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Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease

Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease. Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center. April 24, 2013. Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer.

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Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease

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  1. Prostate Cancer: What’s New?Treatment Options For Advanced Castrate Resistant Disease Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center April 24, 2013

  2. Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer • Modulation of androgen and testosterone • New therapies for castrate resistant prostate cancer

  3. Overcoming resistance mechanisms in prostate cancer: • Intratumoral testosterone • Androgen receptor (AR) mutations and splice variants • Ligand modulation (things that influence the AR) • Targets in advance disease

  4. Semantics • Castrate-treated with androgen deprivation therapy • Non-castrate- not previously treated with androgen deprivation therapy

  5. Conventional categories • Rising PSA after surgery or radiation or both • New metastatic disease and rising PSA :non- castrate (not previously treated with androgen deprivation therapy) • Metastatic castrate prostate cancer

  6. Androgen deprivation Therapy • Orchiectomy • LHRH (GHRH) (Luteinizing hormone releasing hormone) agonists • Anti-androgens

  7. ADT Anti-androgen LHRH Pills Implants and shots LHRH antagonist- degarelix

  8. Side Effects • Tiredness • Metabolic syndrome- weight gain, high blood pressure and high blood sugar • Osteopenia-decreased bone density • Secondary risks for heart attack, blood clot or stroke • Mood changes • Loss of sex drive (libido) • Hot flashes

  9. Other Hormonal Manipulations • Prednisone 10 mg by mouth two times a day can decrease PSA by more than 50% in approximately 1/3 of patients with hormone-refractory progressive prostate cancer (Sartor O et al, The Journal of Urology Vol161, Issue 1, January 1999, Page 360

  10. Other options: ketoconazole + prednisone or hydrocortisone Scholz M et al. J Urol. 2005 Jun;173(6):1947-52. 78 patients 0 1 to 3, >3 lesions bone scan 25, 35, and 18 patients Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively.

  11. NEW Hormonal Manipulations! Lyase inhibitors- get rid of intratumoral testosterone and residual sources of testosterone/androgens • Abiraterone acetate and prednisone • Tax 700 • Toc 1 (dual lyase and AR inhibitor) AR inhibitors- address mutations in the receptor, splice variants MDV3100 Aragon agent Other AR Modulators HSP 90 inhibitors HDAC inhibitors

  12. Other hormonal manipulations • Prednisone • Ketoconazole • Abiraterone

  13. Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy.JClinOncol 26: 2008 (May 20 suppl; abstr 5019) AA (Zytiga) 1000mg qd + pred 5mg twice daily 14 of 35 pts had decrease in PSA of >50% Phase III trial completed post chemotherapy showed overall survival improvement of almost 5 months in a study of 1000+ patients, leading to FDA approval

  14. Abiraterone side effects • Dizziness • Fatigue • Low or high blood pressure • Fluid retention • Elevation of liver enzymes • Low potassium

  15. MDV3100/ Enzalutamide / Xtandi AR modulation

  16. MDV 3100 Phase II trial MDV3100 1:1 randomization Decline docetaxel or are not suitable for docetaxel Something else ? patients Coming soon

  17. MDV 3100 Phase III “AFFIRM” trial MDV3100 2:1 randomization Failed 1 or 2 prior chemotherapies (docetaxel) Placebo 1170 patients Improvement in overall survival of more than 5 months

  18. MDV 3100 Phase III “PREVAIL” trial MDV3100 2:1 randomization Asymptomatic Castrate metastatic disease Placebo 850 patients Closed to accrual in the US

  19. ARN-509 versus MDV3100

  20. ARN-509 versus MDV3100

  21. Phase 1 Study Design Optional FDHT-PET at Baseline, 4 and 12 wks Tumor Evaluation Q 12 wks PSA and CTC Q 4 wks Disease Progression ARN-509 Single Dose ARN-509 once daily until progression PK week Continuous Daily Dosing PK D1-6 Wk 1 2 3 4 5 9 13 Cycle 1 2 3 DLT period for dose escalation • ARN-509 dose escalation cohorts (n=3-6/cohort): • 30, 60, 90, 120, 180, 240, 300, 390 and 480 mg

  22. PSA Response Rates Dose 30 mg 60 mg 90 mg 120 mg 180 mg 240 mg 300 mg 390 mg 480 mg • 14 out of 29 patients (48.3%) • experienced ≥ 50% reduction in PSA at 12 weeks

  23. F-DHT-PET: Pharmacodynamic Marker OF AR INHIBITION IN RESPONSE TO ARN-509 Baseline 4 Weeks

  24. Ongoing Phase 2 Trial ASCO GU 2013

  25. Immunotherapies • Provenge • Prostvac • CARs

  26. IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer • randomized (2:1) to receive 3 doses of sipuleucel-T (n = 341) or placebo (n = 171) intravenously at 2-week intervals • median survival of 25.8 and 21.7 months • survival probability at 36 months of 32.1% and 23.0% in the sipuleucel-T and placebo arms • Kantoff GU ASCO 2010

  27. CARs (ChimericAntigen and T cell Receptor)(Carl June) • Harness antigens expressed uniquely by a cancer (for example Prostate specific membrane antigen, prostate specific stem cell antigen, F77, c-met ) and link to T cells to turn on immunity against the antigen • ongoing trials in leukemia, pancreatic cancer • Can be given IV or into the tumor

  28. XL184 (Cabozantanib) • Targets c-met and VEGFR2 both important targets in prostate cancer • c-met is overexpressed in bone metastases as a later event in men on androgen deprivation therapy • VEGF expressed in aggressive prostate cancer

  29. XL184 (Cabozantanib) • RDT trial in patients previously treated with docetaxel showed 86% had response in bone scan; 65% had improvement in pain • Expanded prostate trial 64% (51/80 pts evaluable) had a PR on bone scans, 24 pts (30%) SD at 100mg daily • other cohort treated at 39 mg daily results pending • Two new phase III trials of XL184 coming

  30. XL 184 Cases

  31. XL 1129-2408 Screening Week 6 Original Normalized CAD Annotated

  32. XL 1129-2426 Screening Week 6 Original Normalized CAD Annotated

  33. XL 1522-2459 Screening Week 6 Original Normalized CAD Annotated

  34. XL 1521-2565 Screening Week 6 Original Normalized CAD Annotated

  35. The Landscape

  36. The future • Biopsy with molecular profile • Treatment with chemotherapy or targeted agents or more hormonal therapy depending on your molecular profile

  37. Hormone Sensitive Hormone Refractory Hormone Sensitive v. Hormone Refractory Prostate Cancer Clinical Trials Open or Planned at UPENN Biology 1. High risk RT+ ADT+/- docetaxel trial 2. everolimus + salvage XRT 3. Phase I Docetaxel/ cmet inhibitor trial 4. CAR-T cells in advanced disease 5. TKI258 plus INC280

  38. TKI258 + INC280 • Combines VEGFR+ FGF inhibitor with a C-met inhibitor. • Phase I/II planned

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