A Phase III Study of Radium-223 Dichloride in Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

The aim of the study was to compare, in patients with symptomatic hormone refractory
prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care plus
Radium-223 dichloride versus best standard of care plus placebo, with the primary efficacy
endpoint being overall survival (OS).

Patients were randomised in a 2:1 allocation ratio (Radium-223 dichloride:Placebo). The
study treatment consisted of 6 intravenous administrations of Radium-223 dichloride or
placebo (saline) each separated by an interval of 4 weeks. The patient were followed until 3
years after first study drug administration.

Within the U.S., the trial was conducted under an IND sponsored by Bayer HealthCare
Pharmaceuticals.

All patients received BSoC (Best Standard of Care).

This study has the original PCD as 14 October 2010, when a total of 316 deaths had been
observed; this resulted in the Independent Data Monitoring Committee's (IDMC's)
recommendation to stop the study as the primary efficacy analysis of overall survival had
crossed the pre-specified boundary for efficacy. Later an updated analysis of primary
endpoint in the first addendum was done with cut-off of 15 July 2011.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate

- Known hormone refractory disease

- Multiple skeletal metastases (≥ 2 hot spots) on bone scintigraphy

- No intention to use cytotoxic chemotherapy within the next 6 months

- Either regular (not occasional) analgesic medication use for cancer related bone pain
or treatment with EBRT (External Beam Radiation Therapy) for bone pain

Exclusion Criteria:

- Treatment with an investigational drug within previous 4 weeks, or planned during the
treatment period

- Eligible for first course of docetaxel, i.e. patients who are fit enough, willing and
where docetaxel is available

- Treatment with cytotoxic chemotherapy within previous 4 weeks, or planned during the
treatment period, or failure to recover from adverse events due to cytotoxic
chemotherapy administered more than 4 weeks ago

- Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 for
the treatment of bony metastases within previous 24 weeks

- Other malignancy treated within the last 5 years (except non-melanoma skin cancer or
low-grade superficial bladder cancer)

- History of visceral metastasis, or visceral metastases as assessed by
abdominal/pelvic CT or chest x-ray within previous 8 weeks