Luteinizing Hormone-releasing Hormone Analogue and Enzalutamide +/- Zoledronic Acid in Prostate Cancer Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Bone Response After Luteinizing Hormone-releasing Hormone Analogue and Enzalutamide +/- Zoledronic Acid in Prostate Cancer Patients With Hormone Sensitive Metastatic Bone Disease: a Prospective, Phase II, Randomized, Multicenter Study

Conditions
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Prostate Cancer, Bone Metastases

Intervention / Treatment
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* Drug: Zoledronic Acid
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of prostate carcinoma, Age > 18 years, 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), No previous hormone or chemotherapeutic treatments given for prostate carcinoma (patients that are receiving LHRH-A therapy for less than 4 months are admitted), Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1, Expected life expectancy ≥ 6 months, Subject capable to swallow the Study's medication and to comply with the Study's requirements, Signed informed consent. Exclusion Criteria: Presence of active serious disease, active infection or co-comorbidity that may prevent the study enrollment make (at the discretion of the clinical Investigator), Known or suspected brain metastases or active leptomeningeal dissemination, History of other malignant neoplasm during the previous 5 years, different from the non-melanoma skin carcinoma, 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), Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2,5 x upper limit of normal (ULN) at Screening Visit, Creatinine > 177 µmol/L (> 2 mg/dL) at Screening Visit, Albumin ≤ 30 g/L (≤ 3,0 g/dL) at Screening Visit, 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, 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; Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months); Major surgery within 4 weeks of enrollment (Day 1 Visit); Radiation therapy for treatment of the primary tumor within 3 weeks of enrollment (Day 1 visit); 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); 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prostate cancer patients with hormone sensitive metastatic bone disease
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: LHRH-A + Enzalutamide<br>Prostate cancer patients with hormone sensitive metastatic bone disease will be treated with LHRH-A + Enzalutamide until patient's progression, consent withdrawal or unacceptable toxicity | Drug: Enzalutamide<br>* Patients from both arms will be treated with LHRH-A + Enzalutamide<br>* Other names: Xtandi;|
| Experimental: LHRH-A + Enzalutamide + Zoledronic Acid<br>Prostate cancer patients with hormone sensitive metastatic bone disease will be treated with LHRH-A + Enzalutamide + Zoledronic Acid until patient's progression, consent withdrawal or unacceptable toxicity | Drug: Zoledronic Acid<br>* Prostate cancer patients with hormone sensitive metastatic bone disease will be treated with LHRH-A + Enzalutamide in the presence or absence of Zoledronic Acid<br>* Other names: Zoledronate;Drug: Enzalutamide<br>* Patients from both arms will be treated with LHRH-A + Enzalutamide<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of change in bone response after 6 and 12 months of treatment compared to baseline | Whole-body Diffusion MRI | Exam will be performed at baseline and after 6 and 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of bone repair | CT Scan | Screening visit; 12 months of treatment | 
| Changes in bone mineral density after 18 months of treatment compared to baseline | Dual energy x-ray absorptiometry (DEXA Scan) | Screening visit; 18 months of treatment | 
| Functional Assessment of Cancer Therapy-Prostate | Functional Assessment of Cancer Therapy-Prostate (FACT- P) Questionnaire will be collected from patients.It consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for prostate related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as a global Qquality of Life (QoL) score. | Monthly until end of treatment (18 months) | 
| Brief Pain Inventory-Short Form Questionnaire | Brief Pain Inventory-Short Form (BPI-SF) Questionnaire will be collected from patients.In particular, a 0-10 numerical rating scale was used to measure pain severity items where 0=no pain and 10=pain as bad as you can imagine or with 0=pain did not interfere with my normal life and 10=pain interferes ompletely. A question about the percentage and duration of pain relief was also included. | Monthly until end of treatment (18 months) | 
| Weight evaluation | Evaluation of patient weight expressed in kg after 18 months of treatment compared to baseline | Screening visit; 18 months of treatment | 
| C-terminal telopeptide analysis | C-terminal telopeptide analysis (CTX, ng/ml) evaluation on peripheral blood samples | Screening visit; 2, 4, 6, 9, 12, 18 months of treatment | 
| Bone alkaline phosphatase analysis | Bone alkaline phosphatase analysis (U/uL) evaluation on peripheral blood samples | Screening visit; 2, 4, 6, 9, 12, 18 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, bone metastasis, enzalutamide, zoledronic acid