DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is  current as of November...
DISCLAIMERParticipants have an implied responsibility to use the newly acquired information    to enhance patient outcomes...
Disclosure of Conflicts of InterestEmmanuel S. Antonarakis, MD, reported a financialinterest/relationship or affiliation i...
Learning Objectives            L      Upon completion of this activity, participants           should demonstrate the abil...
Expert Video Viewpoints onCastration-Resistant Prostate Cancer:     Care Across the Continuum
Section I:                      Identification and Initial                        Treatment of CRPCCRPC = castration-resis...
Testing and Monitoring               for CRPC How   do you identify patients with CRPC?
Prostate Cancer Clinical States                                                     Non-metastatic,                       ...
CRPC           Almost all patients with prostate cancer treated with ADT            eventually experience progression in ...
CRPC: An Evolving Paradigm           AR signaling is a key factor in prostate cancer growth            despite castrate s...
Initial Treatment of CRPC Non-metastatic   CRPC  – Treatment options  – How do we manage? What     treatment choices do ...
4 New FDA Approved Drugs           Sipuleucel-T (4/29/10)              – Asymptomatic or minimally symptomatic mCRPC     ...
New Therapies: Where Do They Fit In?                                             Non-metastatic,                          ...
Sipuleucel-T          Autologous APC vaccine          Leukapheresis product collected          APCs primed with GM-CSF–...
Drake, 2010.
Sipuleucel-T: Phase III IMPACT Trial                                                      P                               ...
IMPACT Trial: Overall Survival                          100                                                        HR = 0....
Sipuleucel-T: Adverse Events            All grades               – Chills (53%)               – Fever (31%)              ...
Treatments Post Sipuleucel-T                          Progression                                                   OS Fol...
Initial Treatment of CRPC What     treatment choices do patients with CRPC have?  – Symptomatic (docetaxel is not label-r...
Docetaxel for mCRPC             The standard of care for mCRPC changed from              mitoxantrone to docetaxel based ...
5 on; 1 off x 6 cycles                           N = 1006                                                 Docetaxel 75 mg/...
Docetaxel for mCRPC (cont.)                           SWOG 9916         TAX-327                                           ...
Docetaxel: The Pivot Point Docetaxel   became a pivot point for the treatment of patients and the design of clinical tria...
Docetaxel Plus Phase III Studies        Docetaxel                           +/- VEGF Trap (VENICE)        Docetaxel     ...
Initial Treatment of CRPC What are the consensus-based treatment guidelines for mCRPC?
NCCN Guidelines for                                 Systemic Therapy       Negative                     for metastases   ...
NCCN Guidelines for                       Systemic Therapy (cont.)        Positive            for metastases             ...
NCCN Guidelines for                  Systemic Therapy (cont.)       Positive        for metastases              – Asympto...
Initial Treatment of CRPC Discussion:           The optimal initiation of chemotherapy for patients with mCRPC
Key Takeaways   Active surveillance involves actively monitoring course of    disease with the expectation to intervene w...
Section II:mCRPC Progression
Identifying and Treating            CRPC Progression What   parameters define CRPC progression?
CRPC Progression         Parameters           that define CRPC progression:                – Two consecutive rises in PSA...
Identifying and Treating      CRPC Progression(cont.) What are the treatment options for patients with mCRPC who progress...
Cabazitaxel: Next Generation Taxane          Novel semi-synthetic taxane that stabilizes           microtubules and may o...
TROPIC: Cabazitaxel Phase III Trial                                  Patients with mCRPC and progression during/after     ...
TROPIC Primary End Point: Survival                                  100                                                   ...
TROPIC: Secondary End PointsTTP = time to progression; NR = no response.De Bono et al, 2010.
TROPIC: Adverse EventsDe Bono et al, 2010.
Cabazitaxel: Prescribing Information         Dose: 25 mg/m2 IV (over 1 hr) q21days         Combine with prednisone 5 mg ...
Abiraterone Acetate: CYP17 Inhibitor                       AbirateroneAttard et al, 2008.
CYP17 Inhibition:                                         Steroid Hormone Suppression                       6             ...
COU-301 Phase III Trial (Post-Chemo)              Patients with mCRPC,              previously treated with              A...
COU-301: Results                              FDA Approved in April 2011NA = not applicable.De Bono et al, 2011.
COU-301: Updated SurvivalScher et al, 2011.
Abiraterone: Adverse Events             Secondary mineralocorticoid excess – all grades                – Edema (26.7%)   ...
Abiraterone:                               Prescribing Information             Dose = 1,000 mg po daily (250 mg tabs x 4)...
Identifying and Treating     CRPC Progression (cont.) What options are available for prevention of skeletal complications...
IV Bisphosphonates                                        (eg, Zoledronate)         Treatment of osteoporosis (accelerate...
Zoledronate: Prevention of SREs                             Placebo             100                                       ...
Denosumab: RANKL MoAbRANKL = receptor activator of nuclear factor kappa-B ligand; MoAb = monoclonal antibody.Roodman, 2007.
Denosumab: SRE Prevention Trial          • Phase III trial of denosumab vs zoledronic acid for            prevention of SR...
Denosumab: Prevention of SREs                                                    HR 0.82 (95% CI: 0.71, 0.95)             ...
Denosumab: Adverse Events         Hypocalcemia                                      (13%)                – Occurs in firs...
Denosumab:                              Prescribing Information            Dose for SRE prophylaxis: 120 mg SQ q4wks     ...
Key Takeaways   Progression of CRPC may be defined by PSA criteria,    radiographic criteria, or clinical criteria   Cab...
Section III:Emerging Treatment Options   for mCRPC Patients
Emerging Therapies for CRPCCTLA-4 = cytotoxic T-lymphocyte associated antigen-4; TKI = tyrosine kinase inhibitor; MET = MN...
