Randomized, Open-Label, Multicenter Study of Docetaxel Versus Abiraterone or Enzalutamide in Metastatic Castration-Resistant Prostate Cancer with Adverse Prognostic Factors

Trial ID: 2024-518623-30-00
Protocol: RADAR-1 CRPC
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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Diseases & Conditions

Hormone-refractory prostate cancer

Objectives

The primary objective of this study is to evaluate whether **docetaxel** is superior to an Androgen Receptor-targeted agent (abiraterone + prednisone or enzalutamide) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who are BRCA negative or have unknown BRCA status and possess negative prognostic factors, specifically in terms of progression-free survival (PFS). This is clinically relevant as it aims to determine the most effective first-line therapy for this patient population, potentially improving disease management and patient outcomes.

Secondary objectives include investigating the superiority of docetaxel over the Androgen Receptor-targeted agents in terms of biochemical response, radiographic progression, overall survival, and quality of life in the same patient cohort. These objectives are crucial for understanding the broader impact of treatment on disease progression and patient well-being.

Participants

The clinical trial involves **male** participants aged 18 years and above, diagnosed with **metastatic castration-resistant prostate cancer** without mutations of BRCA1/2 genes or with unknown status. The sponsor has not provided the total number of participants. The study population was selected based on specific inclusion criteria, including adequate bone marrow and chemistry values, the ability to swallow the study drug whole, and a life expectancy of at least six months. Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease. The trial excludes female subjects and does not involve a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include a documented progression of prostate cancer and at least one negative prognostic feature. Participants must be surgically or medically castrated with testosterone levels below 50 ng/dL and have an ECOG Performance Status of 0 or 2.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy of **docetaxel** versus an androgen receptor-targeted agent, either **abiraterone** or **enzalutamide**, in patients with metastatic castration-resistant prostate cancer (mCRPC) who do not have BRCA1/2 mutations or have an unknown status. The primary objective is to determine if docetaxel is superior in terms of radiographic progression-free survival (rPFS) at 9 months compared to the androgen receptor-targeted therapies. The trial is expected to run from March 31, 2020, to April 19, 2027, with participants involved for a maximum treatment period of 60 weeks for abiraterone and enzalutamide, and 24 weeks for docetaxel.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as adequate bone marrow and chemistry values, ability to swallow tablets, and a life expectancy of at least 6 months. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of PSA response rate, median rPFS, overall survival, and health-related quality of life. The end-of-study visit will conclude the participant's involvement, with final evaluations conducted to gather comprehensive data on the trial's endpoints.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's design ensures rigorous monitoring and data collection to achieve its objectives, with a focus on comparing the safety and efficacy of the treatment arms. The study's methodology adheres to high scientific standards, ensuring the reliability and validity of the findings.

Treatment

The clinical trial involves the administration of **ENZALUTAMIDE**, a chemical compound classified as a hormone antagonist and antiandrogen. ENZALUTAMIDE is provided in the form of a soft capsule, with a maximum daily dose of 160 mg. The medication is administered orally, and the treatment period extends up to 60 days. Participant compliance is monitored to ensure adherence to the dosing schedule.

**DOCETAXEL** is another experimental medication used in this trial. It is a chemical compound categorized under taxanes and is provided as a solution for infusion. The maximum dose is 75 mg/m², administered via intravenous infusion. The treatment period for DOCETAXEL is up to 24 weeks. The administration schedule and participant adherence are closely monitored throughout the trial.

The trial also includes the use of **ABIRATERONE**, a chemical compound used in endocrine therapy and classified as a hormone antagonist. ABIRATERONE is administered in tablet form, with a maximum daily dose of 1000 mg. The route of administration is oral, and the treatment period is up to 60 days. Compliance with the dosing regimen is monitored to ensure accurate data collection.

