Darolutamide With Radium-223 or Placebo and the Effect on Radiological Progression-Free Survival for Patients With mCSPC

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare the combination of Darolutamide with Radium-223 or placebo and the effects on radiological progression-free survival for patients with Metastatic Castration-Sensitive Prostrate Cancer (mCSPC) The main questions it aims to answer are: Radiological progression-free survival (rPFS) in mCSPC Overall Survival (OS) Symptomatic skeletal event-free survival (SSE-FS) Initiation of subsequent antineoplastic therapy Safety Participants will have visits at baseline, treatment is once a month for up to 6 months, and long term follow up will continue until the participant dies, withdraws consent, and/or study is terminated.

Detailed Description
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A novel treatment strategy combining darolutamide and radium-223 is considered for subjects with mCSPC. Response to treatment is monitored every 12 weeks using a continuous measurement. The main scientific question concerns the comparison of radium-223 to placebo and is best addressed by a randomized clinical trial. Use of placebo in this study is considered ethical, as provision is made for subjects to discontinue their treatment and switch to radium-223 due to lack of efficacy on unblinding where it influences current treatment decisions. Switch to rescue medication is an intercurrent event, after which it is still possible to collect the variable measurements as described in sections on study endpoints below. This is also the case after other intercurrent events such as discontinuation of radium-223 treatment due to an adverse event, but not for intercurrent events such as death unrelated to study IP or disease, subject loss to follow-up, or subject withdrawal from all study treatments and procedures.

Official Title
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A Phase III Randomized Study Comparing the Combination of Darolutamide With Radium-223 or Placebo and the Effect on Radiological Progression-Free Survival for Patients With Metastatic Castration-Sensitive Prostrate Cancer (mCSPC)

Conditions
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Metastatic Prostate Cancer

Intervention / Treatment
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* Drug: Darolutamide
* Drug: Radium-223


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is able and willing to provide informed consent. Metastatic castration-sensitive prostate cancer (mCSPC) at screening with histologically or cytologically confirmed diagnosis of prostate adenocarcinoma. Men ≥ 18 years. ECOG performance status of 0, 1 or 2 at screening. Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTc methylene diphosphonate bone scan); equivocal lesions on the bone scan must be confirmed by standard X-ray, CT, or MRI. Ongoing ADT by Investigator's choice with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy for less than 120 days prior to randomization. ADT treatment should be on a stable dose without interruptions of at least 4 weeks prior to first dose of blinded IP. On bone health agents with at least one dose of BHA prior to first dose of blinded IP. Adequate bone marrow and organ function as defined by: Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L (participant must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening) Serum creatinine ≤2 x upper limit of normal ULN Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 1.5 x upper limit of normal (ULN) Total bilirubin < 1.5 x ULN, unless the participant a diagnosis of Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin; in participants with Gilbert's, the total bilirubin should be < 3 x ULN and the elevation should be seen in the unconjugated or indirect bilirubin measurement) Albumin ≥ 2.5 g/dL Fertile male participants, defined as all males physiologically capable of conceiving offspring with female partners of child-bearing potential, must be willing to use condoms plus spermicidal agent during the study treatment period and for 6 months after the last dose of blinded IP, and not father a child or donate sperm during this period. No known contraindication to any study treatment (darolutamide, radium-223, and/or Investigator's choice ADT). Exclusion Criteria: Pathological finding consistent with small cell carcinoma of the prostate. Prior treatment for mCSPC [excluding ADT ≤120 days and first-generation ARI (bicalutamide, nilutamide or flutamide) for ≤120 days when initiating ADT], with the exception of Metastases Directed Therapy (MDT) with EBRT/SBRT (at least 2 bone metastases must be untreated). Prior treatment for localized prostate cancer is allowed (all treatments must have been completed ≥ 1 year prior to randomization) Treatment for mCSPC with ADT starting >120 days prior to randomization. Treatment for mCSPC with first generation ARI (bicalutamide, nilutamide or flutamide) starting >120 days prior to randomization. Prior hemi-body or whole-body external radiotherapy. a. Other types of prior external radiotherapy and brachytherapies are allowed, if more than 28 days prior to randomization. Prior therapy with radionuclides (e.g., including but not limited to radium-223, strontium-89, samarium-153), including prior therapy with investigational radionuclides (e.g., including but not limited to iodine-131, rhenium-186, rhenium- 188, thorium- 277, actinium-225 and lutetium-177). Prior treatment with: Second-generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors. Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer. Chemotherapy including docetaxel or immunotherapy for prostate cancer. Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization. Current involvement in any drug or device trial involving investigational agent or medical device within the last 28 days prior to randomization. Any prior investigational agent for nmCSPC/mCSPC. Known hypersensitivity to compounds related to darolutamide, or radium-223, or to CT and/or MRI contrast media. A blood transfusion ≤ 28 days prior to randomization. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to randomization. No waiting period is required following port-a-cath placement. Superscan on 99mTc methylene diphosphonate bone scan.

