Themen der Veranstaltung in DARMSTADT

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

3. KEY CONCEPTS

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. 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. Optimal ADT (androgen deprivation therapy)

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

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. ADT is about Androgen Availability • 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. 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.

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 < 20 ng/dl and no breakthrough increases > 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. 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. 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. 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. Androgen Receptor (AR) Related Dysfunction • (3) Evaluate for ARM (androgen receptor mutation)– see http://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. 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. Clarke NW, McClure J, George NJR: The effects of orchidectomy on skeletal metabolism in metastatic prostate cancer. Scand J Urol Nephrol 27: 475-483, 1993. • 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. 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. 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. Monoclonal antibody to Receptor Activator of Nuclear Kappa Ligand (RANKL) Stops Bone Resorption & Decreases Skeletal-Related Events Better then Aredia or Zometa.

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

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 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. Taxotere: High or Low Dose ? • I prefer weekly Taxotere regimens at a lower dose (30 mg/m2) then every 3 week regimens at a higher dose (75 mg/m2). • 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. 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. Thank you for your attention.