In addition to the experimental medications, the trial may involve the use of standard-of-care therapies as deemed necessary by the clinical investigators. The trial aims to compare the efficacy of DOCETAXEL against androgen receptor-targeted agents, such as ABIRATERONE and ENZALUTAMIDE, in patients with metastatic castration-resistant prostate cancer (mCRPC) with adverse prognostic factors. The primary objective is to evaluate progression-free survival (PFS) among the participants.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the comparison of **radiographic Progression-Free Survival (rPFS)** rates at 9 months between two treatment arms: chemotherapy (Arm A, docetaxel plus prednisone) and androgen receptor-targeted therapy (Arm B, enzalutamide or abiraterone acetate plus prednisone) in patients with metastatic castration-resistant prostate cancer (mCRPC) who are BRCA negative or have unknown status and possess adverse prognostic factors. Secondary endpoints include the comparison of efficacy in terms of **PSA response rate**, **median rPFS**, and **overall survival**. Additionally, the trial will evaluate the safety profiles of docetaxel, abiraterone, and enzalutamide, as well as the impact on Health-Related Quality of Life (HRQOL) using the FACT-P questionnaire and health status/utility through the EQ-5D-5L test.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Willing and able to provide written informed consent
Male aged 18 years and above
Histologically or cytological confirmed adenocarcinoma of the prostate
Metastatic disease documented by positive bone scan or metastatic lesions other than liver or visceral metastasis on CT, MRI. If lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in diameter. Alternatively, metastatic disease can be diagnosed by PET-Choline or PSMA.
Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria
At least one negative prognostic features between: I. Mildly symptomatic prostate cancer defined as per BPI Question #3 (worst pain in last 24 hours) value 2 or 3 or II. Asymptomatic prostate cancer defined as per BPI Question #3 (worst pain in last 24 hours) value 0 or 1 and at least one between - PSA≥80 ng/dl ; - Gleason Score ≥ 8; - PSA doubling time ≤ 3 months; - Time from start ADT to CRPC less < 1 year
No evidence of mutation in BRCA1 or genes or tumor tissue not evaluated for quality reasons (status unknown)
Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM)
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 2
Adequate bone marrow and chemistry values defined as: a. Hemoglobin ≥ 10.0 g/dL independent of transfusion b. Neutrophil count ≥1500 x 109/L c. Platelet count ≥100,000/μL d. Serum albumin ≥ 3.5 g/dL e. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min f. Serum potassium ≥ 3.5 mmol/L g. Liver function: - Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert’s disease); - AST or ALT < 2.5 x ULN
Able to swallow the study drug whole as a tablet
Life expectancy of at least 6 months
Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 13 weeks after last study drug administration

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Exclusion Criteria

Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
Pathological finding consistent with small cell carcinoma of the prostate greater than 10%
Known brain metastasis
Use of major opiate analgesics for cancer-related pain (codeine and tramadol are allowed)
Previous cytotoxic chemotherapy, or biologic therapies for the treatment of castrationsensitive or castration-resistant prostate cancer (prior use of bicalutamide is permitted). Previous use of new generation androgen receptor inhibitors for castration-sensitive disease is permitted if at least one year has passed since their discontinuation or if treatment has lasted longer than 36 months without evidence of biochemical and radiological progression
Radiation therapy for treatment of the primary tumour within 6 weeks of Cycle 1, Day 1
Radiation or radionuclide therapy for treatment of metastatic CRPC and CSPC
Bicalutamide, nilutamide within 6 weeks of Cycle 1 Day 1
Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by antihypertensive treatment
A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) or history of additional risk factors for “torsaides de pointes” (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval (at least those of class IA and III).
Active or symptomatic viral hepatitis or chronic liver disease
Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline
Uncontrolled Atrial Fibrillation, or other uncontrolled cardiac arrhythmia requiring therapy
Other malignancy with a previous diagnosis within 5 years (with the exclusions of NMIBC)
Concomitant medications as reported in section 7
Known hypersensitivity to docetaxel, abiraterone or enzalutamide active principles and any excipients