Outcome-Adaptive Randomized Multi-Arm Study of Radium-223 Dichloride, Abiraterone Acetate, and Drug Combinations in Metastatic Prostate Cancer Patients
- Trial ID
- 2023-506857-40-00
- Sponsor
- Karolinska Institutet
Trial statistics
Objectives
The primary objective of the study is to determine whether a therapy class choice or de-escalating treatment regimen based on a **biomarker** signature or ctDNA detectability can improve progression-free survival (PFS) compared to a control arm in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). This is clinically relevant as improving PFS can potentially lead to better management of prostate cancer, delaying disease progression and enhancing patient outcomes.
Secondary objectives include:
- Evaluating whether treatment class selection based on biomarker signatures can improve the time from initial study randomization to death from any cause compared to standard care.
- Assessing improvements in quality of life and health economy through biomarker-driven treatment class selection.
- Ensuring that treatment class selection based on biomarker signatures does not increase toxicity, thereby maintaining drug safety.
- Identifying additional predictive and prognostic biomarkers.
- Determining superior treatment sequencing regimens, such as whether treatment A followed by treatment B is superior to the reverse sequence, given a biomarker signature.
Participants
The clinical trial involves a total of **400 male participants** diagnosed with **prostate cancer**, specifically targeting those with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). The study population consists of adult males aged 18 years and older, who are initiating systemic therapy for metastatic disease. Participants were selected based on their histologically confirmed prostate adenocarcinoma and must have adequate health, hematologic, hepatic, and renal function to receive all available treatments in the trial. The trial excludes female subjects and does not involve a vulnerable population. Participants are required to maintain an effective contraceptive method during and up to six months after the study drug treatment and are advised not to donate sperm during this period. The selection criteria ensure that participants have a performance status of 0-2 on the ECOG/WHO scale, and they must be able to understand the patient information and provide written informed consent. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and controlled study aimed at evaluating the efficacy of various therapeutic agents in patients with metastatic **prostate cancer**. The trial will assess the progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival, quality of life, cost-effectiveness, and the frequency and severity of adverse events. The trial is expected to run from January 15, 2019, to June 30, 2031, with participants involved for a maximum treatment period of 60 months, depending on the specific treatment arm.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, health status, and disease characteristics. This visit will include assessments of hematologic, hepatic, and renal function, as well as imaging studies to confirm metastatic disease. Following the screening, participants will be randomized into different treatment arms, receiving either the investigational product or a comparator. The investigational products include **abiraterone acetate**, **darolutamide**, **niraparib**, **docetaxel**, **olaparib**, **apalutamide**, **capivasertib**, and **enzalutamide**, administered either orally or intravenously, depending on the specific agent.
Subsequent follow-up visits will occur at regular intervals to monitor treatment efficacy and safety, with assessments including imaging studies, laboratory tests, and quality of life questionnaires. The end-of-study visit will conclude the participant's involvement, with a final evaluation of treatment outcomes and any long-term effects. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The trial's adaptive design allows for modifications based on interim results, ensuring the most effective treatments are prioritized for further study.
Treatment
**Radium (223Ra) Dichloride** is administered as an intravenous injection. The pharmaceutical form is denoted as PHF00231MIG. The dosage is calculated based on body weight, with a maximum daily dose of 55 kilobecquerels per kilogram (KBq/Kg). The treatment period is limited to a maximum of 6 cycles. This compound is classified under the ATC code V10XX03, indicating its use as a radiopharmaceutical for therapeutic purposes.
**Abiraterone Acetate** is provided in the form of film-coated tablets for oral administration. The maximum daily dose is 1000 milligrams, with a total treatment period of up to 14 days. This medication is categorized as an anti-hormone therapy and is used in the management of metastatic prostate cancer.
**Niraparib Tosylate Monohydrate + Abiraterone Acetate** is available as a film-coated tablet, with two formulations: one containing 159.40 mg (equivalent to 100 mg base) of Niraparib and 500 mg of Abiraterone Acetate, and another with 79.90 mg (equivalent to 50 mg base) of Niraparib and 500 mg of Abiraterone Acetate. Both formulations are administered orally, with a maximum daily dose of 200 mg and 100 mg, respectively, over a 14-day treatment period. This combination acts as a PARP inhibitor and anti-hormone therapy.
**Darolutamide** is administered orally in the form of film-coated tablets. The maximum daily dose is 1200 milligrams, with a treatment duration of up to 60 days. It is classified as an anti-androgen medication, used in the treatment of prostate cancer.
