Rhenium-188-HEDP vs. Radium-223-chloride in Patients With Advanced Prostate Cancer Refractory to Hormonal Therapy

The main objective of this trial is to compare rhenium-188-HEDP (a beta-emitting radiopharmaceutical) with radium-223-chloride (an alfa-emitting radiopharmaceutical), in patients with castration-resistant prostate cancer metastatic to bone, with overall survival as primary endpoint.

For radium-223-chloride, an overall survival benefit has been proven in a large randomized phase III trial. Although such a trial has never been performed for rhenium-188-HEDP, some trials in literature suggest a survival benefit for rhenium as well.

Rhenium has some advantages compared to radium. Firstly, it is easily available as it can be produced in the hospital. Secondly, the costs of rhenium are significantly lower compared to radium. Lastly, rhenium seems to have a favorable pain response. However, no randomized trials have been performed to confirm this.

• Radium-223 chloride (Drug), also known as Xofigo, Radium-223 dichloride: Intravenously 50 kBq/kg every 4 weeks. Total: 6 administrations
• Rhenium-188-HEDP (Drug), also known as Re-188-HEDP, 188Rhenium-etidronate: Intravenously 40 MBq/kg every 8 weeks. Total: 3 administrations

Primary outcomes

• Overall survival [Time from randomization until death due to any cause, an average of 18 months]: Time from randomization until death due to any cause,

Secondary outcomes

• Time to PSA progression [Time from randomization to the date of a minimum of rising PSA levels, an average of 8 months (PSA measured at baseline and every 4 weeks).]: Time from randomization to the date of a minimum of rising PSA levels with an interval of >1week between each determination
• Time to total-ALP progression [Time from randomization to the date of earliest objective evidence of ALP progression, an average of 8 months (ALP measure at baseline and every 4 weeks)]: Time from randomization to the date of earliest objective evidence of ALP progression.
• Clinical progression [Time from randomization to the date of first clinical progression, an average of 12 months]: Time from randomization to the date of first clinical progression.
• Time to first SRE [Time from randomization to the date of first skeletal related events, an average of 12 months]: Time from randomization to the date of first skeletal related events
• Quality of life [Assessed through study completion, an average of 1 year]: Measured by the EORTC quality of Life Questionnaire C30
• Effect on pain [Assessed through study completion, an average of 1 year]: Measured with a visual analogue scale
• Incremental Cost Effectiveness Ratio (IVER) [Assessed through study completion, an average of 1 year]: Ratio between the difference in costs and the difference in benefits (quality of life of treatment with rhenium-188-HEDP of radium-223-chloride)

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Male, 18 years or older
* Histologically confirmed prostate cancer
* Bone metastases (≥ 6 lesions) showing pathological uptake at bone scintigraphy.
* WHO performance status of ≤2
* Life expectancy of at least 6 months
* Castration-resistant disease: serum testosterone level of ≤ 1.7 nmol per liter (≤50 ng per deciliter) after bilateral orchiectomy or during maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist. During study treatment the maintenance androgen-deprivation therapy must be continued.
* Baseline PSA ≥5 ng/ml with evidence of progressively increasing PSA values
* Symptomatic disease with either regular use of analgesic medication or treatment with external-beam radiotherapy for cancer-related bone pain within the previous 12 weeks.
* Progression on or after treatment with docetaxel, or inability to receive docetaxel.
* Adequate renal function (serum creatinine level ≤1.5 x ULN)
* Adequate hematological function defined as absolute neutrophil count ≥ 1.5x10\^9/L and platelet count ≥100x 10\^9/L)
* Written informed consent

Exclusion Criteria:

* Treatment with chemotherapy within the previous 4 weeks
* Continuation of treatment with abiraterone or enzalutamide
* Previous hemibody external radiotherapy
* Systemic radiotherapy with radioisotopes within the previous 24 weeks
* Malignant lymphadenopathy ≥3cm in the short-axis diameter
* Presence of visceral metastases
* Imminent of established spinal cord compression
* Active uncontrolled bacterial, viral or fungal infection
* History of another malignancy within the last five years except adequately treated basal cell carcinoma of the skin
* Organ allografts requiring immunosuppressive therapy.
* Any serious uncontrolled concommitant disease
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule: those conditions should be discussed with the patient before registration in the trial.

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• Alfons JM van den Eertwegh, Prof.dr., Principal investigator, Amsterdam UMC, location VUmc