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Prostate Cancer Future Perspectives Over the past couple of years, the introduction of several new agents with novel mechanisms of action and favorable safety profiles has led to an improvement in OS and quality of life for men with metastatic CRPC. (see Table 1) The impetus for new drug development has followed important advances in our understanding of the molecular biology of prostate cancer, in particular the continued dependency of castrate resistant cells on the AR and AR signaling pathways and the ability of the bone microenvironment to promote skeletal metastasis through its influence on osteoblastic/osteolytic activities. With significant advances in the treatment of CRCP taking place in a relatively short period of time, future initiatives will need to focus on how to best integrate these new therapies into the current treatment paradigm. From a clinical practice and clinical research perspective, a number of important questions remain. For example, should CYP17 inhibitors (Zytiga) or perhaps ARSI’s (enzalutamide) be given to patients prior to or after chemotherapy? Is there an optimal sequence to the use of these agents or a role for combination therapy since they have different but complementary mechanisms of action and non-overlapping toxicities? (see Figure 1). Should bone-targeting agents with diverse mechanisms of action be given sequentially or concurrently to patients with established skeletal metastasis with the hope of further delaying time to first skeletal-related event? Is there a role for combining chemotherapy and immunotherapy in the treatment of metastatic CRPC 36 or using immunotherapeutic agents as adjuvant therapy in high risk patients or in 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 20 Montgomery RB, Mostaghel EH, Vesella R Maintenance ofintratumoral androgen in prostate cancer, a mechanism for castrate resistant tumor growth, Cancer Res, 2008, 68:4447–54 Stanbrough M, Bubley, GS, Ross K et al., Increased expression of genes converting adrenal androgens to testosterone in androgen independent prostate cancer, Can Res, 2006;66:2815–25. Locke JA, Guns ES, Lubik AA, Androgen levels increase by intratumoral de novo steroidogenesis during progression of castrate-resistant prostate cancer Cancer Res, 2008:68;6407–15. de Bono JS, Logothetis CJ, Molina A, et al., Abiraterone and Increased survival in metastatic prostate cancer, N Engl J Med, 2011;364,21:1995–2005. 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Small EJ, Schellhammer PF, Higano CS, et al., Placebo- controlled phase III trial of immunologic therapy sipuleucal-T (APC8015) in patients with metastatic, asymptomatic hormone-refractory prostate cancer, J Clin Oncol, 2006,24:3039–94. Kantoff PW, Higano CS, Shore ND et al., Sipuleucal-T immunotherapy for castrate-resistant prostate cancer, N Engl J Med, 2010, 363:411–22. DiPaolo RS, Plante M, Kaufman H, et al., A Phase I trial of Pox PSA vaccines (PROSTVAC-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM) in patients with prostate cancer, J Trans Med, 2006, 4:1. Kantoff PW, Scheutz TJ, Blumenthal BA et al., Overall survival analysis of a phase II randomized controlled trial of a poxviral based PSA-targeted immunotherapy in metastatic castrate- 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. those with non-metastatic CRPC at a time when the immune system is more robust and the tumor burden low? Recent improvements in genomic technology using multiplex assays and microarrays to analyze the myriad germline, somatic mutations, gene copy number variations, and other alterations affecting gene expression present in individual tumor samples will afford a unique opportunity to develop strategies for truly personalized cancer treatment. Transcriptional and genomic profiling studies have identified recurrent gene fusions, chromosomal gains and losses, and deregulated pathways in prostate cancer including ETS genes, PTEN loss, and AR amplification that can drive the progression to metastatic CRPC. 37 Using exome-based profiling, a diverse group of recurrent and potentially driving mutations and copy number alterations in both known and novel genes and pathways has recently been identified in a cohort of heavily-pre-treated patients with lethal CRPC. 38 The creation of large integrative genomic databases will undoubtedly enable researchers to more fully explore and better understand the relationships between cancer genes and disease progression, mechanisms of resistance, and response to therapy with the goal of matching the most effective drug or drug combinations with the molecular characteristics of the individual patient. 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