Non Castrate Metastatic Prostate Cancer Clinical Trial
Official title:
Phase Ib Dose Finding Study of BKM 120 in Combination With LH-RH Agonists and Bicalutamide in Men With Non Castrate Metastatic Prostate Cancer
To determine the maximum-tolerated dose (MTD) of BKM120 when administered orally in combination with daily bicalutamide and LH-RH agonists to 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.
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