This study was undertaken to evaluate bone response in metastatic prostate cancer patients treated with Enzalutamide with or without Zoledronic Acid in combination with luteinizing hormone-releasing hormone (LHRH) analogue with the use of Whole Boby (WB) DW-MRI.

Most men with fatal prostate cancer develop bone metastases and bone is often the dominant or the only site of metastatic disease. Bone metastases are an important cause of morbidity since they are associated with skeletal related events (SREs) including pathologic fractures, spinal cord compression, and need for surgery or radiation therapy to bone. Osteoclast-mediated bone destruction is the key pathologic mechanism for SREs in prostate cancer and other malignancies. Zoledronic acid (ZA) is a potent inhibitors of osteoclast-mediated bone resorption. ZA has demonstrated to be effective in preventing SREs in patients with castrate resistant disease; however, its efficacy in hormone naïve disease is uncertain.

In the last few years new drugs targeting directly the androgen receptor such as Enzalutamide have shown to be very effective in terms of survival prolongation in the management of castration resistant disease and the efficacy in hormone naïve patients is currently under investigation. Interestingly, the results of a large scale, prospective, randomized clinical trial have shown that Enzalutamide administration is also associated with a reduction in the risk of SREs and this raises the question of the usefulness of the addition of bone resorption inhibitors to Enzalutamide.

The evaluation of bone response of antineoplastic therapies has always been difficult in metastatic bone prostate cancer patients due to their osteoblastic nature. Whole body diffusion-weighted (DW) MRI has been recently proposed as new imaging tool for grading treatment response in patients with skeletal metastases from prostate cancer. According to the literature data DW images can allow the identification of bone marrow infiltration and tumor necrosis induced by treatment. In addition, this technique allows to monitor the bone marrow restoration. This, this technique was selected to evaluate bone response in metastatic prostate cancer patients treated with Enzalutamide with or without Zoledronic Acid in combination with LHRH-A.

Moreover, since androgen-receptor isoform encoded by splice variant 7 (AR-V7) is an androgens' receptor variant that could have a potential clinical utility as a prognostic factor and predictive marker of therapy response, an ancillary study will be conducted to evaluate ARV7 expression in Circulating Tumor Cells (CTC).

Inclusion Criteria:

1. Histological diagnosis of prostate carcinoma,
2. Age > 18 years,
3. Metastatic disease documented as the presence of bone lesions on bone scan associated or not to soft tissue lesions measurable at computed tomography (CT) scan or Magnetic Resonance Imaging (MRI),
4. No previous hormone or chemotherapeutic treatments given for prostate carcinoma (patients that are receiving LHRH-A therapy for less than 4 months are admitted),
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1,
6. Expected life expectancy ≥ 6 months,
7. Subject capable to swallow the Study's medication and to comply with the Study's requirements,
8. Signed informed consent.

Exclusion Criteria:

1. Presence of active serious disease, active infection or co-comorbidity that may prevent the study enrollment make (at the discretion of the clinical Investigator),

2. Known or suspected brain metastases or active leptomeningeal dissemination,

3. History of other malignant neoplasm during the previous 5 years, different from the non-melanoma skin carcinoma,

4. Absolute Neutrophil Count (ANC) < 1.500/µL, platelet < 100.000/µL, or hemoglobin < 5,6 mmol/L (< 9 g/dL) at Screening Visit (notably: patients must not receive neither any growth factor during the previous 7 days nor any blood transfusion during the 28 days preceding the hematology sampling performed at Screening),

5. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2,5 x upper limit of normal (ULN) at Screening Visit,

6. Creatinine > 177 µmol/L (> 2 mg/dL) at Screening Visit,

7. Albumin ≤ 30 g/L (≤ 3,0 g/dL) at Screening Visit,

8. History of seizures or any other seizure-predisposed pathology; history of loss of consciousness or transitory ischaemic attack during the 12 months preceding the Screening visit,

9. Clinically significant cardiovascular disease including:

   • myocardial infarction (6 months preceding the screening)
   • uncontrolled angina (3 months preceding the screening)
   • Congestive heart failure New York Heart Association (NYHA) class 3 or 4, congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within three months results in a left ventricular ejection fraction that is ≥ 45%;
   • 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;
   • Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the Screening visit;
   • Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG;
   • Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the Screening visit;

10. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months);

11. Major surgery within 4 weeks of enrollment (Day 1 Visit);

12. Radiation therapy for treatment of the primary tumor within 3 weeks of enrollment (Day 1 visit);

13. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease Prostate-specific antigen (PSA) levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within four weeks of enrollment (Day 1 visit);

14. Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data.

Prostate cancer