Efficacy and Safety of Radium-223 Dichloride Versus Novel Anti-Hormonal Therapy in Bone-Dominant Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2023-505830-89-00
- Protocol
- 20510
- Sponsor
- Bayer Consumer Care AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **overall survival** of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with **radium-223 dichloride** compared to those receiving a second novel anti-hormonal therapy (NAH). This is clinically relevant as it aims to determine the potential survival benefit of radium-223 dichloride, which could influence treatment decisions for patients with mCRPC, a condition characterized by cancer progression despite hormonal therapy.
Secondary objectives include:
- Assessing the efficacy of radium-223 dichloride compared to second NAH.
- Evaluating the safety profile of radium-223 dichloride in comparison to second NAH.
- Analyzing patient-reported outcomes (PRO) using the FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire.
Participants
The clinical trial involves a total of **292 male participants** diagnosed with **metastatic castrate-resistant prostate cancer (mCRPC)**. The study population consists of adult males aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their ability to swallow specific medications and meet laboratory criteria, including adequate blood counts and liver function. They must have a life expectancy of at least six months and maintain medical or surgical castration. The trial excludes individuals with visceral metastases and includes those with at least two bone metastases. Participants are required to be on bone health agents unless contraindicated. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with contraceptive measures if applicable. The trial does not include female subjects or vulnerable populations.
Plans and Procedures
The clinical trial is a **Phase 4**, randomized, open-label, multicenter study designed to evaluate the efficacy and safety of **radium-223 dichloride** compared to novel anti-hormonal therapy (NAH) in patients with bone-dominant metastatic castration-resistant prostate cancer (mCRPC) who have progressed on or after one line of NAH. The primary objective is to assess overall survival, with secondary endpoints including time to first symptomatic skeletal event, radiological progression-free survival, time to pain progression, adverse events, incidence of fractures, and time to deterioration of the FACT-P total score. The trial is expected to conclude by March 31, 2024, with recruitment having started on November 9, 2020.
Participants will be involved in the study for a maximum treatment period of 48 weeks for those receiving radium-223 dichloride and up to 54 weeks for those on NAH. The trial includes a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, performance status, life expectancy, and laboratory values. Participants must have histologically confirmed adenocarcinoma of the prostate, documented progression of mCRPC, and at least two bone metastases. The screening visit will also assess the ability to swallow the study medications and confirm the maintenance of medical or surgical castration.
Following the screening, participants will be randomized to receive either radium-223 dichloride via intravenous bolus injection or one of the NAH options, which include **abiraterone acetate**, **prednisone**, **prednisolone**, or **enzalutamide**, administered orally. Regular follow-up visits will be scheduled to monitor treatment response, manage any adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
Participants are expected to adhere to the study protocol, including the use of contraception for male participants with partners of childbearing potential. Conditions that may lead to early termination from the study include non-compliance with the protocol, development of exclusion criteria, or investigator's discretion based on the participant's best interest. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Radium Ra 223 dichloride**, marketed as Xofigo, is the experimental treatment in this study. It is provided as a **solution for injection** with a concentration of 1100 kBq/mL. The administration route is via **intravenous bolus injection or IV infusion**. The maximum daily dose is 55 kBq/kg, with a total maximum dose of 330 kBq/kg over a treatment period of 48 weeks. This treatment is designed to assess its efficacy and safety in patients with bone-dominant metastatic castration-resistant prostate cancer (mCRPC).
**Abiraterone acetate**, marketed as ZYTIGA, is one of the comparator treatments. It is available in the form of **500 mg film-coated tablets**. The medication is administered **orally** with a maximum daily dose of 1000 mg, and the treatment can last up to 54 weeks. This medication is used in combination with other treatments to manage mCRPC.
**Prednisone**, marketed as DELTACORTENE, is another comparator treatment. It is provided in **5 mg tablets** and is administered **orally**. The maximum daily dose is 10 mg, with a total maximum dose of 16400 mg over a 54-week period. Prednisone is often used as an anti-inflammatory or immunosuppressant medication in various conditions, including prostate cancer.
