Anti-CTLA-4 therapy (Ipilimumab, Yervoy™) was recently FDA-approved for the treatment of metastatic melanoma based on improved median overall survival observed in Phase III clinical trials. Since anti-CTLA-4 targets a T cell specific molecule, as opposed to a tumor specific molecule, it is being investigated as treatment for multiple malignancies, including prostate cancer. Given that anti-CTLA-4 mediates anti-tumor responses by enhancing T cell responses, it has been postulated that standard agents that enable tumor cell death may allow for priming of a T cell immune response that can be augmented by combination with CTLA-4 blockade. Therefore, we hypothesized that adding ipilimumab to standard androgen ablation (AA) therapy in men with metastatic prostate cancer (mPC) would improve immune and clinical responses. We designed a clinical trial whereby men with castrate-sensitive mPC, ECOG performance status ≤ 2 and normal organ and marrow function are registered ≤1 month of initiation of an LHRH agonist or antagonist (LHRHa). Men with autoimmune diseases, known brain metastases, small cell carcinoma morphology, known HIV, Hepatitis B or C infection, untreated symptomatic spinal cord compressions or chronic immunosuppressive therapies are excluded. Starting on day 29, patients receive 4 monthly doses of 10mg/kg ipilimumab. The primary endpoint of the trial is to estimate the rate of PSA ≤ 0.2ng/mL at 7 months, shown to be a powerful predictor of survival (Hussain et al. J Clin Oncol. 2006; 24:3984). Secondary endpoints include: immune responses, time to testosterone recovery (>50ng/mL), time to disease progression off AA, overall survival and safety of the combination.Accrual is ongoing. Data from 8 patients accrued to date show a significant increase in the frequency of T cells expressing the inducible costimulator (ICOS), as we have previously shown with ipilimumab monotherapy (Liakou et al. Proc Natl Acad Sci U S A. 2008;105:14987; Carthon et al. Clin Cancer Res. 2010;16:2861), and significant increases in memory T cell markers. ICOS+ T cells play an important role in anti-tumor responses mediated by anti-CTLA-4 therapy (Fu et al. Cancer Res. 2011;71:5445). Significant changes in dendritic, natural killer and macrophage cell populations have not been observed. To date, one patient developed an asymptomatic grade 3 transaminitis after 2 doses of ipilimumab that resolved with high dose steroids. Assessment of immune responses induced by the combination of ipilimumab and AA, and evaluation of clinical endpoints are ongoing. Updated data will be presented.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5368. doi:1538-7445.AM2012-5368