Prostate Cancer Management: What Does the Future Hold? Bertrand Tombal  European Urology Supplements  Volume 9, Issue 8, Pages 706-714 (October 2010) DOI: 10.1016/j.eursup.2010.08.002 Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 1 Percentage of patients with prostate carcinoma receiving one or more doses of a gonadotropin-releasing hormone (GnRH) agonist or undergoing orchiectomy within the first 6 mo of diagnosis over the time period 1991–1999. Reproduced with permission from Shahinian VB, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24. European Urology Supplements 2010 9, 706-714DOI: (10.1016/j.eursup.2010.08.002) Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 2 Percentage of patients with prostate carcinoma receiving one or more doses of a gonadotropin-releasing hormone (GnRH) agonist within the first 6 mo of diagnosis without other therapy given (primary use) or receiving one or more doses of a GnRH agonist within 2 mo of radical prostatectomy or radiotherapy performed within 6 mo of diagnosis (adjuvant use) over the period 1991–1999. Reproduced with permission from Shahinian VB, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005;103:1615–24. European Urology Supplements 2010 9, 706-714DOI: (10.1016/j.eursup.2010.08.002) Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 3 Response of testosterone (T) after cessation of luteinising hormone-releasing hormone (LHRH) agonist therapy: (a) box plot analysis; (b) individual responses. Reproduced with permission from Kaku H, et al. Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. The Prostate 2006;66:439–44. M=month. European Urology Supplements 2010 9, 706-714DOI: (10.1016/j.eursup.2010.08.002) Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 4 Physiologic consequences of treatment with abiraterone acetate. (A) Steroid biosynthesis pathway. (B) Abiraterone inhibits 17 α-hydroxylase (crossed out in red), which results in a reduction in serum cortisol and a consequent increase in adrenocorticotropic hormone (ACTH) that drives the steroid biosynthesis pathway. Levels of deoxycorticosterone and corticosterone increase by a median of 10- and 40-fold, respectively. Up to a four-fold increase in 11-deoxycortisol is observed, but there is complete inhibition of C17,20-lyase (crossed out in red) and significant suppression of dehydroepiandrosterone (DHEA), androstenedione, and testosterone. (C) Addition of dexamethasone 0.5mg/d to abiraterone acetate results in suppression of ACTH to three-fold less than baseline levels, a consequent decrease in deoxycorticosterone levels to less than the limit of sensitivity of the assay used (<5 ng/dl), and a consequent decrease in corticosterone levels by two-fold. Similarly, 11-deoxycortisol levels decrease. Downstream steroid levels remain suppressed. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Attard G, et al. J Clin Oncol 2008;26:4563–71. European Urology Supplements 2010 9, 706-714DOI: (10.1016/j.eursup.2010.08.002) Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 5 Waterfall plot of percentage change in prostate-specific antigen (PSA) from baseline. (A) Maximum decrease from baseline; (B) decrease at 12 wk from baseline (red lines show patients who discontinued treatment before 12 wk for an adverse event or disease progression); (C) 12-wk decreases by dose. Reprinted from The Lancet, 375(9724), Scher HI, et al, Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study, 1437–46, Copyright (2010), with permission from Elsevier. European Urology Supplements 2010 9, 706-714DOI: (10.1016/j.eursup.2010.08.002) Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 6 Kaplan-Meier estimate of probability of cardiovascular events over time. Reproduced with permission from Saigal CS, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110:1493–500. ADT=androgen-deprivation therapy; NA=not applicable; CL=confidence limits. European Urology Supplements 2010 9, 706-714DOI: (10.1016/j.eursup.2010.08.002) Copyright © 2010 European Association of Urology Terms and Conditions