Background: Prostate cancer (PC) is a major health problem for men in the U.S. and is the second most common cause of cancer-related deaths in males. Although most PCs are initially sensitive to androgen-deprivation therapy (ADT), the duration of response is variable, and eventually, the cancer becomes resistant to ADT and progresses to metastatic castration-resistant prostate cancer (mCRPC). For mCRPC patients, many initially respond to second-line ARIs (eg. enzalutamide and abiraterone) or docetaxel-based chemotherapy however durable responses are rare. Therefore, it is vital to investigate additional therapeutic strategies to delay or prevent the transition of castration-sensitive prostate cancer (CSPC) to mCRPC. Methods: We treated castration-sensitive human PC cells with various anti-androgen inhibitors to investigate the direct association between Bcl2 expression and AR-pathway. We used a lentiviral-based over-expression method to develop BCL2 over-expressed experimental PC cell line systems and subjected them to various in-vitro and in vivo studies. We studied the combinational effect of Bcl2 and AR inhibitor on the in vitro growth of hormone-sensitive human PC cells and in vivo mice model. Results: We observed that treatment with androgen inhibits but ARIs (eg enzalutamide, apalutamide) restore Bcl2 expression in human CSPC cell lines indicating there is possible direct negative-regulation of the Bcl2 by the AR-signaling pathway. BCL2 over-expressed LNCaP cells show deregulation of the AR pathway, induces PSMA expression, and exhibit relative resistance to enzalutamide indicating that over-expression of BCL2 induces castration resistance in hormone-sensitive PC cells. Our cell growth inhibition assay showed an overall strong additive effect on growth inhibition with enzalutamide and the pharmacological Bcl2 inhibitor (venetoclax) combination on LNCaP cells and 22Rv1 cells. We also observed a negative association between BCL2 and AR pathway in clinical PC cohorts (Localized and mCRPC). In the isograft mice model, we showed the combination of enzalutamide and venetoclax significantly reduces subcutaneous prostate tumor growth and increases overall survival (~2 weeks) compare to control groups of mice. Moreover, using Isogenic cell lines (control and BCL2 over-expressed LNCaP) we showed higher uptake of [⁶⁸Ga]-PSMA-11 in BCL2 over-expressed prostate tumors compared to control tumors in immunodeficient mice indicating that BCL2 over-expressed PC can monitor non-invasively by PSMA-PET imaging. Conclusions: Our current study develops a rationale for combining ADT with Bcl2-inhibitors for CSPC. We believe this combinatorial therapeutic approach will show great potential for future clinical trials of high-risk hormone-sensitive PC patients and may block the ADT-induced shift of CSPC to mCRPC.