**Prednisolone**, available as 5 mg tablets, is also used as a comparator treatment. It is administered **orally** with a maximum daily dose of 10 mg, similar to prednisone, and the treatment duration is up to 54 weeks. Prednisolone is a glucocorticoid used for its anti-inflammatory and immunosuppressive properties.
**Enzalutamide**, marketed as Xtandi, is provided in **40 mg soft capsules**. This comparator treatment is administered **orally** with a maximum daily dose of 160 mg, and the treatment can extend up to 54 weeks. Enzalutamide is an androgen receptor inhibitor used in the treatment of mCRPC.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The study aims to compare the overall survival rates and safety profiles of these treatments in patients with mCRPC.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **overall survival (OS)** in patients with bone-dominant metastatic castration-resistant prostate cancer (mCRPC) who are progressing on or after one line of novel anti-hormonal therapy (NAH). This is a Phase 4, randomized, open-label, multicenter study comparing the standard dose of radium-223 dichloride to standard doses of NAH. Secondary endpoints include time to first symptomatic skeletal event (SSE), radiological progression-free survival (rPFS), time to pain progression as measured by the Brief Pain Inventory-Short Form (BPI-SF), adverse events assessments using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, incidence of fractures, and time to deterioration of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score.
The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, with the primary endpoint of overall survival being a critical measure. The secondary endpoints will provide additional insights into the treatment's impact on disease progression, symptom management, and quality of life. The trial is designed to ensure rigorous assessment of these parameters to determine the comparative efficacy of the treatment regimens under investigation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥18 years of age inclusive, at the time of signing the informed consent. The lower limit may be higher if legally required in the participating country.
- Participants who have histologically confirmed adenocarcinoma of the prostate.
- Participants with mCRPC progressing on/after one line of an approved ARPI (eg. abiraterone, enzalutamide, apalutamide, or darolutamide, after being treated for at least 3 months) in an authorized prostate cancer indication.
- One prior taxane treatment regimen (at least 2 cycles) for metastatic prostate cancer (mHSPC and mCRPC) or refusal or ineligibility of such a regimen.
- Prostate cancer progression documented by PSA according to the Prostate Cancer Working Group 3 (PCWG3) criteria or radiological progression according to RECIST, version 1.1.
- At least 2 bone metastases on bone scan within 4 weeks prior to randomization with no current or history of lung, liver, other visceral, and / or brain metastasis.
- Symptomatic prostate cancer. A worst pain score (WPS) of at least 1 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours). This is to be assessed once during the Screening period.
- Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7 nmol/L). If the participant is being treated with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists (participant who has not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study. Skin cancer or low-grade superficial bladder cancer)
- Participants must be on a BHA treatment, such as bisphosphonates or denosumab treatment unless such treatment is contraindicated or not recommended per investigator's judgement and inclusion is agreed to by the medical monitor. Magnetic resonance imaging (MRI). Participants with history of spinal cord compression should have completely recovered.
- Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
- Life expectancy ≥ 6 months.
- Able to swallow abiraterone and prednisone / prednisolone or enzalutamide as whole tablets/capsules.
- Laboratory requirements: a. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L b. Platelet count ≥ 100 x 10^9/L c. Hemoglobin (Hb) ≥ 9.0 g/dL (90 g/L; 5.6 mmol/L) d. Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (except for participants with documented Gilbert's disease) e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN f. Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2 as calculated using the Cockcroft-Gault equation g. International normalized ratio (INR) of prothrombin time (PT; PTINR) and partial thromboplastin time (PTT) ≤ 1.5 times the ULN. Participants treated with warfarin or heparin will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of PT-INR / PTT will be required until stability is achieved (as defined by local standard of care and based on pre-study PT-INR / PTT values) h. Serum albumin > 30 g/L I. Serum potassium ≥ 3.5 mmol/L.
- Male. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. Male participants who have partners of childbearing potential (or whose partner is pregnant at study start) must use a condom during intercourse or sexual activity while receiving treatment and for 6 months following completion of treatment with radium-223 dichloride, 13 weeks after the last administration of abiraterone and 3 months after the last administration of enzalutamide. The contraception measures must be discussed with the participant. For a non-pregnant partner of childbearing potential, additional contraception recommendations should also be considered. Suitable contraception could be, for example, the use of an oral contraceptive by the partner. Note: Conservation of sperm: There are no human data on the effect of radium-223 dichloride on fertility; however, based on studies in animals, there is a potential risk that radiation from radium-223 dichloride could cause adverse effects on fertility. Participants should seek advice on conservation of sperm prior to treatment. b. Female participants: not applicable
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Exclusion Criteria
- Active infection or other medical condition that would make prednisone / prednisolone (corticosteroid) use contraindicated.
- Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone / prednisolone equivalent daily for more than 2 months.
- Pathological finding consistent with tumors with predominant neuroendocrine features or small cell carcinoma of the prostate (ie. tumors documented as having a small cell carcinoma histology and those having predominant neuroendocrine features [if mixed histology]).
- History of osteoporotic fracture.
- History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations.
- History of or known brain metastasis.
- Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.
- Other malignancy treated within the last 3 years (except nonmelanoma skin cancer or low-grade superficial bladder cancer)
- Imminent spinal cord compression based on clinical findings and / or magnetic resonance imaging (MRI). Participants with history of spinal cord compression should have completely recovered.
- Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg). Participants with a history of hypertension are allowed provided blood pressure is controlled by antihypertensive treatment.
- Active or symptomatic viral hepatitis.
- History of pituitary or adrenal dysfunction.
- Any other serious illness or medical condition such as, but not limited to: a. Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 Grade 2. b. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe orunstable angina, or New York Heart Association (NYHA) Class II to IV heart disease or cardiac ejection fraction measurement of <50% at baseline. c. Current clinical evidence of any uncontrolled cardiac arrhythmia. d. Crohn's disease or ulcerative colitis. e. Bone marrow dysplasia. f. Moderate and severe hepatic impairment (Child-Pugh Classes B and C). g. Unmanageable fecal incontinence.
- Any condition, which in the opinion of the investigator would preclude participation in this trial (eg, history of seizure).
- Hypersensitivity to the active substances or to any excipients of radium-223 dichloride, or abiraterone acetate or enzalutamide.
- Prior therapeutic systemic radiation with any radiopharmaceutical medication for the treatment of prostate cancer, including but o tlimited to lutetium-177, strontium-89, samarium-153, iodine-131, rhenium-186, rhenium-188, or radium-223. Radiopharmaceutical compounds used for diagnosis purposes only are allowed.
- Prior hemibody external radiotherapy is excluded. Participants who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for Hb, ANC, and platelet count.
- Blood transfusion or erythropoietin stimulating agents 4 weeks prior to Screening and during the whole Screening period before randomization.
- Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin is found in multivitamins, including prenatal multivitamins, biotin supplements, and dietary supplements for hair, skin, and nail growth at levels that may interfere with laboratory tests.
- Prior administration of an investigational therapeutic for CRPC.
- Previous (within the last 4 weeks of randomization) or concurrent participation in any interventional clinical study with investigationa lstudy drug administration.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 09 Nov 2020 | 12 |
 Czechia | Not Recruiting | 09 Nov 2020 | 40 |
 Finland | Not Recruiting | 09 Nov 2020 | 25 |
 France | Not Recruiting | 09 Nov 2020 | 107 |
 Germany | Not Recruiting | 09 Nov 2020 | 15 |
 Hungary | Not Recruiting | 09 Nov 2020 | 15 |
 Italy | Not Recruiting | 09 Nov 2020 | 40 |
 Lithuania | Not Recruiting | 09 Nov 2020 | 35 |
 Poland | Not Recruiting | 09 Nov 2020 | 90 |
 Spain | Not Recruiting | 09 Nov 2020 | 135 |
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 |
|---|---|---|---|---|---|---|
ZYTIGA 500 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 1000 | 54 | PRD4502160 |
DELTACORTENE 5 mg compresse | Comparator | COMPRESSE | ORAL | 10 | 54 | PRD349594 |
Xofigo 1100 kBq/mL solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 55 | 48 | PRD970869 |
Prednisolone 5mg Tablets | Comparator | TABLETS | ORAL | 10 | 54 | PRD992060 |
Xtandi - 40 mg soft capsules | Comparator | SOFT CAPSULES | ORAL | 160 | 54 | PRD894075 |