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darolutamide with Radium-223<br>Darolutamide: Dosage:600mg Route: By mouth (PO) Frequency: Twice a day, throughout the duration of the study Radium-223: Dosage: 55 kBq/kg body weight or 1.49 microcurie/kg body weight Route: IV Frequency: Every 28+/-7 days, a maximum of 6 cycles | Drug: Darolutamide<br>* Participants will continue treatment with darolutamide until radiological progression, withdrawal, death, termination, or study completion. The maximum time for darolutamide dose interruption period is 28 consecutive days beyond scheduled dose (>56 days between cycles). Any participant requiring dose interruption >28 consecutive days beyond the scheduled dose may restart treatment with darolutamide if clinical benefit is anticipated and after discussion with and approval from the study Medical Monitor. Until primary endpoint is reached, participants are not allowed to switch ARPI (Abiraterone, Apalutamide or Enzalutamide) during the study. Switching to other ARPI following radiographic progression should be considered a subsequent life prolonging therapy and documented accordingly.<br>* Other names: Nubeqa;Drug: Radium-223<br>* Radium-223 should be given for 6 cycles, administered IV on Day 1 of each cycle or until radiological progression, withdrawal, death, termination, or study completion. The placebo will be administered in precisely the same fashion as the active drug. Subsequent cycles 2-6 should be scheduled to occur every 28 ± 7 days following the previous cycle, but dosing may be delayed up to 28 days per cycle (maximum 56 days between cycles). Any participant requiring dose interruption >28 consecutive days (>56 days between cycles) may restart treatment with radium-223/placebo if clinical benefit is anticipated and after discussion with the Medical Monitor. Participants will continue with darolutamide irrespective of Radium-223 administration. Upon radiological progression, further treatments are decided by the site investigator according to standard local practice.<br>* Other names: Xofigo;|
| Placebo Comparator: Darolutamide with Placebo<br>Darolutamide: Dosage:600mg Route: By mouth (PO) Frequency: Twice a day, throughout the duration of the study Placebo: Dosage: 55 kBq/kg body weight or 1.49 microcurie/kg body weight Route: IV Frequency: Every 28+/-7 days, a maximum of 6 cycles | Drug: Darolutamide<br>* Participants will continue treatment with darolutamide until radiological progression, withdrawal, death, termination, or study completion. The maximum time for darolutamide dose interruption period is 28 consecutive days beyond scheduled dose (>56 days between cycles). Any participant requiring dose interruption >28 consecutive days beyond the scheduled dose may restart treatment with darolutamide if clinical benefit is anticipated and after discussion with and approval from the study Medical Monitor. Until primary endpoint is reached, participants are not allowed to switch ARPI (Abiraterone, Apalutamide or Enzalutamide) during the study. Switching to other ARPI following radiographic progression should be considered a subsequent life prolonging therapy and documented accordingly.<br>* Other names: Nubeqa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological progression-free survival (rPFS) in mCSPC patients | The primary objective of this study is to compare the radiological progression-free survival (rPFS) in mCSPC patients treated with darolutamide plus radium-223 versus darolutamide plus placebo. The primary endpoint is radiological progression-free survival rPFS, defined as time to first occurrence of 99mTc MDP+ bone scan progression per PCWG3 criteria, and/or soft tissue progression by CT/MRI per PCWG3 modifications to RECIST 1.1 criteria, or death from any cause. Randomization will be stratified by ECOG performance status 0 vs 1-2, and metastatic disease status, specifically low volume (<4 bone lesions) versus high volume (≥4 bone lesions). | First occurrence bone scan progression and/or soft tissue progression per #RECIST 1.1 criteria, participant dies, withdraws consent and/or study is terminated, whichever comes first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) & Symptomatic Skeletal Event-Free Survival (SSE-FS) | Overall survival and SSE-FS will be compared between the two arms using a stratified log-rank test, HR (Darolutamide + radium-223 dichloride / Darolutamide + placebo) with 95% CI. Kaplan-Meier estimates and plots for both treatment arms will be produced to accompany these analyses. The median, 25th and 75th percentiles and event free rates at different timepoints with associated 95% CI will be generated. SSE-FS as defined as the time from randomization until any one of the following: the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms, the occurrence of new symptomatic pathologic bone fractures, the occurrence of new symptomatic spinal cord compression, a tumor-related orthopedic surgical intervention, or death. | Randomization until death. | 
| Initiation of Subsequent Antineoplastic Therapy | Time to initiation of subsequent antineoplastic therapy will be compared considering death as a competing risk. Treatment arms will be compared with stratified competing risk HR (Darolutamide + radium-223 dichloride / Darolutamide + placebo) with 95% CI. Event rates will be estimated by cumulative incidence. | Randomization to initiation of first subsequent antineoplastic therapy for prostrate cancer. | 
| Safety of the combination of radium-223 and Darolutamide | Safety of the combination of radium-223 and Darolutamide will be assessed by the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) per Common Toxicity Criteria for Adverse Events (CTCAE) v5.0. Exposure-adjusted incidence rates (EAIR) may be provided. | First treatment dose until last dose + 30 Days |