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Update on the Treatment of Prostate Cancer

Update on the Treatment of Prostate Cancer. David M. Nanus, MD Chief, Division of Hematology and Medical Oncology Weill Medical College of Cornell University New York Presbyterian Hospital. Demographics. 238,590 estimated new cases in 2013 - 27.9% of all cancers in males

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Update on the Treatment of Prostate Cancer

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  1. Update on the Treatment of Prostate Cancer David M. Nanus, MD Chief, Division of Hematology and Medical Oncology Weill Medical College of Cornell University New York Presbyterian Hospital

  2. Demographics • 238,590 estimated new cases in 2013 - 27.9% of all cancers in males • most common cancer in men • Lifetime risk: 16% (1 in 6) • 29,720 estimated deaths - 9.7% of cancer deaths in males - second to lung cancer in men

  3. Death from other causes Death from Prostate cancer Clinical Metastases Non-Castrate Clinically Localized Disease Rising PSA Castrate Metastatic Disease Castrate Rising PSA Adapted from Scher et al.

  4. PSA – Like a Clint Eastwood Movie • The Good PSA-based early detection decreases mortality • The Bad Not perfectly sensitive or specific  Over-detection compounded by Over-treatment • The Ugly Treatment arbitrary, variable, often unnecessary and increasingly costly

  5. Screening Recommendations • Shared decision making • Annual PSA and DRE • from age of 40 (AUA); age 50 (ACS) • High risk: 40-45 (African American; 1rst degree relative) • Frequency • AUA: annually (based on initial PSA) • ACS: annually (every 2 year if PSA < 2.5 ng/ml) • Discontinue: life expectancy <10 years

  6. The Changing Face of Prostate Cancer in the United States Cooperberg et al. J Urol 2007; 178:S14

  7. Significance of cancer:Determining need for treatment • Patient (age, comorbidities) • Gleason score • - sum of two predominant areas • Tumor characteristics • - Number of positive cores • - Percent positive within each core • Molecular profile

  8. Surveillance in low risk patients is feasible and associated with a limited risk of progression Progression can be quantitated Predictors of progression and treatment can be identified Screening results in the detection of very early stage/grade lesions - many indolent Current staging/grading techniques accurate Natural history prolonged and can be measured Active Surveillance Rationale Hypotheses

  9. Intervention Overall Survival Ca-Specific Survival 62% free of intervention at 10 y 97% at 10 years N=452 5/452 patients All PSADT ≤ 1.6 years Klotz L, et al. J Clin Oncol 2010;26:126–31

  10. Defining the Triggers for Intervention • Change in PSA kinetics: PSADT <3 y • Progression on follow-up biopsy • Increase in Gleason grade • Increase in tumor volume • Increase in absolute cores involved with cancer • Increase in percent of positive cores >33% • Increase in absolute tumor length (mm) • Increase in percent of tumor tissue >50% within single core • Patient preference • Clinical/radiographic evidence of local/distant progression

  11. What’s new in prostate cancer therapy? • Targeting the androgen axis • Immunotherapy • Chemotherapy • Bone targeted therapies • Molecular genetics • Circulating prostate cancer tumor cells

  12. Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients: Results of S9346 (INT-0162), An international phase III trial • 3040 hormone naïve metastatic patients • PS 0-2 • PSA ≥ 5 ng/ml • treated with 7 months of goserelin + bicalutamide • 1535 pts PSA ≤4 ng/ml • - randomized to CAD or IAD • Primary objective: non-inferior • Median Follow up: 10 years

  13. Management of Castrate Resistant Metastatic Prostate Cancer • Androgen Signaling Axis Therapy • Abiraterone • Enzalutamide (MDV3100) • Chemotherapy • Docetaxel • Cabazitaxel • Mitoxantrone • Bone Targeted • Radium-223

  14. Intra-cellular androgen Alternatively-spliced AR Adapted from Harris et al. Nature Reviews Clin Onc 2009

  15. Simplified view of cholesterol  testosterone synthesis cholesterol Occurs in: Testes, Adrenal Gland, Prostate cancer cells pregnenolone CYP17 17α-hydroxy- pregnenolone Mineralocorticoids CYP17 DHEA androstenedione Cortisol Testosterone DHT Montgomery et al. Cancer Res 2008 Locke et al. Cancer Res

  16. Oral irreversible inhibitor of CYP17 • - 17α –hydroxylase • - C17,20-lyase • Inhibits testosterone production in testis, adrenal, and prostate Abiraterone Acetate cholesterol pregnenolone CYP17 17α-hydroxy- pregnenolone Mineralocorticoids CYP17 DHEA androstenedione Cortisol Testosterone DHT Montgomery et al. Cancer Res 2008 Locke et al. Cancer Res

  17. COU-AA-301Abiraterone Acetate + prednisone vs Placebo + prednisone in men with progressive metastatic CPRC after docetaxel Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone. de Bono JS et al. N Engl J Med 2011;364:1995-2005. Fizazi et al. Lancet Oncol 2013;13:983.