Emerging Treatment Options for        mCRPC Patients What   anti-androgens are being studied?
Abiraterone: COU-302 (Pre-Chemo)           Patients with mCRPC,       Accrual Completed 4/2010           docetaxel-naïve, ...
Abiraterone: Phase I/II StudiesRECIST = Response Evaluation Criteria in Solid Tumors.Ryan et al, 2010; Attard et al, 2009;...
Phase II Data: PSA Responses                                              PRE–DOCETAXEL PSA Response after 12 weeks       ...
MDV3100: Novel AR Antagonist          Second generation AR antagonist          Binds AR more potently than bicalutamide ...
MDV3100: PSA Declines (Phase I/II)                     Pre-Chemotherapy (n=65)   Post-Chemotherapy (n=75).       MDV-3100 ...
MDV3100: Radiologic ResponsesPR = partial response; SD = stable disease; FDG-PET = fludeoxyglucose-positron emission tomog...
AFFIRM Phase III Trial (Post-Chemo)                                N = 1170               Accrual complete                ...
PREVAIL Phase III Trial (Pre-Chemo)                          N = 1680                    Ongoing                          ...
Other Novel Hormonal Agents   TAK-700 (CYP17 lyase inhibitor) – Orteronel    – Pre-chemo/post-chemo phase III studies ong...
Emerging Treatment Options      for mCRPC Patients What   immunotherapies are being studied?
Sipuleucel-T:                     Phase III Study in Hormone-Naïve mPCa                                N = 1684           ...
Ipilimumab: Anti-CTLA4             Human MoAb that binds to and blocks activity of              CTLA-4 on T cells, modula...
CTLA4 Blockade: IpilimumabDrake, 2010.
Ipilimumab in CRPC             Phase I trials                – Ipilimumab combined with GM-CSF (N = 24)                – ...
Ipilimumab: Post-Chemo Phase III Trial                         N = 800                    Ongoing                         ...
Ipilimumab: Pre-Chemo Phase III Trial                          N = 600                    Ongoing                         ...
ProstVac-VF             Vaccinia and fowlpox-based vectors expressing PSA              antigen and 3 costimulatory molecu...
ProstVac-VF (cont.)Drake, 2010.
ProstVac-VF: Phase II Trial                                                      P                                       P...
Phase II Trial: Treatment SchemaKantoff, Schuetz, et al, 2010.
Phase II Trial: Results                                  PFS                  OS                                 P = 0.6  ...
ProstVac-VF: ECOG 1809 Trial                              N = 144                    Ongoing                              ...
ProstVac-VF: PROSPECT Trial                                              Pending Activation                        N = 120...
Emerging Treatment Options      for mCRPC Patients What   are the bone-targeted approaches?
Bone-Seeking                                      Radiopharmaceuticals              Strontium-89                 – Beta(b...
Radium-223: Phase III ALASYMPCA Trial                               N = 900                                 R             ...
Radium-223: Press Release (6/5/11)            Pre-planned interim analysis conducted            OS longer with Radium-22...
Emerging Treatment Options      for mCRPC Patients What   other novel agents are being studied?
Dasatinib in CRPC            Phase II trial, 38 patients with metastatic CRPC             treated with one prior chem reg...
Cabozantinib (XL184)            Cabozantinib: TKI that blocks MET and VEGFR2             – MET and its ligand HGF drive i...
SLD % Change in Prostate Cancer Subjects                                                      Cabozantinib      % Change f...
Cabozantinib (cont.)                       Baseline      Week 12              Baseline       Week 12                      ...
Key Takeaways   Several novel androgen synthesis inhibitors and    next generation AR antagonists are in    development ...
Section IV:Putting Evidence Into Practice: Expert Perspective on Case          Examples
Case Study: Part 1             57-yr-old man – T3a PCa, Gleason 4+4 = 8,              PSA = 8.2 ng/mL             Underg...
Case Study: Part 1         Discussion Questions Does   this patient meet criteria for CRPC? How   would you manage this ...
Case Study: Part 2   Same patient – non-mCRPC   Enrolls in phase II study or oral TAK-700 (orteronel)   Has a PSA respo...
Case Study: Part 2          Discussion Question How   would you manage this patient now?
Case Study: Part 3   Same patient – asymptomatic mCRPC   Patient receives 3 infusions of sipuleucel-T   PSA rises after...
Case Study: Part 3          Discussion Question How   would you manage this patient now?
Case Study: Part 4   Same patient – symptomatic mCRPC   He receives docetaxel q3wks and denosumab q4wks   Obtains PSA r...
Case Study: Part 4          Discussion Question How   would you manage this patient now?
Key Takeaways   Different treatment strategies may be appropriate for    patients with different disease states    –   No...
Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Care Across the Continuum
Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Care Across the Continuum
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Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Care Across the Continuum

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Presented by the Johns Hopkins University School of Medicine and
produced in collaboration with the Institute for Medical Education & Research (IMER).
Review a downloadable slide deck by, covering the most clinically relevant new data reported from Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Care Across the Continuum by:

Emmanuel Antonarakis, MBBCh
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Leonard G. Gomella, MD, FACS
Thomas Jefferson University
Jefferson Kimmel Cancer Center

A. Oliver Sartor, MD
Tulane University School of Medicine

Target Audience

Medical oncologists, urologists, radiation oncologists, and other healthcare professionals involved in the treatment of patients with castration-resistant prostate cancer (CRPC). There are no prerequisites.

Activity Overview

In this video, a panel of expert thought leaders will discuss the optimal management and emerging agents across the CRPC treatment continuum. Topics will include identification and initial treatment of CRPC, metastatic CRPC progression, future novel treatment for CRPC patients, and expert perspectives on case examples to decipher optimal treatment of CRPC.

Slide Deck Disclaimer

This slide deck in its original and unaltered format is for educational purposes and is current as of December 2011. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

Usage Rights

This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.

