Radium-223 is indicated for the treatment of patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease. However, very few data have been reported in patients with mCRPC who are asymptomatic or mildly symptomatic. Recently, results from an International Expanded Access Program have also suggested a benefit of radium-223 in asymptomatic patients with mCRPC. In addition, the mechanism of action of radium-223 should not be correlated with the presence/absence of the AR-V7 mutation, although this issue has not yet been evaluated.

The aim of this study is to assess the efficacy of radium-223 in asymptomatic patients with mCRPC, and to establish the association between AR-V7 status and radium-223 activity.

Primary objective:

To assess the efficacy of radium-223 in asymptomatic patients with mCRPC who have progressed while on abiraterone acetate or enzalutamide treatment.

Primary endpoint:

To determine the efficacy of radium-223 in terms of radiological rPFS.

Secondary objectives:

• Safety profile.
• To determine the association between AR-V7 status (positive vs. negative) and PFS.
• To establish the relationship between CTCs number with radium-223 efficacy.

Secondary endpoints:

Safety AEs will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) of the US National Cancer Institute (NCI) version 4.0 [20]. Grade 3 or 4 AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the various combinations of drugs.

Efficacy

• Radiographic progression-free survival (rPFS) depending on AR-V7 status.
• Overall survival (OS).
• Time to first symptomatic skeletal event (SSE).
• Time to prostate specific antigen (PSA) progression according to the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) study criteria.
• Determination percentage of PSA progression.
• Alkaline phosphatase level response (AF), normalization of alkaline phosphatase level, according to the ALSYMPCA study criteria.

Molecular aspects

• Assessment of AR-V7 mutation evolution during the study treatment.
• Determination changes in CTCs number during the study treatment.

Inclusion Criteria:

• Subject is an adult ≥ 18 years at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
• Subject has histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
• Subject has bone metastases due to the prostate cancer and absence of visceral metastases.
• Subject has a serum testosterone of ≤ 1.7 nmol/L (or ≤ 50 ng/dL) at screening.
• Subject must have received a minimum of 24 weeks of treatment with abiraterone acetate or enzalutamide within its approved label indication and has discontinued use at least four weeks prior to start of study drug at day 1.
• Prior use of docetaxel is allowed in castration-naïve patients (maximum of six cycles).
• Subject receives and will continue to receive ongoing androgen deprivation with luteinising hormone-releasing hormone (LHRH) analogue therapy throughout the course of the study or has had a bilateral orchiectomy.
• Subject is asymptomatic from prostate cancer, defined as patients with the score on brief pain inventory (short form) (BPI-SF) Question #3 must zero and no use of opiate analgesics for prostate cancer-related pain currently or anytime within two weeks prior to screening.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at screening.
• Subject receiving bisphosphonate or other approved bone-targeting therapy must have been on stable doses for at least four weeks prior to start of study drug at day 1.
• Subject has a life expectancy of more than or equal to 12 months.
• Subject agrees not to participate in another interventional study while on study drug.
• Subject and his female partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for six months after final study drug administration.

Exclusion Criteria:

• Subject has received any anti-neoplastic therapy (including ketoconazole and chemotherapy) following abiraterone acetate or enzalutamide discontinuation and prior to start of study drug at day 1.
• Subject has known or suspected brain metastases or active leptomeningeal disease.
• Subject has concurrent disease or any clinically significant abnormality following the investigator's review of the physical examination and safety laboratory tests at screening, which in the judgment of the investigator would interfere with the subject's participation in this study or evaluation of study results.
• Subject has a history of another invasive cancer within three years prior to screening, with the exceptions of non-melanoma skin cancers or a non-infiltrating muscle bladder cancer that have a remote probability of recurrence in the opinion of the investigator in consultation with the medical monitor.
• Subject had major surgery within one month prior to screening.
• Subject has received investigational therapy within 28 days or 5 half lives, whichever is longer, prior to start of study drug at day 1.
• Subject has absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, and hemoglobin < 6.25 mmol/L (or < 10 g/dL) at screening (Note: Subjects must not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at screening).
• Subject has total bilirubin > 1.5 times the upper limit of normal (ULN) at screening, except for subjects with documented Gilbert's syndrome.
• Subject has creatinine > 2.5 mg/dL at screening.
• Subject has albumin ≤ 30 g/L (or ≤ 3.0 g/dL) at screening.

Baseline up to 2 years after last dose.

For several endpoints, the upper confidence interval could not be calculated because either 50% of patients at the endpoint were not reached (in the case of DFS) or were reached very late in the study, close to EoS (such as rPFS, OS and PSA) and we could not meaningfully state the value of this data due to lack of information.