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Treatment of Advanced Prostate Cancer: The Changing Landscape

Treatment of Advanced Prostate Cancer: The Changing Landscape. Wm. Kevin Kelly, DO Professor, Medical Oncology and Urology Director, Division of Solid Tumor Oncology Thomas Jefferson University. Disclosures. Sanofi – Aventis: Research support. Outline. Evolving Biology of CRPC

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Treatment of Advanced Prostate Cancer: The Changing Landscape

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  1. Treatment of Advanced Prostate Cancer: The Changing Landscape Wm. Kevin Kelly, DO Professor, Medical Oncology and Urology Director, Division of Solid Tumor Oncology Thomas Jefferson University

  2. Disclosures Sanofi – Aventis: Research support

  3. Outline • Evolving Biology of CRPC • Novel Agents for the treatment of CRPC • Androgen Biosynthesis Inhibitors (ABI’s)/novel anti-androgens • Abiraterone, Enzalutamide (MDV-3100) • Cytotoxics • Cabazitaxel • Immunotherapies • Sipuleucel-T • Bone\micro-environment directed therapies • Alpharadin • “Picking the right treatment for the right patients at the right time”

  4. Prostate Cancer: Growth Rate and Progression Prostate Cancer Death Metastatic Disease Cancer Progression Localized Disease Early Detection Onset of Cancer Natural Death Life Expectancy

  5. Prostate Cancer Clinical States: A Framework for ClinicalPractice, Drug Development, and Biomarker Qualification Non-Castrate Androgen depletion / blockade (bicalutamide) Castration resistant: deaths from disease 186,320 28,660 3 Clinical Metastases: Castrate 1st Line Docetaxel Standard 4 Clinical Metastases: Castrate 2nd Line No Standard Clinical Metastases: Non-Castrate 2 Clinical Metastases: Castrate Pre- Clinically Localized Disease Rising PSA 1 Rising PSA: Castrate With detectable metastases: deaths from cancer exceed that from other causes Diagnoses

  6. Docetaxel – CRPCOverall Survival—TAX 327 1.0 Docetaxel 3 wkly 0.9 Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 Probability of Surviving Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Months Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.

  7. What to do when first line Docetaxel treatment fails? Three years ago the choices were limited VS. Palliative Chemotherapy Phase I study Beach

  8. Understanding the Biology of CRPC Driver Pathways of Dependency of PC Primary Mets • Androgen Receptor (AR) 55% 100% • PTEN loss 25% 80% • PI3K/Akt, Ras/Raf, RB 42% 100% • TMPRSS2-ETS fusion 50% 33% • Genetic variants of androgen transporter genes Tomlins, S. A. Eur Urol 2009 Taylor, B et al, Cancer Cell 2010 Kong D. Cancer Sci 2008 Jenkins, R. B. Cancer Res 1997 Khor, L. Y. Clin Cancer Res 2007

  9. Intratumoral Androgen Levels Are Increased Due To Overexpression of The Androgen Synthetic Enzymes Testosterone 4.0 Primary prostate cancers 3.5 Metastatic prostate cancers Benign prostate 3.0 2.5 Control tissues (bladder, liver, lung) Testosterone (ng/gm) 2.0 1.5 1.0 0.5 0.0 P1 P2 P3 P4 P5 P6 C1 C2 C3 M1 M2 M3 M4 M5 M6 M7 M8 Prostate samples Control and Metastatic autopsy ( eugonadal) samples (castrate) Squaline Monoxygenase Non-castrate metastatic Castrate metastatic LIVER Positive control Gerald et al, Amer J Pathol 164:217, 2004 Steroid content Montgomery et al. Cancer Res 68:4447, 2008

  10. Prostate Cancer: “Adapting” to castrate environment Hormone Therapy selective pressure CoACT AR T • AR • DEREGULATION • amplification • overexpression • MUTATION • gain of function • ABERRANT • MODIFICATION • GF, cytokines • Src ALTERN. SPLICING • COFACTOR • PERTURBATION • CoAct gain • CoR loss/dismissal INTRACRINE ANDROGEN SYNTHESIS adaptation >30% CRPC RESTORED AR ACTIVITY (rising PSA) CRPC RECURRENT TUMOR DEVELOPMENT RESTORED AR ACTIVITY (rising PCa) AC DHT DHT CRPC development CoACT AR AR P Sumo Penning & Knudsen 2010 THERAPEUTIC FAILURE

  11. Targeting the Androgen Pathway • Androgen Biosynthesis Inhibitors • *Abiraterone Acetate • TAK 700 • VN/124-1 (TOK-001) • Novel Anti-Androgens • *MDV3100 • RD 162 • EPI-001 (AR N-Terminal) • SNARE-1 (selective nuclear receptor exporter-1) * FDA approved