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Transcript of "Expert Video Viewpoints on Castration-Resistant Prostate Cancer: Care Across the Continuum"

  1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of November 2011. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
  2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’sproduct information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses ofagents that are not indicated by the FDA. JHU and IMER do not recommend the use of any agent outside of the labeled indications. The opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own. Use of Johns HopkinsUniversity School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specificdrugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients.
  3. 3. Disclosure of Conflicts of InterestEmmanuel S. Antonarakis, MD, reported a financialinterest/relationship or affiliation in the form of: Consultant: sanofi-aventisLeonard G. Gomella, MD, FACS, reported a financialinterest/relationship or affiliation in the form of: Consultant: AstellasPharma US, Inc. , Centocor Ortho Biotech Services, LLC, DendreonCorporation, Ferring Pharmaceuticals, Inc.; Grant/Research Funding:Centocor Ortho Biotech Services, LLC; Data/Safety Monitoring Board:sanofi-aventis U.S.A. Oliver Sartor, MD, reported a financial interest/relationship oraffiliation in the form of: Advisory Board: Algeta ASA, Bristol-MyersSquibb Company, Centocor Ortho Biotech Services, LLC, DendreonCorporation, Medivation, Inc., sanofi-aventis U.S., TakedaPharmaceutical Company; Grant/Research Funding: AstraZenecaPharmaceuticals LP, Centocor Ortho Biotech Services, sanofi-aventisU.S., Takeda Pharmaceutical Company, Algeta ASA
  4. 4. Learning Objectives L Upon completion of this activity, participants should demonstrate the ability to: Identify characteristics of a patient with CRPC and the implications those factors have on treatment options Outline the appropriate treatment choices for patients with non-metastatic, metastatic, asymptomatic, and symptomatic disease based upon treatment guidelines Define the optimal initiation of treatment and management of a patient who progresses Identify future treatments for patients with CRPC and their potential effect on treatment decisions Review novel and emerging bone targeted therapies for use in patients with CRPC
  5. 5. Expert Video Viewpoints onCastration-Resistant Prostate Cancer: Care Across the Continuum
  6. 6. Section I: Identification and Initial Treatment of CRPCCRPC = castration-resistant prostate cancer.
  7. 7. Testing and Monitoring for CRPC How do you identify patients with CRPC?
  8. 8. Prostate Cancer Clinical States Non-metastatic, Non- Hormone-responsive >200,000 60,000 Prostate cancer metastatic CRPC Clinically Biochemically Localized Relapsed Prostate cancer Prostate cancer >30,000 Prostatectomy Salvage Metastatic, Radiation ± ADT Radiation Metastatic Chemo-refractory Brachytherapy Hormone-responsive CRPC CRPC Primary ADT Prostate cancer Active Surveillance Prostate cancer- specific death Death from co-morbidities 10 - 15 years +ADT = androgen deprivation therapy.Scher et al, 2008; Jemal et al, 2010.
  9. 9. CRPC  Almost all patients with prostate cancer treated with ADT eventually experience progression in the setting of castrate serum testosterone levels (< 50 ng/dL) – Rising PSA, new symptoms, or radiographic findings  Several “secondary” hormonal therapies are used in this setting – Anti-androgens (eg, bicalutamide, nilutamide, flutamide) – Ketoconazole – Estrogens (eg, DES, megestrol) – Steroids (eg, prednisone, dexamethasone)PSA = prostate specific antigen; DES = diethylstilbestrol.Gelmann, 2002; Hussain et al, 2006.
  10. 10. CRPC: An Evolving Paradigm  AR signaling is a key factor in prostate cancer growth despite castrate serum testosterone (< 50 ng/dL) – Promoted by a number of different factors • AR overexpression/amplification • AR mutations • Increased AR ligand expression • AR coactivators • Ligand-independent AR activation  Persistent AR signaling leads to tumor growth and proliferationAR = androgen receptor.Gelmann, 2002; Debes et al, 2004.
  11. 11. Initial Treatment of CRPC Non-metastatic CRPC – Treatment options – How do we manage? What treatment choices do patients with CRPC have? – Asymptomatic/minimally symptomatic
  12. 12. 4 New FDA Approved Drugs  Sipuleucel-T (4/29/10) – Asymptomatic or minimally symptomatic mCRPC  Cabazitaxel (6/17/10) – mCRPC, after failure of a docetaxel-containing regimen  Denosumab (11/18/10) – Prophylaxis against SREs for bone mCRPC  Abiraterone (4/28/11) – mCRPC, after receipt of docetaxel-containing chemotherapymCRPC = metastatic CRPC; SREs = skeletal-related events.Provenge® prescribing information, 2011; Jevtana® prescribing information, 2011;Xgeva® prescribing information, 2010; Zytiga® prescribing information, 2011.
  13. 13. New Therapies: Where Do They Fit In? Non-metastatic, Non- Hormone-responsive metastatic Prostate cancer CRPC Clinically Biochemically Localized Relapsed Prostate cancer Prostate cancer Prostatectomy Salvage Metastatic, Radiation ± ADT Radiation Metastatic Chemo-refractory Brachytherapy Hormone-responsive CRPC CRPC Primary ADT Prostate cancer Active Surveillance Observation  Androgen Deprivation Therapy (ADT)  Secondary hormonal therapies Zoledronic Acid or Denosumab Abiraterone, Docetaxel Cabazitaxel, Mitoxantrone Sipuleucel-TNCCN, 2011.
  14. 14. Sipuleucel-T  Autologous APC vaccine  Leukapheresis product collected  APCs primed with GM-CSF–PAP fusion protein  Reinfused back into patient  Mature APCs present PAP peptide to CD8 T cells  T cells initiate lytic antitumor responseAPCs = antigen-presenting cells; GM-CSF = granulocyte-macrophage/colony stimulating factor; PAP = prostatic acid phosphatase.Drake, 2010; Higano et al, 2010.
