Dose Finding Study of BKM 120 in Combination With LH-RH Agonists and Bicalutamide in Men With Non Castrate Metastatic Prostate Cancer

Prostate cancer is the second leading cause of cancer and the third cause of death in male. Majority of patients had local disease that is cured by local treatment. Metastases are rare at the time of diagnosis but may occur after failure of local treatment (SEER). Recommended treatment for non castrate metastatic prostate cancer (NCMPC) is castration by orchiectomy or medical castration by LH-RH (luteinizing hormone-releasing hormone) agonists alone and or combined androgen blockage with LH-RH agonists and anti androgen. Immediate treatment versus deferred treatment improve specific survival for advanced prostatic cancer : initial results of the Medical Research Council trial. Continuous castration is superior to intermittent one with a median survival of 49 months. Chemotherapy combined with castration demonstrate a survival improvement compared to castration alone for high volume disease defined by visceral involvement and or 4 or more bone metastatis with almost one apendicular metastasis. For low volume disease or non selected metastatic hormone sensitive prostate cancer, Docetaxel demonstrated no survival benefit evaluated in a recent phase III trial (Sweeney C et al abs ASCO 2014). However, most patients showing an initial response to hormonal therapy for advanced prostate cancer will progress to a castration-resistant phase of the disease with a much poorer prognosis. Median duration to androgen deprivation is 24 to 36 months, after patients become castrate resistant and docetaxel and other hormonal therapy like abiraterone and enzalutamide demonstrate survival improvement in castrate resistant prostate cancer. Despite the considerable progress made with new agents such as abiraterone acetate or MDV3100 in metastatic castration resistant prostate cancer (mCRPC), new therapies are critical to improve castration sensitivity. Understanding the mechanisms of resistance to AR and identifying directed new therapies is a real challenge in this situation. Prostate cancer is characterized by its dependence on AR and its frequent activation of the Phosphatidylinositol-3-kinase (PI3K) pathway. Besides the resistance mediated by the mutation in the AR, among the non-steroid alternative pathways two major pathways have been associated with AR activation and CRPC, namely Ras/Raf/MEK/ERK and PI3K/AKT. More specifically a genomic profiling of human prostate cancer was recently reported where 42% of primary and 100% of the metastatic lesions studied had upregulated PI3K signaling mostly via loss of phosphatase activity such as PTEN (Phosphatase and tensin homolog) or INPP4B (inositol polyphosphate 4-phosphatase type II). Dysregulation of the PI3K/PTEN pathway has also been associated with resistance to conventional antiandrogen therapies. Preclinical data support the potential for a reciprocal negative feedback between the AR and PI3K pathway. Development of castration resistance is multifactorel including weak antagonist binding affi nity to AR, up-regulation of AR co-stimulatory pathways and increased intratumoural androgen levels as a result of intracrine androgen, as well as partial agonists properties of antiandrogens when AR is overexpressed.