as PSMA-PET positive and/or ≥ 1.5 cm in short axis by anatomic imaging; and/or * Visceral metastases of any size or distribution ** If a participant has a history of visceral metastases at any time before day 0, they should be coded as having visceral metastases at baseline
• Total bilirubin ≤ 2 x the institutional upper limit of normal (ULN), with total bilirubin ≤ 3 x ULN permitted for patients with known Gilbert’s syndrome * Participants with moderate hepatic impairment may enroll with darolutamide dose adjustment per prescribing information
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 x ULN, or ≤ 5.0 x ULN for patients with liver metastases * Participants with moderate hepatic impairment may enroll with darolutamide dose adjustment per prescribing information
• Serum testosterone must be obtained at screening * For participants not yet receiving ADT, testosterone must be obtained before ADT initiation. A historical pre-ADT testosterone ≥ 50 ng/dL within 90 days before ADT initiation or bilateral orchiectomy for the current metastatic episode should be recorded when available. Absence of a historical pre-ADT testosterone value is not exclusionary if ADT or bilateral orchiectomy for the current metastatic episode was initiated/performed ≤ 12 weeks before day 0 and the investigator documents no prior evidence of castration-resistant prostate cancer
• Albumin ≥ 2.5 g/dL
• ADT or bilateral orchiectomy for the current metastatic episode must have been initiated/performed no earlier than 12 weeks before day 0, or must be planned to start before or on day 0. A first-generation antiandrogen (e.g. bicalutamide) used for flare prevention is permitted but must be discontinued before day 0
• If patient is a sexually active male and/or his female partner is of childbearing potential, patient must agree to use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) from screening through 3 months after the last dose of study drugs. Two acceptable methods of birth control include condom (barrier method is required) AND 1 of the following: * Consistent and correct usage of established hormonal contraceptives that inhibit ovulation by the female partner; * Established intrauterine device or intrauterine system by the female partner; * Tubal ligation in the female partner performed at least 6 months prior to your screening visit; * Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) performed at least 6 months prior to screening * Total abstinence is an acceptable method of birth control when this is consistent with your lifestyle preference. Patients must use a condom throughout the study if engaging in sexual intercourse with a pregnant woman and you must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug * Any man whose partner becomes pregnant while taking part in the study dosing period or within 90 days of study dosing discontinuation should immediately tell his study doctor. In the event the female partner of a male subject becomes pregnant, the male subject will be asked to provide information regarding the outcome of the female partner’s pregnancy, if known

Exclusion Criteria

• ADT or bilateral orchiectomy for the current metastatic episode initiated/performed > 12 weeks before day 0 is exclusionary. Prior darolutamide for prostate cancer is exclusionary. Prior second-generation androgen-receptor–signaling inhibitor (ARSI) therapy for the current metastatic episode before day 0 is exclusionary, including abiraterone, apalutamide, enzalutamide, or investigational androgen receptor pathway inhibitors. However, patients who received ADT and/or ARSI for localized, locally advanced, adjuvant, or salvage treatment are eligible, provided this treatment was completed > 12 months before metastatic diagnosis and there is no evidence of castration-resistant prostate cancer before day 0. When available, testosterone recovery should be documented before ADT initiation for the current metastatic episode
• Evidence of castration-resistant prostate cancer before day 0 is exclusionary, defined as clinical, radiographic, or PSA progression while receiving ADT with castrate testosterone
• Uncontrolled intercurrent illness or any condition that, in the investigator’s judgment, places the participant at unacceptable risk or would preclude protocol adherence. Examples include, but are not limited to: active infection requiring IV antimicrobials; New York Heart Association (NYHA) III–IV heart failure; unstable angina or myocardial infarction within 6 months; clinically significant unstable arrhythmia; sustained hypertension > 160/100 mmHg on ≥ 2 measurements despite therapy; Child–Pugh C cirrhosis; or psychiatric/social circumstances that would preclude protocol adherence * Participants with estimated glomerular filtration rate (eGFR) 15-29 mL/min/1.73 m^2 who are not receiving hemodialysis may enroll with darolutamide dose adjustment per prescribing information. Participants with end-stage renal disease (eGFR < 15 mL/min/1.73 m^2) or severe hepatic impairment (Child-Pugh C) are excluded
• Participants with known small-cell/neuroendocrine carcinoma of the prostate or known brain metastasis
• Cognitive, functional, social, or physical limitations that, in the judgment of the treating investigator, would preclude reliable use of a wrist-worn accelerometer
• Prior systemic anti-prostate cancer therapy for metastatic prostate cancer before day 0 is exclusionary, except ADT and permitted first-generation antiandrogen therapy as described in the eligibility criteria. Prior therapy initiated as standard-of-care management before day 0 may be allowed only after study lead principal investigator (PI) review if it is not expected to create unacceptable safety risk, preclude protocol adherence, or materially confound interpretation of functional endpoints
• Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
• Diagnosis of another malignancy requiring active treatment is not exclusionary unless, in the judgment of the treating investigator, the malignancy or its treatment is expected to substantially impair physical function or materially confound interpretation of functional endpoints (e.g., step count, performance measures, or patient-reported outcome measures). If uncertainty exists, the treating investigator/site should contact the study lead PI for review and determination prior to enrollment or continuation on study
• Concurrent or subsequent standard-of-care anticancer therapy for prostate cancer is permitted at the treating investigator’s discretion, including treatment intensification with docetaxel, radiopharmaceutical therapy, radiation therapy, bone-modifying agents, or other standard-of-care therapies, provided that the therapy is not expected to create unacceptable safety risk or preclude protocol adherence. If uncertainty exists, the treating investigator/site should contact the study lead PI for review and determination
• Receipt of investigational anticancer agents and/or participation in another interventional anticancer treatment clinical trial is not permitted while the participant is on study treatment or undergoing protocol-defined assessments. Participation in non-interventional observational studies is permitted if participation does not interfere with protocol adherence or functional endpoint assessment
• Active or unstable clinically significant cardiac disease posing unacceptable short-term safety risk, defined as any of the following: * NYHA class III/IV congestive heart failure within 6 months prior to informed consent form (ICF) signature, unless treated with improvement and echocardiogram or MUGA demonstrates ejection fraction (EF) > 45% with improvement in symptoms to class < III ** History or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk to participant safety, including concomitant clinically significant cardiac arrhythmias, sustained ventricular tachycardia, complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, or third-degree AV block) * Cardiac or cardiac repolarization abnormality, including history of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature