Registry of Treatment Outcomes in a non-study population of Symptomatic Metastasized Castration Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223 (ROTOR-registry).

Every year approximately 12,000 men are diagnosed with prostate cancer in the
Netherlands and approximately 2,400 die of this disease. When prostate cancer
is limited to the prostate, patients can be operated or radiated with a
curative intention, however, metastasized disease is incurable. Initially,
prostate cancer responds to testosterone at castration level and treatment with
androgen receptor signaling inhibitors. However, after an average of 24 months,
prostate cancer will reach a castration resistant stage (mCRPC), which is
associated with high morbidity and mortality. Since the introduction of
Docetaxel in 2004, multiple treatments for mCRPC have become available. All
these treatments have a proven beneficial effect on quality of life and all
expand life expectancy. An important clinical problem is that approximately 50%
of older patients are not able or not willing to receive docetaxel treatment.
These patients are also not eligible for treatments of docetaxel refractory
disease. Therefore, there is a need for effective treatments with little site
effects.

In the phase 3, ALSYMPCA study 921 patients were randomized between Rad-223
(Xofigo®) and placebo in a 2:1 distribution1. Patients with symptomatic bone
metastases, limited lymph node involvement, adequate bone marrow, kidney and
liver functions were included in this trial. Patients were previously treated
with docetaxel or could not receive docetaxel, declined docetaxel or docetaxel
was not available. At a planned interim analysis after 538 deaths, the primary
end point overall survival (OS) was 14.9 months in the Radium-223 treated arm
and 11.3 months in the placebo arm (HR 0.70; 95% CI 0.58-0.83). All secondary
end points were at the favor of Radium-223 treated patients, including time to
first skeletal related event, quality of life and various biochemical end
points. However, patient reported pain scores were not collected in the trial.
Radium-223 treatment was well tolerated, with the most prominent side effects
(all grades) thrombocytopenia 12 and 6%, neutropenia 5 and 1% and diarrhea 25
and 15% in the Radium-223 and placebo arm, respectively.
A post-hoc analysis showed an equal efficacy of Radium-223 treatment in
docetaxel pre-treated patients as in docetaxel naïve patients.
In this registry we aim to evaluate the efficacy of Radium-223 treatment and
first subsequent therapy in a non-study population. Various parameters will be
collected, including changes in patient reported pain score. Moreover, changes
in serum and blood levels of biomarkers of bone metabolism and levels of blood
osteoclast precursors in Radium-223 treated patients will be evaluated for
their potential to predict treatment outcome. Frequencies of
osteoclastprecursors (GMODP/MODP) of radium-223 patients, will be compared to
the frequencies of osteoclastprecursors in patients with localized prostate
cancer, without bone metastases.

1.To evaluate the efficacy of Radium-223 treatment in a non-study population by
effects on Symptomatic Skeletal Event (SSE)
2. Evaluate Radium-223 treatment efficacy by patient reported analgesic use and
pain outcome
3. Evaluate Radium-223 treatment efficacy in a non-study population of CRPC
patients by clinical parameters.
4. Evaluate Radium-223 treatment tolerability in a non-study population of CRPC
patients.
5. Evaluate the efficacy of the first subsequent therapy by clinical parameters
6. Identification of predictive clinical and explorative biomarkers of
Radium-223 efficacy
7. Substudy: Test if the frequency of GMODP/MODP (osteoclast precursors) could
be used as a predictive biomarker for response on radium-223 treatment in mCRPC
patients with bone metastases

This registry aims to evaluate the efficacy of Rad-223 treatment in a non-study
population of CRPC patients treated earlier with Docetaxel and patients not
treated earlier with Docetaxel and efficacy of the first subsequent therapy.
The indication for treatment with Radium-223 will be at the physician*s
decision. All patients treated with Radium-223 can be included in this
registry. The registry only dictates the collection of base line
characteristics, expansion of regular blood tests and patient reported pain
scores.

The only burden associated with this registry are the monthly questionnaires
and the extra blood withdrawals.

Substudy (osteoclastprecursors): For the control group in the substudy, the
blood withdrawals are the extra burdon. (They will not fill out qny
questionnaires.)