  15. 15. Drake, 2010.
  16. 16. Sipuleucel-T: Phase III IMPACT Trial P R Treated at Sipuleucel-T O Physician’s S Q 2 weeks x 3 G Discretion U Asymptomatic R R or minimally 2:1 E Cross-over V symptomatic mCRPC S I (N=512) S V Treated at Placebo I Physician’s A Q 2 weeks x 3 O Discretion L N Primary endpoint: Overall survival Secondary endpoint: Progression-free survivalKantoff, Higano, et al, 2010.
  17. 17. IMPACT Trial: Overall Survival 100 HR = 0.78 [95% CI 0.61 - 0.98] P = 0.03 (Cox model) 75 Median Survival Benefit = 4.1 mo Percent Survival 50 Sipuleucel-T (n = 341) Median survival: 25.8 mo 25 BUT, no difference in Placebo (n = 171) PFS (median 14.6 vs Median survival: 21.7 mo 14.4 wk compared to placebo; P = 0.648) 0 0 6 12 18 24 30 36 42 48 54 60 66 Survival (Months) FDA-Approved in April 2010Kantoff, Schuetz, et al, 2010.
  18. 18. Sipuleucel-T: Adverse Events  All grades – Chills (53%) – Fever (31%) – Back pain (30%) – Headache (18%) – Flu-like illness (10%)Provenge® prescribing information, 2011.
  19. 19. Treatments Post Sipuleucel-T Progression OS Following DPOS = overall survival; DP = disease progression.Gomella et al, 2011.
  20. 20. Initial Treatment of CRPC What treatment choices do patients with CRPC have? – Symptomatic (docetaxel is not label-restricted to symptomatic patients)
  21. 21. Docetaxel for mCRPC  The standard of care for mCRPC changed from mitoxantrone to docetaxel based on data from 2 randomized phase III studies – SWOG 9916: Docetaxel/estramustine improved median survival vs. mitoxantrone/prednisone – TAX-327: Docetaxel/prednisone improved survival as well as pain responses, PSA responses, and QOL vs. mitoxantrone/prednisoneSWOG = Southwest Oncology Group; QOL = quality of life.Petrylak et al, 2004; Tannock et al, 2004.
  22. 22. 5 on; 1 off x 6 cycles N = 1006 Docetaxel 75 mg/m2 m R o d n e a z Prednisone 10 mg q day i Docetaxel for mCRPC (cont.)Q 21 days up to 10 cycles Mitoxantrone 12 mg/m2 SWOG 9916 Prednisone 5 mg bid Q 21 days N = 770 Docetaxel 60 mg/m2 d 2 Estramustine 280 mg d1-5 Dexamethasone 20 mg, tid d 1 & 2 m R o d n e a z i Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles TAX 327 Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles N = 1006 Docetaxel 75 mg/m2 m R o d n e a z Prednisone 10 mg q day i Q 21 days up to 10 cyclesPetrylak et al, 2004; Tannock et al, 2004. 2
  23. 23. Docetaxel for mCRPC (cont.) SWOG 9916 TAX-327 HR: 0.83, P=0.03Petrylak et al, 2004; Tannock et al, 2004.
  24. 24. Docetaxel: The Pivot Point Docetaxel became a pivot point for the treatment of patients and the design of clinical trials – Before docetaxel – With docetaxel – After docetaxel
  25. 25. Docetaxel Plus Phase III Studies  Docetaxel +/- VEGF Trap (VENICE)  Docetaxel +/- lenalidomide (MAINSAIL)  Docetaxel +/- custirsen (SYNERGY)  Docetaxel +/- zibotentan (ENTHUSE)  Docetaxel +/- dasatinib (READY)  OthersVEGF = vascular endothelial growth factor.
  26. 26. Initial Treatment of CRPC What are the consensus-based treatment guidelines for mCRPC?
  27. 27. NCCN Guidelines for Systemic Therapy  Negative for metastases – Clinical trial (preferred) – Observation – Antiandrogen – Antiandrogen withdrawal – Ketoconazole – Steroids – DES or other estrogenNCCN = National Comprehensive Cancer Network.NCCN, 2011.
  28. 28. NCCN Guidelines for Systemic Therapy (cont.)  Positive for metastases – Symptomatic, visceral disease • Docetaxel (category 1) • Mitoxantrone • Abiraterone acetate (category 2B) • Palliative RT or radionucleide for symptomatic bone metastases • Clinical trialRT = radiotherapy.NCCN, 2011.
  29. 29. NCCN Guidelines for Systemic Therapy (cont.)  Positive for metastases – Asymptomatic • Sipuleucel-T (category 1) • Secondary hormone therapy – Antiandrogen – Antiandrogen withdrawal – Ketoconazole or abiraterone acetate (category 2B) – Steroids – DES or other estrogen • Clinical trialNCCN, 2011.
  30. 30. Initial Treatment of CRPC Discussion: The optimal initiation of chemotherapy for patients with mCRPC
  31. 31. Key Takeaways Active surveillance involves actively monitoring course of disease with the expectation to intervene with curative intent if the cancer progresses There is no standard of care for the treatment of non- mCRPC, but reasonable options include observation, secondary hormones, ketoconazole Sipuleucel-T is indicated for men with mCRPC and no/minimal symptoms Docetaxel chemotherapy is the first-line standard for symptomatic mCRPC; FDA label should be adhered to
  32. 32. Section II:mCRPC Progression
  33. 33. Identifying and Treating CRPC Progression What parameters define CRPC progression?
  34. 34. CRPC Progression  Parameters that define CRPC progression: – Two consecutive rises in PSA – Progressive disease in measurable (soft tissue, visceral) radiographic lesions defined by RECIST – Two or more new bone lesions on 99mTc-bone scan … in the setting of persistent castrate levels of serum testosterone (<50 ng/dl)Scher et al, 2008.
