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221 Background: Androgen targeted therapy remains the mainstay for advanced prostate cancer (PC). Second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ), re-targets persistent AR activity in castrate-resistant (CR) PC tumors, and is approved for CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients succumb to PC. Mechanisms underlying resistance to ENZ are incompletely understood. Prior work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in ENZ-resistant growth of PC. Methods: Levels of Jak2 and Stat5 activation in PC cells, tumors and patient samples were evaluated by immunohistochemistry, 3D tumor explant cultures and western blotting. Jak2 and Stat5 were inhibited by lentiviral (expression of) shRNA or pharmacologically. Levels of mRNA were assessed by QPCR and gene expression profiling. Results: ENZ induced a robust increase in Stat5 activation in PC cells in vitro, in xenograft tumors in vivo and in patient-derived PCs during ENZ treatment. Mechanistically, ENZ activation of Stat5 involves a positive feed-forward mechanism where ENZ-liganded AR induces rapid and sustained Jak2 phosphorylation in PC cells through a process involving Jak2-specific phosphatases. This results in a formation of a positive feed-forward loop in PC where activated Stat5 induces Jak2 mRNA and protein levels in PC. We showed that active Stat5 increased viability of PC cells during ENZ treatment and, at the same time, inhibition of Stat5 as a second-line treatment induced excessive death of PC cells surviving ENZ treatment. Importantly, pharmacological Stat5 blockade inhibited CR growth of PC xenograft tumors after ENZ resistance developed. Conclusions: Collectively, this work introduces a novel concept for a pivotal role of Jak2-Stat5 signaling in mediating resistance of PC to ENZ. Pharmacological Jak2-Stat5 inhibition may provide efficacious therapy in advanced PC in combination with ENZ or after ENZ fails.

4628 Background: The Early Prostate Cancer (EPC) program is an ongoing study of the effect of adding bicalutamide (CASODEX) 150 mg to standard care (radiotherapy [RT], radical prostatectomy [RP], or watchful waiting [WW]) for men with localized or locally advanced prostate cancer. At a median 7.4 years’ follow-up, bicalutamide significantly improved objective progression-free survival (PFS) in men with locally advanced disease, irrespective of standard care, and improved overall survival in the RT setting. There was no PFS benefit in patients with localized disease. Lymph-node involvement is an established risk factor for progression, so we conducted an exploratory analysis among patients with locally advanced disease to assess the influence of this risk factor on PFS. Methods: The EPC program (n = 8113) comprises 3 randomized trials designed for combined analysis. Patients with localized (T1–2, N0/Nx) or locally advanced (T3–4, any N; or any T, N+) non-metastatic prostate cancer received bicalutamide (n = 4052) or placebo (n = 4061) once daily plus standard care. This subanalysis studied the effect of nodal status (N−, N+, Nx) in locally advanced disease. Results: In patients with locally advanced disease, PFS improvements were irrespective of nodal status. The treatment effect increased as the risk of progression increased from N− to Nx to N+ disease. The greatest reduction in risk was seen in RP patients with N+ disease. Conclusions: The reduction in risk of progression with bicalutamide was seen irrespective of nodal status. The most significant reduction in risk of progression was in RP patients with N+ disease; survival data by nodal status for these patients will be presented. [Table: see text] [Table: see text]

4624 Background: Prostate-specific antigen (PSA) progression is the first sign of prostate cancer recurrence after primary therapy. In the Early Prostate Cancer (EPC) program, men with locally advanced disease who received bicalutamide 150 mg (CASODEX) in addition to standard care (radiotherapy [RT], radical prostatectomy [RP], or watchful waiting [WW]) had significantly improved objective progression-free survival (PFS) vs standard care alone. In the RT setting, this translated into improved overall survival (OS). Here, we compare PSA-PFS in the 3rd analysis of the EPC program with the results for objective PFS. Methods: The EPC program consists of 3 trials in which patients (all M0) with either localized (T1–2, N0/Nx) or locally advanced (T3–4, any N; or any T, N+) prostate cancer were randomized to receive standard care plus either bicalutamide 150 mg (n = 4052) or placebo (n = 4061). The primary end points were OS and objective PFS. PSA-PFS was a secondary end point. A PSA progression event was defined as PSA rising to ≥2× baseline or ≥0.4 ng/mL in men with non-quantifiable baseline PSA, death, or objective progression. PSA-PFS and objective PFS were analyzed for stage/therapy subgroups using a Cox proportional hazards model. Results: At 7.4 years’ median follow-up, bicalutamide plus standard care was associated with significantly improved PSA-PFS vs placebo (p < 0.001), irrespective of primary therapy or disease stage. However, PSA-PFS benefit only translated into a significant objective PFS benefit in locally advanced disease ( table ). Conclusion: Adding bicalutamide 150 mg to standard care significantly improves PSA-PFS for men with early, non-metastatic prostate cancer. The significant improvement in PSA-PFS was only accompanied by a significant improvement in objective PFS in locally advanced disease. Consequently, a significant PSA-PFS benefit cannot always be assumed to translate into a significant objective PFS benefit. [Table: see text] [Table: see text]

4629 Background: Progression of prostate cancer to bone metastases impacts seriously on patients (pts)’ quality of life and increases treatment costs. The 3rd analysis of the Early Prostate Cancer (EPC) program revealed that bicalutamide (CASODEX) 150 mg plus standard care (radiotherapy [RT], radical prostatectomy [RP] or watchful waiting [WW]) significantly improved progression-free survival (PFS) vs standard care alone in locally advanced disease. Adjuvant bicalutamide 150 mg also improved overall survival for RT pts with locally advanced disease. Here, we report an exploratory analysis of the effect of bicalutamide on delaying bone metastases in pts with locally advanced disease in the EPC program. Methods: The EPC program comprises 3 trials in which pts (n = 8113) were randomized to standard care plus bicalutamide 150 mg or placebo. This exploratory analysis included only pts with locally advanced disease (T3–4, any N; or any T, N+; bicalutamide n = 1367, placebo n = 1315). Distant metastases were assessed by bone scan. Metastatic PFS was defined as time from randomization to either first bone scan-confirmed progression or death in the absence of bone-scan data. A Cox proportional hazards regression model was used for the WW and adjuvant subgroups; each was analyzed separately with covariates for trial, treatment, prior therapy, baseline prostate-specific antigen level, and tumor grade. Results: At 7.4 years’ median follow-up, bicalutamide significantly improved metastatic PFS vs placebo (hazard ratio [HR] 0.64, p < 0.001 for WW; HR 0.77, p = 0.005 for RT/RP; table). The most common adverse events were gynecomastia and breast pain. Conclusion: Addition of bicalutamide 150 mg to standard care significantly reduced the risk of distant metastases in locally advanced prostate cancer, irrespective of standard care. Both the efficacy and tolerability of treatment must be considered, and therefore, bicalutamide is an option for men with locally advanced prostate cancer. [Table: see text] [Table: see text]