1. Themen der Veranstaltung in DARMSTADT  Algorithmen  Gleason Score  Optimierte ADT  Androgenentzugs - syndrom  Zeichen des AUPK  Wann Chemotherapie  High vs Low doseTaxotere  Andere Medikamente  Falldiskussionen 2

2. KEY CONCEPTS DRIVING OUTCOMES QUALITY OF LIFE OVERALL SURVIVAL 3

3. NATURE OF PC GLEASON SCORE PLOIDY PSA KINETICS IHC EXTENT OF PC COMBIDEX 18F PET/CT CT SCAN BONE SCAN VOLUME OF PC CORE % TISSUE % PSA DENSITY EOD ON BONE SCAN KEY CONCEPTS 4

4. GLEASON SCORE (GS) & ALGORITHMS  GS Integral Part of All Risk Assessment Tools  Patient Status is Endpoint for these Tools  Nomograms, ANN (Artificial Neural Nets) are involved at all stages of PC (prevention to end of life)  GS relates to Nature of PC ○ PSA less reliable as GS gets higher (8 to 10) ○ Need to check other Biomarkers with GS 8-10 such as CEA, CGA, NSE, PAP. See page 64 in Primer. 5

5. Moving Concepts into Strategy This is the thought flow that is critical in any assessment of a living entity. It is the key to obtaining successful outcomes. 6

6. Optimal ADT (androgen deprivation therapy) 7

7. 6 Ways to Optimize ADT 1) Block androgen access to the PC cell 2) Ensure significant lowering of Testosterone 3) Measure testosterone using accurate lab assay 4) Use US-PSA as biologic endpoint for ADT 5) Use measures that down-regulate (dR) sensitivity of the androgen receptor (AR) 6) Block bone-derived growth factors that are released due to excessive osteoclast activity (induced by androgen deprivation) 8

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11. Are We Using the Optima Dose of Dutasteride ? Dr. Mostaghel's group looked for gene changes in 75 men with localized PC. Twenty-five had RP alone, 26 were given neoadjuvant dutasteride at 0.5 mg, and the remaining 24 received dutasteride, 3.5 mg orally per day for 4 months prior to RP. 12

12. ADT is about Androgen Availability Huggins won Nobel Prize 43 years ago showing PC dependence on Androgens. Testosterone assays inaccurate at low T levels: need to use LC/MS/MS based assays.  PC growth is mediated by androgens.  We call it Androgen Dependent PC (ADPC) or Androgen Independent PC (AIPC) or Castration Resistant PC (CRPC) but PC growth is androgen related.  PC mets even synthesize their own androgens.  Testosterone level (T) is a key Biological End Point.  T not measured in 95% of men with PC.  “Castration” threshold should be < 20 ng/dl.  Further lowering of T may enhance response. 13

13.  Lowest T level with impact on survival was 32 ng/dl.  Mean survival, free of developing AIPC, in men with breakthrough increases in T > 32 ng/dl was 88 months (CI 55-121 mos).  Mean survival in men with T 32 ng/dl was 137 mos (CI 104-170).  In men with breakthrough increases > 50 ng/dl, those men with maximal ADT had a significantly longer survival free of AIPC. <20 20-50 > 50 14

14. Importance of US-PSA (ultra-sensitive) to Monitor ADT  PSA nadir > 0.05 highly correlated with shorter time to progressive PC & prostate cancer-specific survival.  15

15. The achievement of a PSA nadir of 0.05 or less was the most significant endpoint insofar as time to progressive PC and PC mortality. 16

16. Androgen Receptor (AR) Related Dysfunction  (1) Reduce AR sensitivity Prolactin Inhibitors 5AR inhibitors EGCG HSP inhibitors PPAR-G ligands DIM & POMx Silymarin Melatonin  (2) Avoid Drugs Stimulating “Promiscuous” AR Avoid or use cautiously standard glucocorticoids such as prednisone & dexamethasone Use triamcinolone instead e.g. HDK with triamcinolone instead of Hydrocortisone (HC) 17

17. Androgen Receptor (AR) Related Dysfunction  (3) Evaluate for ARM (androgen receptor mutation)– see http://www.prostate- cancer.org/education/andeprv/Strum_IADT.htmlhttp://www.prostate- cancer.org/education/andeprv/Strum_IADT.html ○ Withdraw anti-androgen, progestin, estrogen to see if PSA or other marker is reduced. ○ If possible ARM due to Casodex need 6 weeks to eliminate Casodex (bicalutamide) from body.  (4) Avoid agents that stimulate ARM ○ Steroidal anti-androgens such as CPA (cyproterone acetate) ○ Progestins, in certain contexts. 18