  35. 35. Identifying and Treating CRPC Progression(cont.) What are the treatment options for patients with mCRPC who progress after docetaxel? – Cabazitaxel – Abiraterone
  36. 36. Cabazitaxel: Next Generation Taxane  Novel semi-synthetic taxane that stabilizes microtubules and may overcome taxane resistance  Preclinical data show activity against taxane- sensitive and -resistant cell lines and tumor models  In phase I trials, antitumor activity seen in mCRPC, including in men with docetaxel-refractory disease  DLT was neutropeniaDLT = dose limiting toxicity.Attard et al, 2006; Pivot et al, 2008; Mita et al, 2009.
  37. 37. TROPIC: Cabazitaxel Phase III Trial Patients with mCRPC and progression during/after treatment with a docetaxel-containing regimen (N=755) – 146 sites in 26 countries Stratification factors ECOG PS (0, 1 vs. 2) and measurable vs. non-measurable disease Cabazitaxel 25 mg/m² q 3 wk + Mitoxantrone 12 mg/m² q 3 wk + prednisone 10mg QD for 10 cycles prednisone 10mg QD for 10 cycles (n=378) (n=377) Primary endpoint: OS Secondary endpoints: PFS, RR, safetyPFS = progression-free survival; RR = response rate; ECOG = Eastern Cooperative Oncology Group;PS = performance status.De Bono et al, 2010.
  38. 38. TROPIC Primary End Point: Survival 100 MP CBZP Median OS (months) 12.7 15.1 80 HR 0.70 Proportion Surviving (%) 95% CI 0.59–0.83 p Value < .0001 60 Cabazitaxel 40 20 Mitoxantrone 0 0 months 6 months 12 months 18 months 24 months 30 monthsMP = mitoxantrone, prednisone; CBZP = carbazitxel; FDA Approved in June 2010HR = hazard ratio; CI = confidence interval.De Bono et al, 2010.
  39. 39. TROPIC: Secondary End PointsTTP = time to progression; NR = no response.De Bono et al, 2010.
  40. 40. TROPIC: Adverse EventsDe Bono et al, 2010.
  41. 41. Cabazitaxel: Prescribing Information  Dose: 25 mg/m2 IV (over 1 hr) q21days  Combine with prednisone 5 mg po bid  Premeds – Diphenhydramine 25, dexamethasone 10, ranitidine 50  Caution in liver impairment (hepatic excretion)  Consider primary GCSF prophylaxis for men ≥ 65 yrs old – Patients ≥ 65 years of age are more likely to experience neutropenia and febrile neutropenia  Avoid concurrent CYP-3A4 inhibitors or inducers – Azole antifungals, rifampin, clarithromycin, phenytoinIV = intravenous; po bid = by mouth, twice daily; GCSF = granulocyte colony stimulating factor.Jevtana® prescribing information, 2011.
  42. 42. Abiraterone Acetate: CYP17 Inhibitor AbirateroneAttard et al, 2008.
  43. 43. CYP17 Inhibition: Steroid Hormone Suppression 6 2 5 Testosterone Androstenedione 4 gd Lower limit of n/ l 3 sensitivity 1 m 2 o n / l 1 0 0.07 10 20 60 70 At Start of treatment Days progression At progression 1 Start of treatment 28 Days 56 12.5 12.5 DHEA Estradiol 10.0 10.0 7.5 7.5 m o m ρ/ l o n / l 5.0 5.0 2.5 2.5 0 0 10 Start of 20 30 40 50 60 28 Days 56 At progression treatment Days post treatmentDHEA = dehydroepiandrosterone.Attard et al, 2008.
  44. 44. COU-301 Phase III Trial (Post-Chemo) Patients with mCRPC, previously treated with Abiraterone 1000 mg QD docetaxel, keto-naïve Prednisone 5 mg BID n = 797 Randomization 2:1 Placebo-Controlled, Double-Blind Placebo QD Prednisone 5 mg BID n = 398 Primary Objective: 25% overall survival improvement Sample size: 1195De Bono et al, 2011.
  45. 45. COU-301: Results FDA Approved in April 2011NA = not applicable.De Bono et al, 2011.
  46. 46. COU-301: Updated SurvivalScher et al, 2011.
  47. 47. Abiraterone: Adverse Events  Secondary mineralocorticoid excess – all grades – Edema (26.7%) – Hypokalemia (28%) – HTN (9%)  LFT elevations (10%)  Cardiac abnormalities (13%) – Tachycardia – Atrial fibrillationHTN = hypertension; LFT = liver function test.De Bono et al, 2011; Zytiga® prescribing information, 2011.
  48. 48. Abiraterone: Prescribing Information  Dose = 1,000 mg po daily (250 mg tabs x 4)  Combine with prednisone 5 mg po bid  Take on an empty stomach  Dose reduction in hepatic impairment: 250 mg  Caution if EF < 50% or heart failure (NYHA III/IV)  Avoid co-administration with CYP 2D6 substrates – SSRIs, beta-blockers, ondansetron, metoclopramideEF = ejection fraction; NYHA = New York Heart Association; SSRIs = selective serotonin reuptake inhibitors.Zytiga® prescribing information, 2011.
  49. 49. Identifying and Treating CRPC Progression (cont.) What options are available for prevention of skeletal complications in men with mCRPC?
  50. 50. IV Bisphosphonates (eg, Zoledronate)  Treatment of osteoporosis (accelerated by ADT use)  Treatment of hypercalcemia  Prevention of fractures and SREs  Pain relief from bone metastases  Improved QOL  Antitumor effects (?)Doggrell, 2009; Winter et al, 2009.