  18. Secondary End Points de Bono JS et al. N Engl J Med 2011;364:1995-2005.

  19. Hazard Ratios for the Risk of Death, According to Subgroup de Bono JS et al. N Engl J Med 2011;364:1995-2005.

  20. COU-AA-302 Abiraterone 1000 mg/d Prednisone mg bid Chemo-naïve CRPC (n=1088) Asymptomatic or mildly symptomatic Placebo daily Prednisone mg bid Primary endpoint: Radiographic PFS, OS Secondary endpoints: Time to – opiate use; chemotherapy; EOCS-PS deterioration; progression

  21. COU-AA-302: Updated interim results * did not cross the prespecified boundary for significance (p = 0.0035) Ryan CJ et al. N M2013;368:138-148 + GU ASCO 2013

  22. Adverse Events of Special Interest. Ryan CJ et al. N Engl J Med 2013;368:138-148.

  23. AFFIRM: Enzalutamide (MDV3100) Scher HI et al. N Engl J Med 2012;367:1187-1197.

  24. Subgroup Analyses of Hazard Ratios for Death in the Two Study Groups Scher HI et al. N Engl J Med 2012;367:1187-1197.

  25. Enzalutamide • PREVAIL trial: Phase 3 CRPC before chemotherapy • TERRAIN trial: Phase 2 comparing Enzalutamide with bicalutamide in men who have progressed on LHRH analogue therapy or following surgical castration • Other studies: • Enzalutamide + docetaxel • Enzalutamide + abiraterone

  26. Cabazitaxel/Prednisone vs Mitoxantrone/Prednisone de Bono et al, Lancet 2010: 1147-54

  27. Immunotherapy • Cancer vaccines • Modulation of immune regulatory mechanisms • Blocking CTLA-4 • Blocking PD-1 or PDL-1 • Monoclonal antibody targeting of tumour growth

  28. IMPACT Trial HR=0.759(95% CI: 0.606, 0.951) P=.017 (Cox model) Median Survival Benefit: 4.1 months Sipuleucel-T (n=341) Median Survival: 25.8 months 36-months survival: 32.1% Control (n=171) Median Survival: 21.7 months 36-months survival: 23.0% Kantoff et al, ASCO GU 2010

  29. Radium-223 Targets Bone Metastases Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Radium-223 is excreted by the small intestine Ca Ra Parker et al; ECCO-ESMO 2011

  30. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT 6 injections at 4-week intervals PATIENTS STRATIFICATION • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel R AND OMI S ED Radium-223 (50 kBq/kg) + Best standard of care • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care 2:1 N = 922 Clinicaltrials.gov identifier: NCT00699751. Parker et al; ECCO-ESMO 2011

  31. ALSYMPCA Overall Survival 100 HR 0.695; 95% CI, 0.552-0.875P = 0.00185 90 80 70 60 Radium-223, n = 541 Median OS: 14.0 months % 50 40 30 Placebo, n = 268 Median OS: 11.2 months 20 10 0 Parker et al; ECCO-ESMO 2011

  32. CRPC Therapeutic Options

  33. Phase III Randomized Trials vs. Docetaxel + Prednisone Primary Endpoint: Overall Survival

  34. Molecular Markers • Beyond the microscope • May be diagnostic, prognostic, and/or predictive • Gene fusions • TMRPSS2-ERG • Expression of abnormal proteins • Many may be targetable • Circulating Tumor Cells (CTCs)

  35. Molecular Classification of Prostate Cancer * Discoveries led by NYP-Weill Cornell Medical College

  36. Neuroendocrine or anaplastic prostate cancer

  37. Multi-institutional Phase II Trial of The Aurora kinase A inhibitor MLN8237 for Patients with Neuroendocrine Prostate Cancer • Inclusion Criteria: • Pathologic diagnosis • Clinical diagnosis: visceral metastases in absence of PSA progression, elevated serum neuroendocrine marker • MLN8237 50 mg bid orally x 7 d on 21 day cycle • Molecular biomarkers • Tumor biopsies • CTC analyses • Exome/transcriptome sequencing

  38. Bone Targeted Therapy

  39. CALGB 90202: A Randomized, Double-Blind, Placebo-Controlled Phase III Study of Early versus Standard Zoledronic Acid (ZA) to Prevent Skeletal Related Events in Men with Prostate Cancer Metastatic to Bone • Eligibility: • > 1 bone metastasis, ADT therapy within 6 mos of enrollment • Therapy: • Zoledronic acid or placebo q 4 weeks • Median time to first SRE (skeletal-related event) • 32.5 vs 29.8 mos (HR = 0.96 [0.76-1.22]; P=0.74) • > Grade 3 toxicity same (15% vs. 12% in ZA and P) • Overall survival (HR= 0.89 [0.70-1.14]; P=0.34) Smith MR et al. 2013 GU Cancers Symposium

  40. Y denosumab Y Y Y Y Y Y Y Y Y Y Y Y Y

  41. Targeted Therapy: Denosumab vs zoledronic acid for Skeletal Related Events risk-reduction in CRPC Fizazi et al, Lancet 2011; 377: 813

  42. Denosumab vs placebo to improve bone-metastases free survival Smith et al, Lancet 2011

  43. Management of Metastatic CRPCSequencing??? • Chemotherapy • Docetaxel, Cabazitaxel, Mitoxantrone • Androgen Signaling Axis Therapy • Abiraterone • Enzalutamide • Bone Targeted • Denosumab • Alpharadin

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