18. Androgen Deprivation Therapy (ADT) Immediately Induces Bone Resorption  Surgical Orchiectomy  LH-RH agonists like Zoladex, Lupron  GnRH antagonists like Degarelix  Anti-Androgens like bicalutamide, eulexin  Ketoconazole  Estrogens  Androgen Receptor Antagonists Goal Block bone-derived growth factors released due to ADT effect on bone resorption. 19

19.  This is NOT new information but we continue to neglect this downside of ADT.  We should be preventatively blocking bone resorption prior to starting ADT.  This may improve (likely) the natural history of men with PC, as well as other malignancies that metastasize to bone. 20

20. Testosterone (T) Inhibits Osteoclast Activation.  T normally inhibits PTH (parathormone).  PTH causes bone loss by activating osteoclasts.  ADT lowers T and osteoclast inhibition lost and bone loss occurs. 21 Chen Q, Kaji H, Sugimoto T, et al: Testosterone inhibits osteoclast formation stimulated by parathyroid hormone through androgen receptor. FEBS Lett 491:91- 3, 2001.

21. All of Biology is a Two Edged Sword  Part of optimizing ADT is recognition of the above statement.  We need to start therapies to minimize the down- sides of any treatment we use, including ADT.  A key focus should be to prevent osteoclast activation with release of bone-derived growth factors.  Agents like bisphoshonates & Denosumab should be used early in the treatment of men with PC. 22

22. Monoclonal antibody to Receptor Activator of Nuclear Kappa Ligand (RANKL) Stops Bone Resorption & Decreases Skeletal-Related Events Better then Aredia or Zometa. 23

23. When we decrease the side-effects of any treatment, we improve the therapeutic index (TI) 24 Treatment Benefits Treatment Side Effects = TI http://www.prostate- cancer.org/resource/pdf/Is2-1.pdfhttp://www.prostate- cancer.org/resource/pdf/Is2-1.pdf

24. 25 CRPC still not good term: No agreed upon castration level Hypersensitivity of AR AR mutation Promiscuous AR PC mets synthesize androgens Level 1: PSA serially rising Testosterone < 20 ng/dl ARM excluded Level 3: Estrogen given Estradiol blood levels checked Rxs to prevent side-effects Level 2: HDK given (properly) Keto blood levels High-dose Keto given AIPC or CRPC

25. When to Start Chemo ?  Progressive PC on ADT ADT3 or ADT4 used HDK given Estrogen Rx given  No chance for salvage RP, RT or Cryo  Other Rx options used Vaccine AR antagonist Clinical trial  No serious patient co- morbidities present Heart disease Kidney disease Bone marrow suppression 26 More…

26. When to Start Chemo ?  Aggressive PC needing more intense Rx Neuroendocrine PC or other aggressive features, perhaps detected by gene expression signatures may require early chemo or chemo- hormonal therapy. See the very first issue of Insights at http://prostate- cancer.org/resource/pdf/Is1-1.pdf.  Expertise in administration of chemo exists and patient context indicates need 27

27. Taxotere: High or Low Dose ?  I prefer weekly Taxotere regimens at a lower dose (30 mg/m 2 ) then every 3 week regimens at a higher dose (75 mg/m 2 ).  Patient tolerance & quality of life is far better with weekly regimen.  Complaints of severe fatigue are less.  Pre-meds used with every 3 week do not need to be used with weekly (perhaps very low dose steroid in first few weeks).  Survival data in (TAX 327) randomized trial better for every 3 week Taxotere, but difference involved weeks: median survivals 18.9 mos versus 17.4 mos.  Patients, even older men in 70’s or greater, able to tolerate weekly chemo far better then every 3 wk Rx.  Lowering of WBC greater for every 3 wk regimen vs weekly regimen. 28

28. Alternative Medikamente  HDK + triamcinolone Insights 2001 Keto blood levels with goal of at least 3.0 Monitor liver function  Estrogens You have access to Estradurin which has good published results End Point E2 level of at least 1,000 pg/ml  GM-CSF combos Combine with retinoid acid Combine with Thalidomide or Revlimid Use alone as per Small et al  PPAR-gamma agonists Low dose (7.5mg/d) Actos Combine with HDAC inhibitor like Valproic acid or COX-2 inhibitor like Celebrex  Memantine: NMDA receptors on PC cells  Celebrex + Dostinex combination 29

29. 30 Thank you for your attention.