  51. 51. Zoledronate: Prevention of SREs Placebo 100 P = .001  SREs – Radiation to bone – Pathologic fracture 50 Zoledronic acid – Spinal cord compression – Surgery to bone E P 0 1 n v a e s i / t – Change in cancer therapy 0 0 12 24 MonthsSaad et al, 2002.
  52. 52. Denosumab: RANKL MoAbRANKL = receptor activator of nuclear factor kappa-B ligand; MoAb = monoclonal antibody.Roodman, 2007.
  53. 53. Denosumab: SRE Prevention Trial • Phase III trial of denosumab vs zoledronic acid for prevention of SREs R A • Patients with Denosumab 120 mg SQ q4w N bone-metastatic D CRPC O N=1904 M • No prior I bisphosphonates Zoledronic acid 4 mg IV q4w Z E • Primary endpoint: prevention of 1st SRE (non-inferiority) • Secondary endpoints: superiority analysis, safetyFizazi, Carducci, et al, 2011.
  54. 54. Denosumab: Prevention of SREs HR 0.82 (95% CI: 0.71, 0.95) 1.00 Risk P=0.0002 (Noninferiority) Reduction P=0.008 (Superiority) 0.75 18% 0.50 Median (mo) 0.25 Denosumab 20.7 Zoledronic acid 17.1 W M R E S P u h e n p o r f t i 0 0 3 6 9 12 15 18 21 24 27 (Mo) Zoledronic acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 FDA-Approved in Nov 2010Fizazi, Carducci, et al, 2011.
  55. 55. Denosumab: Adverse Events  Hypocalcemia (13%) – Occurs in first 6 months – Grade 3 (5%)  Acute phase reactions (8%)  ONJ (2%)  Fatigue, nausea, decreased appetite, constipation, hypophosphatemia, anemia, back pain, bone painONJ = osteonecrosis of the jaw.Xgeva® prescribing information, 2010; Fizazi, Carducci, et al, 2011.
  56. 56. Denosumab: Prescribing Information  Dose for SRE prophylaxis: 120 mg SQ q4wks  Should correct hypocalcemia prior to initiation  Consider using concurrent calcium/vitamin D  No dose adjustments for renal impairment – CrCl < 30 mL/min may increase risk of hypocalcemia  Perform oral exam; no invasive dental proceduresSQ = subcutaneous; CrCl = creatinine clearance.Xgeva® prescribing information, 2010.
  57. 57. Key Takeaways Progression of CRPC may be defined by PSA criteria, radiographic criteria, or clinical criteria Cabazitaxel is a novel taxane approved for mCRPC after failure of a docetaxel-containing regimen Abiraterone is a novel androgen synthesis inhibitor approved for mCRPC after receipt of prior docetaxel Denosumab is a novel osteoclast-inhibiting agent that is superior to zoledronate in preventing SREs in men with castration-resistant bone metastases
  58. 58. Section III:Emerging Treatment Options for mCRPC Patients
  59. 59. Emerging Therapies for CRPCCTLA-4 = cytotoxic T-lymphocyte associated antigen-4; TKI = tyrosine kinase inhibitor; MET = MNNG HOS transforming gene;VEGFR = vascular endothelial growth factor receptor..
  60. 60. Emerging Treatment Options for mCRPC Patients What anti-androgens are being studied?
  61. 61. Abiraterone: COU-302 (Pre-Chemo) Patients with mCRPC, Accrual Completed 4/2010 docetaxel-naïve, ketoconazole-naïve, Abiraterone 1000 mg QD asymptomatic or mildly Prednisone 5 mg BID symptomatic n = 500 Randomization 1:1 Placebo-Controlled, Double-Blind Placebo QD Prednisone 5 mg BID n = 500 Primary Objective: 20% OS improvement Sample size: 1000 (fully accrued 4/2010 – data maturing)US NIH, 2011a.
  62. 62. Abiraterone: Phase I/II StudiesRECIST = Response Evaluation Criteria in Solid Tumors.Ryan et al, 2010; Attard et al, 2009; Reid et al, 2010; Danila et al, 2010.
  63. 63. Phase II Data: PSA Responses PRE–DOCETAXEL PSA Response after 12 weeks Attard G, et al. JCO 2009; 27: 3742-8. POST–DOCETAXEL PSA Response after 12 weeks Reid A, et al. JCO 2010; 28: 1489-95.Attard et al, 2009; Reid et al, 2010.
  64. 64. MDV3100: Novel AR Antagonist  Second generation AR antagonist  Binds AR more potently than bicalutamide  MDV3100 is not a partial agonist of AR  Inhibits translocation of AR into nucleus and decreases AR binding to DNA  Oral agent: 160 mg daily (seizures at higher doses)  Ongoing randomized phase III trials of MDV3100 vs. placebo (post-chemo/pre-chemo)DNA = deoxyribonucleic acid.Tran et al, 2009.
  65. 65. MDV3100: PSA Declines (Phase I/II) Pre-Chemotherapy (n=65) Post-Chemotherapy (n=75). MDV-3100 induced >50% PSA declines in 56% of mCRPC patientsScher et al, 2010.
  66. 66. MDV3100: Radiologic ResponsesPR = partial response; SD = stable disease; FDG-PET = fludeoxyglucose-positron emission tomography.Scher et al, 2010.
  67. 67. AFFIRM Phase III Trial (Post-Chemo) N = 1170 Accrual complete R A MDV-3100 160 mg QD Men with N 2 docetaxel- D pretreated O Placebo-Controlled, Double-Blind mCRPC M (keto-naïve) I 1 Placebo QD Z E Primary Objective: 25% overall survival improvement (median OS 12 mo → 15 mo)US NIH, 2011b.
  68. 68. PREVAIL Phase III Trial (Pre-Chemo) N = 1680 Ongoing R A MDV-3100 160 mg QD N 1 Men with D chemo-naïve O Placebo-Controlled, Double-Blind mCRPC M I 1 Placebo QD Z E Co-Primary Endpoints: OS + PFS Secondary Endpoints: SREs, time-to-chemo-initiationUS NIH, 2011c.
