Darolutamide in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer

Phase 3

Completed

• Conditions: Metastatic Hormone-sensitive Prostate Cancer
• Interventions: Drug: Standard ADT (androgen deprivation therapy); Drug: BAY1841788 / darolutamide (ODM-201); Drug: Placebo; Drug: Docetaxel

• Registration Number: NCT02799602
• Lead Sponsor: Bayer

Brief Summary

The purpose of the study is to assess the efficacy and safety of BAY1841788 (darolutamide (ODM-201)) in combination with standard androgen deprivation therapy (ADT) and docetaxel in patients with metastatic hormone sensitive prostate cancer.

Detailed Description

This is a randomized, double-blind, placebo-controlled, multicenter phase III study. The study population will consist of approximately 1300 subjects with metastatic hormone sensitive prostate cancer (mHSPC), who will be randomized (1:1 ratio) to receive 600 mg (2 x 300 mg tablets) of darolutamide (ODM-201)/placebo twice daily with food, equivalent to a total daily dose of 1200 mg, in addition to standard androgen deprivation therapy (ADT) and docetaxel. Subjects will be stratified at randomization for the extent of disease and for Alkaline Phosphatase levels. All subjects will be treated with ADT as standard therapy. Six cycles of docetaxel will be administered after randomization.

The subjects considered for inclusion in the study will have metastatic prostate cancer and will be candidates for ADT and docetaxel.

Treatment with darolutamide (ODM-201)/placebo will be administered until symptomatic progressive disease, change of antineoplastic therapy, unacceptable toxicity, until subject withdraws consent, withdrawal from the study at the discretion of the investigator or his/her designated associate(s), death, non-compliance, or if sponsor terminates the study.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Related News

Study Timeline

• Study First Submitted: 2016-06-06
• Study First Submitted QC: 2016-06-10
• Study First Posted: 2016-06-15
• Study Start: 2016-11-30
• Primary Completion: 2021-10-25
• Results First Submitted: 2022-10-25
• Results First Submitted QC: 2023-01-29
• Results First Posted: 2023-02-24
• Study Completion: 2023-04-11
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-24
• Last Update Posted: 2024-04-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 1306

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of prostate.
• Metastatic disease
• Candidates for ADT and docetaxel.
• Started ADT with or without first generation anti androgen, but no longer than 12 weeks before randomization
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate bone marrow, liver and renal function

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Exclusion Criteria

• Prior treatment with: LHRH agonist/antagonists; second generation androgen receptor (AR) inhibitors such as enzalutamide, ARN-509, darolutamide (ODM-201), other investigational AR inhibitors; CYP17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer; chemotherapy or immunotherapy for prostate cancer prior to randomization.
• Treatment with radiotherapy/radiopharmaceuticals within 2 weeks before randomization.
• Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)
• Had a prior malignancy. Adequately treated basal cell or squamous cell carcinoma of 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 5 years before randomization and from which the subject has been disease-free
• Gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study treatment.
• Inability to swallow oral medications

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + standard ADT + Docetaxel	Standard ADT (androgen deprivation therapy)	Co-administration of Placebo matching BAY 1841788 / darolutamide (ODM-201) tablets, standard ADT and docetaxel
BAY1841788 /darolutamide (ODM-201)+standard ADT+Docetaxel	BAY1841788 / darolutamide (ODM-201)	Co-administration of BAY 1841788 / darolutamide (ODM-201), standard ADT and docetaxel
BAY1841788 /darolutamide (ODM-201)+standard ADT+Docetaxel	Standard ADT (androgen deprivation therapy)	Co-administration of BAY 1841788 / darolutamide (ODM-201), standard ADT and docetaxel
Placebo + standard ADT + Docetaxel	Placebo	Co-administration of Placebo matching BAY 1841788 / darolutamide (ODM-201) tablets, standard ADT and docetaxel
BAY1841788 /darolutamide (ODM-201)+standard ADT+Docetaxel	Docetaxel	Co-administration of BAY 1841788 / darolutamide (ODM-201), standard ADT and docetaxel
Placebo + standard ADT + Docetaxel	Docetaxel	Co-administration of Placebo matching BAY 1841788 / darolutamide (ODM-201) tablets, standard ADT and docetaxel

Primary Outcome Measures

Name	Time	Method
OS From Date of Randomization Until Death From Any Cause - Number of Events	From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)	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.
OS From Date of Randomization Until Death From Any Cause - Month	From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)	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

