Analyze the Predictive Value of Gene TMPRSS2-ETS in Response to Enzalutamide in Patients With Prostate Cancer

Phase II Multicenter Study to Analyze the Predictive Value of Fusion Gene TMPRSS2-ETS in Response to Enzalutamide in Patients With Metastatic CRPC no Previously Treated With Chemotherapy

Prostate cancer is the most common non-skin tumor diagnosed in men and the second leading cause of cancer death in men in Western countries.

Between 10-20% of patients are diagnosed at metastatic stage and about half of those diagnosed in early stages will develop metastases.

After the clinical benefit of mitoxantrone and the improved survival of 2-3 months provided by docetaxel in first line, the second search is driven to look for effective second lines treatments. In recent years, there are new drugs for the treatment of prostate cancer, revolutionizing the therapeutic sequence and survival.

Thus, androgen deprivation therapy, treatment of choice, induces an improvement of symptoms in approximately 70-80% of patients, but it is limited by the development of mechanisms of resistance to androgen deficiency. Docetaxel was the first chemotherapy drug to increase survival in patients with metastatic prostate cancer. The second cytotoxic drug approved in the second line treatment of metastatic CRPC has been cabazitaxel.

Enzalutamide improves survival in patients with metastatic CRPC who had progressed to chemotherapy and also in patients who had not received chemotherapy.

To date, there are no biomarkers available that allow us to identify which patients from a clinical or molecular view are those that will be able to benefit from the treatment options currently available. The presence of the TMPRSS2-ETS rearrangement has been shown to correlate with efficacy in clinical practice abiraterone.

There is scientific and preclinical background that makes one suspect that the molecular alteration may influence the same way enzalutamide antiandrogen activity, but it has not been determined to date.

The objective of this study is to determine whether the efficacy and safety of enzalutamide, when administered to patients with castration resistant prostate cancer prior to administration of docetaxel is influenced by the presence or absence of the fusion gene TMPRSS2- ETS.

Inclusion Criteria:

• Patients aged 18 years and above, willing and able to provide written informed consent.
• Prostate adenocarcinoma with histological or cytological confirmation without neuroendocrine differentiation nor small cell characteristics
• Androgen deprivation therapy with GnRH analogs or bilateral orchiectomy (pharmacological or surgical castration). Patients without bilateral orchiectomy must follow a GnRH analog therapy during the trial.
• Testosterone serum level <= 1,73 nmol/L (50 ng/dL) in screening visit.
• Patients under bisphosphonate therapy must have received stable doses for the last 4 weeks.
• Progression disease at inclusion, defined by one or more of the following three criteria during androgen deprivation therapy (according with the criterion nº 3): - PSA progression defined as two elevation of the PSA serum level with >=1 week between each measure. Patients who have received an antiandrogen must present disease progression (>=4 weeks since the last dose of flutamide or >=6 weeks since the last dose of bicalutamide or nilutamide). PSA value in screening visit must be >=2 μg/L (2 ng/mL). - Soft tissue progression defined by RECIST 1.1 criteria - Bone lesion progression defined by PCWG2 criteria, with two or more new lesions in a scintigraphy
• Metastatic disease with bone lesions detected by scintigraphy, or measurable soft tissue lesions by CT/MR. Patients with ganglionar disease will be suitable if they have at least one ganglionar lesion with smallest diameter > 2,5 cm.
• Patients without previous cytotoxic chemotherapy for prostate cancer
• Patients without previous abiraterone acetate therapy for prostate cancer - - Asymptomatic patient or mild symptomatic about prostate cancer, (answer in the question nº 3 of the Brief Pain Inventory Short From < 4) 11. ECOG = 0-1.
• Life expectancy of at least 6 months
• Patient must be able to swallow the investigation product and to follow the protocol requirements.
• Biomarker study informed consent

Exclusion Criteria:

• Active infection or other medical condition which, in the opinion of the investigator, would preclude participation in this trial.
• Known brain metastasis or leptomeningeal active involvement
• Other malignancy in the last five years, except non-melanoma skin cancer treated and resolved.
• Hematologic parameters: - Absolute neutrophil count <=1500/μL - Platelet count <100 000/μL - Haemoglobin < 5,6 mmol/L (9 g/dL)
• Liver function: Serum bilirubin, SGPT/ALT or SGOT/AST > 2,5 x ULN
• Renal function: Creatinine >177 μmol/L (2 mg/dL).
• Serum albumin <30 g/L (3,0 g/dL)
• History of epilepsy or other medical condition which could cause an epileptic crisis as syncope or transient ischemic attack in the last twelve months.
• Clinically significant cardiovascular disease.
• Known gastrointestinal (GI) disease that could interfere with the GI absorption.
• Significant surgery within 4 weeks before enrollment.
• Use of opioids to control cancer pain within 4 weeks before enrollment.
• Radiation therapy for treatment of the primary tumor in the last 3 weeks before enrollment
• Radiation therapy for treatment of metastases in the last two months
• Radionuclide therapy for treatment of bone metastasis
• Prior flutamide treatment within 4 weeks before enrollment
• Bicalutamide or nilutamide therapy within 6 weeks before enrollment
• 5-a reductase inhibitors, estrogen o cyproterone therapy within 4 weeks before enrollment
• Biologic therapy or other antitumoral drugs for the treatment of CRPC in the last 4 weeks
• History of cancer progression with ketoconazole
• Prior therapy or enrollment in a trial with an investigational product which blocks androgen synthesis (abiraterone, TAK-700, TAK-683, TAK-448) or blocks androgen receptors (ARN507, BMS 641988).
• Included in a previous trial with enzalutamide (MDV3100).
• Administration of an investigational drug in the last 4 weeks before enrollment
• Use of phytotherapy products which hormonal activity against prostate cancer or which reduce PSA levels, or systemic corticosteroids in a dose greater than the equivalent of prednisone 10mg/day, within 4 weeks before enrollment
• Hereditary fructose intolerance
• Any condition which, in the opinion of the investigator, would preclude participation in this trial.