  69. 69. Other Novel Hormonal Agents TAK-700 (CYP17 lyase inhibitor) – Orteronel – Pre-chemo/post-chemo phase III studies ongoing TOK-001 (CYP17 inhibitor and AR antagonist) – Phase II study underway ARN-509 (AR antagonist, related to MDV3100) – Phase I study underway
  70. 70. Emerging Treatment Options for mCRPC Patients What immunotherapies are being studied?
  71. 71. Sipuleucel-T: Phase III Study in Hormone-Naïve mPCa N = 1684 Pending Activation R A Androgen deprivation therapy (ADT) N 1 Men with → Sipuleucel-T hormone- D naïve O Open Label study metastatic M prostate I 1 cancer Z Androgen deprivation therapy (ADT) alone E Primary Endpoint: Overall survival Secondary Endpoints: Time to castration-resistance Chemotherapy-free survivalFizazi, Powles, et al, 2011.
  72. 72. Ipilimumab: Anti-CTLA4  Human MoAb that binds to and blocks activity of CTLA-4 on T cells, modulating immune response  Ipilimumab has shown significant activity against metastatic melanoma (with or without vaccine), with a survival benefit demonstrated in pretreated patients and in the first-line settingHodi et al, 2010.
  73. 73. CTLA4 Blockade: IpilimumabDrake, 2010.
  74. 74. Ipilimumab in CRPC  Phase I trials – Ipilimumab combined with GM-CSF (N = 24) – 1 patient had PR – 3 patients had PSA declines > 50% at highest dose  Phase II trials – Ipilimumab combined with RT (N = 26) – 6 patients had > 50% PSA declines – 1 patient had PRFong et al, 2009; Beer et al, 2008.
  75. 75. Ipilimumab: Post-Chemo Phase III Trial N = 800 Ongoing R A XRT to bone lesion → Men with N 2 Ipilimumab IV (induction, maintenance) docetaxel- D pretreated O Placebo-Controlled, Double-Blind CRPC with M bone mets I 1 XRT to bone lesion → Z Placebo IV (induction, maintenance) E Primary Endpoint: Overall SurvivalUS NIH, 2011d.
  76. 76. Ipilimumab: Pre-Chemo Phase III Trial N = 600 Ongoing R A Men with N 1 Ipilimumab IV (induction, maintenance) minimally/ D asymptomatic docetaxel- O Placebo-Controlled, Double-Blind naïve M mCRPC I 1 Z Placebo IV (induction, maintenance) E Primary Objective: Overall SurvivalUS NIH, 2011e.
  77. 77. ProstVac-VF  Vaccinia and fowlpox-based vectors expressing PSA antigen and 3 costimulatory molecules (TriCom) designed to stimulate immune responses against prostate cancer  TriCom – B7.1 (CD80) – ICAM-1 (CD54) – LFA-3 (CD58)  Randomized phase II trial in mCRPC demonstrated no significant difference in PFS with ProstVac-VF vs. control, but significantly improved OS at 3 yearsTriCom = triad of costimulatory molecules.Drake, 2010; Kantoff, Schuetz, et al, 2010.
  78. 78. ProstVac-VF (cont.)Drake, 2010.
  79. 79. ProstVac-VF: Phase II Trial P ProstVac-VF R Treated at TriCom + O Physician’s S GM-CSF G Discretion U Asymptomatic (n = 84) R or minimally R E Cross-over V symptomatic 2:1 mCRPC S I (N=125) S V Treated at Empty Vector I Physician’s A + Placebo O Discretion L (n = 41) N Primary endpoint: PFS Secondary endpoint: OSKantoff, Schuetz, et al, 2010.
  80. 80. Phase II Trial: Treatment SchemaKantoff, Schuetz, et al, 2010.
  81. 81. Phase II Trial: Results PFS OS P = 0.6 P = 0.006Kantoff, Schuetz, et al, 2010.
  82. 82. ProstVac-VF: ECOG 1809 Trial N = 144 Ongoing R A ProstVac-VF sq Days 1, 15, 29, 43, 57 N 2 Men with → Docetaxel / Prednisone docetaxel- D naïve O mCRPC M I 1 Z Docetaxel / Prednisone (up-front) E Primary Objective: 70% overall survival improvement (median OS 21 mo → 36 mo)US NIH, 2011f.
  83. 83. ProstVac-VF: PROSPECT Trial Pending Activation N = 1200 R ProstVac-VF sq Wks 1, 3, 5, 9, 13, 17, 21 Men with A GM-CSF sq Wks 1, 3, 5, 9, 13, 17, 21 minimally/ N asymptomatic D docetaxel- O ProstVac-VF sq Wks 1, 3, 5, 9, 13, 17, 21 naïve M mCRPC I Z Placebo sq Wks 1, 3, 5, 9, 13, 17, 21 E Primary Endpoint: Overall SurvivalUS NIH, 2011g.
  84. 84. Emerging Treatment Options for mCRPC Patients What are the bone-targeted approaches?
  85. 85. Bone-Seeking Radiopharmaceuticals  Strontium-89 – Beta(b)-emitter, t½ = 51 days – FDA approved (1993) for pain palliation of bone metastases  Samarium-153 – Beta(b)-emitter, t½ = 46 hours – FDA approved (1998) for pain palliation of bone metastases  Radium-223 (investigational) – Alpha(a)-emitter, t½ = 11 days – Higher energy transfer with shorter range (< 100 mm)Lewington et al, 1991; Serafini et al, 1998; Nilsson et al, 2007.
  86. 86. Radium-223: Phase III ALASYMPCA Trial N = 900 R A 2 Radium-223 IV q4wk (x6) Men with N symptomatic D mCRPC and O Placebo-Controlled, Double-Blind bone mets M I 1 Placebo IV q4wk (x6) Z E Primary Endpoint: Overall SurvivalUS NIH, 2011h.