Secondary Outcome Measures

Name	Time	Method
Number of Participants With TEAEs	From the first dose of darolutamide or placebo until 30 days after the last dose of darolutamide or placebo administration up to cut-off date for the final completion analysis 11 APR 2023 (approximately 77 months)	TEAEs = Treatment-emergent adverse events, were defined as any event(s) arising or worsening after the first dose of darolutamide or placebo, until 30 days after the last dose of darolutamide or placebo administration.
Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events	From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months	Time to castration-resistant prostate cancer was defined as the time from randomization to the first occurrence of one of the following events: PSA progression, Radiological progression by bone lesions, or Radiological progression by soft tissue and visceral lesions.; Treatment period: 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.
Time to Castration-Resistant Prostate Cancer (CRPC) - Month	From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months	Time to castration-resistant prostate cancer was defined as the time from randomization to the first occurrence of one of the following events: PSA progression, Radiological progression by bone lesions, or Radiological progression by soft tissue and visceral lesions.; Treatment period: 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.; NA = Value cannot be estimated due to censored data
Symptomatic Skeletal Event Free Survival (SSE-FS) - Month	From randomization of the first participant to the first occurrence of an SSE event or death from any cause, whichever occurred first up to 25 OCT 2021 cut-off date approximately 59 months	Symptomatic skeletal event-free survival (SSE-FS) was defined as the time from randomization to the first occurrence of an SSE or death from any cause, whichever occurred first.; Treatment period: 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.; NA = Value cannot be estimated due to censored data
Time to Pain Progression - Number of Events	From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months	Time to pain progression was defined as the time from randomization to the first date a patient experienced pain progression.; 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.
Time to Pain Progression - Month	From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months	Time to pain progression was defined as the time from randomization to the first date a patient experienced pain progression.; 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.; NA = Value cannot be estimated due to censored data
Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events	From randomization of the first participant to the first occurrence of an SSE event or death from any cause, whichever occurred first up to 25 OCT 2021 cut-off date approximately 59 months	Symptomatic skeletal event-free survival (SSE-FS) was defined as the time from randomization to the first occurrence of an SSE or death from any cause, whichever occurred first.; 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.
Time to First Symptomatic Skeletal Event (SSE) - Number of Events	From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months	Time to the first SSE was defined as the time from randomization to the first occurrence of an SSE. Identical to the definition used for SSE-FS. Death was not considered as an event in this endpoint.; 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.
Time to First Symptomatic Skeletal Event (SSE) - Month	From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months	Time to the first SSE was defined as the time from randomization to the first occurrence of an SSE. Identical to the definition used for SSE-FS. Death was not considered as an event in this endpoint.; 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.; NA = Value cannot be estimated due to censored data
Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events	From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months	Time to initiation of subsequent systemic antineoplastic therapy was defined as the time from randomization to the initiation of first subsequent systemic antineoplastic therapy.; Treatment period: 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.
Time to Initiation of Subsequent Antineoplastic Therapy - Month	From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months	Time to initiation of subsequent systemic antineoplastic therapy was defined as the time from randomization to the initiation of first subsequent systemic antineoplastic therapy.; Treatment period: 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.; NA = Value cannot be estimated due to censored data
Time to Worsening of Disease-Related Physical Symptoms - Month	From randomization of the first participant to the first increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire up to 25 OCT 2021 cut-off date approximately 59 months	Time to worsening of disease-related physical symptoms was defined as the time from randomization to the first date a patient experienced an increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire.; 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.
Time to Worsening of Disease-Related Physical Symptoms - Number of Events	From randomization of the first participant to the first increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire up to 25 OCT 2021 cut-off date approximately 59 months	Time to worsening of disease-related physical symptoms was defined as the time from randomization to the first date a patient experienced an increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire.; 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.
Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events	From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months	Time to the initiation of opioid use for ≥7 consecutive days was defined as the time from randomization to the date of the first opioid use for ≥7 consecutive days. Data of opioid use related to cancer pain was included in the analysis, and opioid use for non-malignant causes was excluded.; Treatment period: 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.
Time to Initiation of Opioid Use for ≥7 Consecutive Days - Month	From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months	Time to the initiation of opioid use for ≥7 consecutive days was defined as the time from randomization to the date of the first opioid use for ≥7 consecutive days. Data of opioid use related to cancer pain was included in the analysis, and opioid use for non-malignant causes was excluded.; Treatment period: 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.; NA = Value cannot be estimated due to censored data