**Docetaxel** is administered via intravenous drip, with a maximum daily dose of 75 milligrams per square meter (mg/m²). The treatment period is limited to 6 cycles. It is classified under the ATC code L01CD02 as a neoplastic taxane agent.
**Olaparib** is provided as film-coated tablets for oral administration. The maximum daily dose is 1000 milligrams, with a treatment period of up to 6 cycles. It is categorized as an anti-neoplastic agent.
**Apalutamide** is administered orally in the form of film-coated tablets. The maximum daily dose is 240 milligrams, with a treatment duration of up to 14 days. It is classified as an anti-androgen medication.
**Capivasertib** is available in two formulations of film-coated tablets for oral administration, with maximum daily doses of 400 mg and 640 mg, respectively. The treatment period is limited to 6 cycles. It functions as an AKT inhibitor.
**Cabazitaxel** is administered via intravenous infusion, with a maximum daily dose of 20 milligrams per square meter (mg/m²). The treatment period is limited to 6 cycles. It is classified as an anti-neoplastic agent.
**Enzalutamide** is provided as film-coated tablets for oral administration. The maximum daily dose is 160 milligrams, with a treatment duration of up to 14 days. It is classified as an androgen receptor signaling inhibitor.
**Nubeqa (Darolutamide)** is administered orally in the form of 300 mg film-coated tablets. The maximum daily dose is 1200 milligrams, with a treatment duration of up to 60 days. It is classified as an anti-androgen medication.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **progression-free survival** (PFS), which is defined according to the disease stage at trial entry. For metastatic hormone-sensitive prostate cancer (mHSPC), progression is determined by the time to development of castration-resistance as per the European Association of Urology (EAU) guidelines or death. For metastatic castration-resistant prostate cancer (mCRPC), progression is defined as the time to no longer clinical benefiting (NLCB) according to the Prostate Cancer Working Group (PCWG3) guidelines.
Secondary endpoints include overall survival (OS) and quality of life, which will be assessed using validated instruments such as the EORTC-QLQ-C30, EQ-5D-5L, and BPI-SF for all patients enrolled in the ProBio trial. Additionally, for patients with ctDNA-undetectable mHSPC, the EORTC QLQ-PR25 will be used to evaluate hormonal and sexual subdomains. Cost-effectiveness will be analyzed using the EQ-5D-5L instrument to estimate health utilities, with treatment costs based on drug costs and reimbursement data. The frequency and severity of adverse events (AEs) will also be monitored as part of the secondary endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ● Male patients, aged above 18 years, with histologically confirmed prostate adenocarcinoma, initiating systemic therapy for metastatic disease, encompassing: ○ Newly diagnosed (i.e. de-novo) metastatic hormone-sensitive prostate cancer (mHSPC) or ○ Recurrent (i.e. metachronous) mHSPC ■ Patients that have had prior local treatment with curative intent (e.g. primary radiotherapy or radical prostatectomy) and subsequently develop metachronous metastatic disease. These metachronous or recurring mHSPC patients are those observed in the setting of rising PSA until metastasis develops. Patients are not required to be ADT-naïve, but must have normal levels of testosterone (>50 ng/dL or 1.7 nmol/L) at ProBio screening and liquid biopsy collection or ○ First-line mCRPC, i.e. first evidence of progressive metastatic prostate cancer under castrate levels (<50 ng/dL) of serum testosterone, as defined by the EAU guidelines, encompassing: ■ Biochemical progression: Three consecutive rises in PSA 1 wk apart, resulting in two 50% increases over the nadir, and PSA >2 ng/ml and/or ■ Radiologic progression: The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using the Response Evaluation Criteria in Solid Tumours. ● For the initial identification of patients with metastatic disease, distant metastases can either be identified by conventional imaging (i.e. bone scan or metastatic lesions on CT or MRI), or molecular imaging (i.e. miM1 disease on prostate-specific membrane antigen (PSMA) targeting positron emission tomography (PET)). Radiology taken within 6 weeks of screening may be used, if older a new scan needs to be taken. It is important to note that PSMA PET/CT can be used for initial identification and enrollment of patients with metastatic disease, but that it may not be used for response assessment or to infer disease progression. Radiographic follow-up and assessment of progression need to be performed with conventional imaging. ● Adequate health, hematologic, hepatic, and renal function, as assessed by the investigator, to receive all available treatments in the trial in each disease state (mHSPC and mCRPC) (i.e. haemoglobin ≥ 100 g/L (blood transfusion not less than 21 days prior to screening), absolute neutrophil count ≥ 1.5 x 10^9/L, platelets ≥100 x 10^9/L and Total bilirubin < 1.5 ULN (patients with Gilberts Syndrome bilirubin < 40 µg/L) and AST and ALT ≤ 1.5 ULN (or ≤ 3 ULN in the presence of liver metastases) and serum creatinine not greater than 1 ULN (if serum creatinine is between 1 and 1.5 ULN, patients may be eligible provided that the calculated GFR is at least 50 ml/min measured directly by 24-hour urine sampling OR using Cockcroft-Gault method) ● Albumin greater than or equal to 28 g/L ● ECOG/WHO performance status 0-2 ● Agrees to use an effective contraceptive method during and up to 6 months after study drug treatment and should not donate sperm during this period. ● Able to understand the patient information and sign written informed consent.