  87. 87. Radium-223: Press Release (6/5/11)  Pre-planned interim analysis conducted  OS longer with Radium-223 than with placebo – 14.0 months vs. 11.2 months (p = .002)  IDMC closed the study early  Men now may cross over from placebo to Radium-223Algeta Press Release, Oslo, Norway, 6/5/2011.
  88. 88. Emerging Treatment Options for mCRPC Patients What other novel agents are being studied?
  89. 89. Dasatinib in CRPC  Phase II trial, 38 patients with metastatic CRPC treated with one prior chem regimen – Median duration of therapy – 55 days – 46% had dose reduction or treatment delay – One patient had stable disease for > 6 mos – Tolerability was improved by reduction in starting dose to 100 mg/d  Ongoing phase III trial, dasatinib + docetaxel/ prednisone versus placebo + docetaxel/prednisoneUS NIH, 2011i; Twardowski et al, 2011.
  90. 90. Cabozantinib (XL184)  Cabozantinib: TKI that blocks MET and VEGFR2 – MET and its ligand HGF drive invasion and metastasis – MET and VEGFR2 synergize to promote angiogenesis – Bone metastases have high levels of MET expression • HGF and VEGF direct crosstalk between tumor cells, osteoblasts, and osteoclasts  In prostate cancer – Preclinically, androgen ablation ↑ MET expression – MET ↑ with progression and metastasis in bone and LNsHGF = hepatocyte growth factor; LNs = lymph nodes.Hussain et al, 2011.
  91. 91. SLD % Change in Prostate Cancer Subjects Cabozantinib % Change from Baseline 70 50 RESPONSES IN SOFT TISSUE LESIONS 30 74% of patients showed tumor regressions 10 * * * -10 * ** ** * -30 Docetaxel-Naïve ** -50 Docetaxel-Pretreated * -70 * Prior Abiraterone or MDV3100 100 100 80 SERUM BAP 80 PLASMA CTx 60 40 (Formation marker) 60 40 (Resorption marker) 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 m % -80 Bisphosphonate-Treated B C o g n h s e a r f i l -100 -100 Bisphosphonate-NaïveBAP = bone-specific alkaline phosphatase; CTX = carboxy-terminal cross-linking telopeptide of type I collagen.Hussain et al, 2011.
  92. 92. Cabozantinib (cont.) Baseline Week 12 Baseline Week 12 Docetaxel - naïve Docetaxel - pretreated Bone Scan Improvements Seen in 76% of Patients (bone pain improvement in 67%)Hussain et al, 2011.
  93. 93. Key Takeaways Several novel androgen synthesis inhibitors and next generation AR antagonists are in development Ipilimumab,ProstVac-VF, Zibotentan, dasatinib, and lenalidomide have entered late stage clinical trials Radium-223 is the fifth drug to show OS improvement in men with mCRPC Cabozantinib (XL184) is a new TKI with marked effects on castration-resistant bone metastases
  94. 94. Section IV:Putting Evidence Into Practice: Expert Perspective on Case Examples
  95. 95. Case Study: Part 1  57-yr-old man – T3a PCa, Gleason 4+4 = 8, PSA = 8.2 ng/mL  Undergoes radical prostatectomy  Develops PSA recurrence with PSADT = 6 months  Started on leuprolide + bicalutamide, and responds for 18 months  Then develops rising PSA, despite bicalutamide withdrawal  PSAs: 4.2 → 5.6 → 7.2 ng/mL  Testosterone: 28 ng/dL  Bone scan and CT scan: Negative for metastatic diseasePSADT = prostate-specific antigen doubling time; CT = computed tomography.NCCN, 2011.
  96. 96. Case Study: Part 1 Discussion Questions Does this patient meet criteria for CRPC? How would you manage this patient?
  97. 97. Case Study: Part 2 Same patient – non-mCRPC Enrolls in phase II study or oral TAK-700 (orteronel) Has a PSA response lasting 6 months Then PSA begins to rise: 4.6 → 7.5 → 11.2 ng/mL Testosterone: 2 ng/dL CT scan repeated: Remains normal Bone scan: New lesions left 5th rib and L1 vertebral body He remains asymptomatic – no bone pain – ECOG 0
  98. 98. Case Study: Part 2 Discussion Question How would you manage this patient now?
  99. 99. Case Study: Part 3 Same patient – asymptomatic mCRPC Patient receives 3 infusions of sipuleucel-T PSA rises after 3 months, and again after 6 months CT scan: Para aortic lymphadenopathy (up to 3.8 cm) Bone scan: 2 rib, 2 vertebral, and 1 pelvic bone lesion Patient reports new rib and back pain (intensity 3/10) ECOG PS 0
  100. 100. Case Study: Part 3 Discussion Question How would you manage this patient now?
  101. 101. Case Study: Part 4 Same patient – symptomatic mCRPC He receives docetaxel q3wks and denosumab q4wks Obtains PSA response and objective radiologic response After 8 cycles, stops docetaxel due to grade 3 neuropathy 4 months later, he has further PSA progression CT: New liver lesions (up to 4 cm) and lung lesions (8 mm) Bone lesions: Stable Has persistent grade 2 peripheral neuropathy ECOG PS 1
  102. 102. Case Study: Part 4 Discussion Question How would you manage this patient now?
  103. 103. Key Takeaways Different treatment strategies may be appropriate for patients with different disease states – Non mCRPC – Asymptomatic mCRPC – Symptomatic mCRPC – Docetaxel pretreated CRPC Bone-targeting therapies should be considered for men with castration-resistant bone metastases, and can be given concurrently with anticancer therapies Palliative approaches (eg, RT, radiopharmaceuticals) should also be considered for patients with bone pain

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