Radium-223 for High-Volume Metastatic Hormone Sensitive Prostate Cancer

The trial will enroll competitively up to 50 patients with mHSPC and high volume disease (i.e. ≥4 bone metastatic foci in Tc-99m bone scanning, with at least one focus located outside the pelvis or vertebral bodies in the spine AND/OR visceral metastasis shown on computed tomography or magnetic resonance imaging not including lymph nodes). Patients should have started and be on treatment as per standard of care with first-line triplet therapy consisting of chemical or surgical androgen deprivation therapy (ADT), docetaxel and darolutamide. At least four cycles of docetaxel should have been administered and the last dosing of docetaxel be < 12 weeks prior the first planned dose of Ra223. Patients should have a good performance status (ECOG PS 0-2 and Charlson score ≤ 3) and have recovered from any prior toxicity from triplet therapy. Previous treatments other than chemotherapy for locoregional disease are acceptable.

Additionally to the IMPs and AXMPs, the study includes the administration of at least two doses of a bone protecting agent (zoledronic acid or denosumab) is required before the first administration of Ra223, and the bone protecting agent should have been started at least 6 weeks before the first administration of Ra223. Patients should also start treatment with vitamin D and calcium supplements

Inclusion criteria

Subjects must fulfill all of the following inclusion criteria to be eligible for enrollment to the study:

• Patients must be fully informed about the study and sign the informed consent form (ICF) before any study specific assessment.
• Patients ≥18 years old.
• ECOG performance status of 0 to 2 and Charlson score ≤ 3 prior to study entry, after docetaxel.
• Patients with histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.
• Patients should have received triplet therapy with ADT (luteinizing hormone releasing hormone analogue (LHRHA) for continuous treatment or previous bilateral orchidectomy), docetaxel and darolutamide as first-line therapy for mHSPC. The following conditions apply:

• Received ≥ 4 cycles of docetaxel.
• Treatment with docetaxel should be finished ≤ 12 weeks before the first planned dose of Ra223.
• Having no progression of the disease after triplet therapy completion and before inclusion.

Note: patients with prior therapies for locoregional disease are acceptable

• Patients should have recovered from any prior toxicity from ADT, darolutamide or docetaxel to CTCAE grade 1 or baseline levels.
• Presence of at least 4 bone metastasis on the screening bone scan, with or without lymph node and/or visceral metastases.
• Asymptomatic or mildly symptomatic (defined as short form question #3 in Brief Pain Inventory worst pain must be < 4).
• Patients should be willing to initiate or continue bisphosphonates /denosumab, calcium and vitamin D supplements (Section 7.4.4) prior to the first dose of Ra223.

Note: Patients must start treatment with a bone protecting agent (at doses used to reduce the incidence of skeletal related events) before the time of signing the ICF. A minimum of two doses is recommended before the first administration of Ra223. The first administration of Ra223 should be scheduled at least 6 weeks after the first administration of the bone protecting agent.

• T-score ≥ -2.5 on a DXA scan done in the past 12 months. A DXA scan performed during the screening period will be encouraged but not mandated.
• Adequate organ and bone marrow function as follows (subject must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory):

• Absolute neutrophil count (ANC) ≥ 1.5 x109/L;
• Platelets ≥ 100 x109/L;
• Hemoglobin ≥ 9.0 g/dl;
• Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN), except for patients with Gilbert's disease ≤ 5.0 x ULN;
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN;
• Creatinine ≤ 1.5 x ULN;
• CrCl < 30 mL/min;
• Albumin > 25 g/L.
• Participants who have pregnant partners must use a condom and those with partners of childbearing potential must use a condom and another adequate birth control measure if engaging in sexual activities during the study treatment period and for at least 1 week after last dose of darolutamide and 6 months after the last dose of Ra223. A highly effective method of birth control is defined as those which result in low failure rate (i.e., less than 1% per year) when used consistently and correctly.

Exclusion criteria

Subjects with any of the following could not enroll in this study:

• Presence of tumor lesion in central nervous system through radiologically confirmed diagnosis.
• Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin, in-situ carcinoma or low-grade superficial bladder cancer, or the patient has been free of malignancy for a period of 3 years prior to inclusion).
• Patients experiencing progression during previous ADT or meeting criteria for castration resistant prostate cancer (CRPC).

Note: Prior ADT is allowed.

• External irradiation, brachytherapy, or local treatment (including radiofrequency ablation, cryotherapy, high intensity focused ultrasound, etc.) within 4 weeks prior to the first dose of study treatment.
• Received prior chemotherapy for prostate cancer other than as part of first-line triplet therapy for mHSPC.
• Major surgery within 4 weeks prior to treatment.
• Prior hemibody external radiotherapy.
• Corticosteroids are allowed only at a dose ≤ 10 mg of prednisone (or equivalent) no matter the indication.
• Receiving abiraterone treatment as part of the first-line triplet therapy for mHSPC.

Note: An increased risk of death and fractures was observed in a clinical study in which Ra223 was added to abiraterone acetate and prednisone/prednisolone in patients with asymptomatic or mildly symptomatic CRPC and this is the rationale to not include patients with this combination.

• Plan to receive any other antitumor therapies during this trial.
• Treatment with an investigational drug within the previous 4 weeks, or planned during the treatment period.
• Any other serious illness or medical condition such as, but not limited to:

• Any uncontrolled infection ≥ Grade 2 according to NCI-CTCAE v6.0;
• Gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease);
• Crohn's disease or ulcerative colitis;
• Osteonecrosis of the jaw;
• Non-malignant bone disease with an osteoblastic activity;
• Bone marrow dysplasia;
• Fecal incontinence;
• Life-threatening illness unrelated to cancer.
• Significant cardiovascular disease including:

• Uncontrolled angina within 3 months prior to screening;
• Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%. Of note, MUGA scans at baseline will not be mandated.
• History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);
• History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
• Uncontrolled hypertension as indicated by a resting systolic blood pressure > 160 millimeters of mercury (mm Hg) or diastolic blood pressure > 100 mm Hg at screening; Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to inclusion. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from each blood pressure assessment must be ≤ 160/100 mm Hg in order for a patient to be eligible for the study.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs. No known hypersensitivity to Ra223 (refer to summary of product characteristics [SmPC]).
• Contraindication to both CT and MRI contrast agents.
• Contraindications for the use of bisphosphonates or denosumab as per physician judgment.
• Involvement in another therapeutic trial involving an experimental drug.
• Drug or alcohol abuse.
• Any medical condition that in the opinion of the investigator will negatively affect patients' clinical status when participating in this trial.