Exclusion Criteria
- ● Other malignancies within 5 years except non-melanoma skin cancer ● Within 6 months of randomisation: myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke, TIA, or congestive heart failure NYHA class III or IV ● Uncontrolled hypertension: SBP > 160 mmHg and or DBP > 95 mmHg. Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment ● Uncontrolled hypotension: SBP < 90 mmHg and/or DBP < 50 mmHg ● Upon entering the mHSPC phase of the trial, prior systemic therapy (including ADT) is not allowed. Patients with mCRPC may not enter the trial when they have already received prior systemic therapy (with the exception of standard ADT) for mCRPC. ● Any severe acute or chronic medical condition that places the patient at increased risk of serious toxicity or interferes with the interpretation of study results. This includes a medical history significant for arrhythmia (e.g. multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigators judgement with cardiologist consultation recommended. ● Unable to comply with study procedures ● Current participation in another clinical trial that will be in conflict with the present study, e.g. administration of an investigational therapeutic or invasive surgical procedure within 28 days prior to study enrolment. Imaging-based interventional trials are allowed as long as the conventional imaging intervals within ProBio are preserved. ● Patients who are unlikely to comply with the protocol (e.g. uncooperative attitude, inability to return for subsequent visits) and/or otherwise considered by the Investigator to be unlikely to complete the study ● Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subject’s participation in this study. This includes a history of QT prolongation associated with other medications that required discontinuation of that medication; and other factors that increase the risk of OTc prolongation or risk of arrhythmic events, hypokalemia of grade >1, potential for Torsade de Pointes, congenital long QT syndrome. ● Any medical condition that would make use of the study treatments contraindicated, according to the SmPC, e.g. significant heart or liver disease. The investigator should check the SmPC and/or IB for the assigned study treatments. This includes a family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. ● The determination of a biomarker signature is necessary to randomise patients during ProBio mCRPC. Patients with detectable ctDNA and having a microsatellite unstable (MSI) or hypermutated tumor will be excluded from the trial since the plethora of mutations obscures a proper assessment of the disease-driving biomarker signature. Patients will therefore be excluded in case of: a. For patients in mCRPC: undetectable levels of ctDNA. b. For patients in mHSPC and mCRPC: microsatellite unstable (MSI+) or hypermutated tumor.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 15 Jan 2019 | 750 |
 Denmark | Not Yet Recruiting | 15 Jan 2019 | 80 |
 Finland | Not Yet Recruiting | 15 Jan 2019 | 100 |
 Norway | Recruiting | 15 Jan 2019 | 250 |
 Sweden | Recruiting | 15 Jan 2019 | 750 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
APALUTAMIDE | Test | PHF00082MIG | ORAL | 240 | 14 | SCP30338911 |
ENZALUTAMIDE | Test | PHF00007MIG | ORAL | 160 | 14 | SCP271579 |
NUBEQA 300 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1200 | 60 | PRD7991449 |
Niraparib tosylate monohydrate+ abiraterone acetate - Film coated tablet- 159.40 mg (eq. 100mg base)+ 500mg | Test | FILM COATED TABLET | ORAL | 200 | 14 | PRD8913617 |
Capivasertib | Test | FILM-COATED TABLET | ORAL | 640 | 6 | PRD10312009 |
OLAPARIB | Comparator | — | ORAL | 1000 | 6 | SUB32234 |
CABAZITAXEL | Comparator | — | INTRAVENIOUS INFUSION | 20 | 6 | SUB31282 |
RADIUM (223RA) DICHLORIDE | Comparator | PHF00231MIG | INTRAVENOUS | 55 | 6 | SCP31339869 |
Capivasertib | Test | FILM-COATED TABLET | ORAL | 400 | 6 | PRD10312011 |
ABIRATERONE | Test | PHF00245MIG | ORAL | 1000 | 14 | SCP50382059 |