  12. Hormonal Impact of Abiraterone Low-dose steroid replacement minimizes mineralocorticoid-related toxicity O H O O O H O P 4 5 0 S C C Aldosterone H O H O O O C h o l e s t e r o l P r e g n e n o l o n e P r o g e s t e r o n e C o r t i c o s t e r o n e P 4 5 0 2 1 - h y d r o x y l a s e 1 7 a O H ( 1 - h y d r o x y l a s e ) 1 - h y d r o x y l a s e 7α 1bb O O O H O O H O H O H Abiraterone Abiraterone H O O O 7α 1 - H y d r o x y p r e g n e n o l o n e 1 - H y d r o x y p r o g e s t e r o n e 7αa C o r t i s o l P 4 5 0 t e s t o s t e r o n e 1 7 a ( C - l y a s e ) - r e d u c t a s e 5α 1 7 , 2 0 O H O O O H O H O O O H T e s t o s t e r o n e D e h y d r o e p i a n d r o s e r o n e A n d r o s t e n e d i o n e - D i h y d r o t e s t o s t e r o n e 5α

  13. Abiraterone Suppresses Steroids Downstream of C17,20-lyase: Proof-of-Concept Phase I Trial 2 Testosterone (by LC-MS/MS) Androstenedione 6 5 4 ng/dL nmol/L Lower Limit of Sensitivity 1 3 2 1 0.07 0 0 10 20 60 70 28 56 At Progression At Progression 1 Start of Treatment Start of Treatment Days Days 12.5 12.5 DHEA Estradiol 10.0 10.0 7.5 7.5 ρmol/L Nmol/L 5.0 5.0 2.5 2.5 0 0 28 56 At Progression 10 20 30 40 50 60 Start of Treatment Days Post Treatment Days Confidential. For Internal Use Only. Do not distribute.

  14. Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer 1Ryan et al. J Clin Oncol 2009; 27(suppl):245s (abstract 5046) 2Reid et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5047) 3Danila et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5048)

  15. COU-AA-301 Study Design RANDOMIZED 2:1 Efficacy endpoints (ITT) Abiraterone1000 mg daily Prednisone 5 mg BID n=797 • Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) • Stratification according to • ECOG performance status (0-1 vs 2) • Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present]) • Prior chemotherapy (1 vs 2) • Type of progression (PSA only vs radiographic progression with or without PSA progression) Patients • Primary end point • OS (25% improvement; HR 0.8) • Secondary endpoints (ITT) • TTPP • PFS • PSA response • 1195 patients with progressive mCRPC • Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel Placebo daily Prednisone 5 mg BID n=398 Abbreviations: ; BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastatic castrate-resistant prostate cancer. Source: Clinicaltrials.gov identifier: NCT00638690. deBono N Engl J Med. 2011 May 26;364(21):1995-2005

  16. COU-AA-301: Abiraterone Acetate Improves OS in mCRPC 100 HR=0.646 (0.54-0.77) P <0.0001 Abiraterone: 14.8 months (95% CI: 14.1, 15.4) 80 60 Overall Survival, % 40 Placebo: 10.9 months (95% CI: 10.2, 12.0) 20 1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo 0 300 500 0 400 600 700 100 200 Days from Randomization deBono N Engl J Med. 2011 May 26;364(21):1995-2005

  17. Survival Benefit Consistently Observed Across Patient Subgroups 0.5 0.75 1 1.5 Favors Abiraterone FavorsPlacebo Abbreviations: HR=hazard ratio; ALK-P=alkaline phosphatase. deBono N Engl J Med. 2011 May 26;364(21):1995-2005

  18. COU-AA-301: Summary of AEs deBono N Engl J Med. 2011 May 26;364(21):1995-2005

  19. Overall Study Design of COU-AA-302 RANDOMIZED 1:1 Efficacy end points Patients AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) • Co-Primary: • rPFS by central review • OS • Secondary: • Time to opiate use (cancer-related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP • Progressive chemo-naïve mCRPC patients(Planned N = 1088) • Asymptomatic or mildly symptomatic Placebo daily Prednisone 5 mg BID (Actual n = 542) Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs 1 Ryan et al. ASCO 2012

  20. Statistically Significant Improvement in rPFS Primary End Point 100 80 60 Progression-Free (%) 40 20 AA + P PL + P 0 3 6 9 12 15 18 0 Time to Progression or Death (Months) AA PL 546 542 489 400 340 204 164 90 46 30 12 3 0 0 Data cutoff 12/20/2010. NR, not reached; PL, placebo. Ryan et al. ASCO 2012

  21. Strong Trend in OS Primary End Point 100 80 60 Survival (%) 40 20 AA + P PL + P 0 3 6 9 12 15 18 21 24 27 30 33 0 Time to Death (Months) 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 AA PL Updated GU ASCO 2013: Rathkopf et al. Abstract # 5 -r PFS 16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p = <0.0001 - OS 35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96) p= 0.0151

  22. No New Safety Concerns Identified with Longer AA Treatment than in 301 Study Most ALT and AST increases occurred during the first 3 months of treatment Ryan et al. ASCO 2012

  23. Subsequent Therapy Was Commonand Still a Survival Trend Observed *Prior to unblinding (e.g. not per protocol) Ryan et al. ASCO 2012

  24. TAK-700 (Ortoronel) in mCRPC: PSA Response and Safety • inhibit the enzyme 17,20-lyase • 53% with PSA decreases ≥ 50% at 12 wks • Serious AEs in 25 patients (26%): hypokalemia (n = 3), acute renal failure (n = 3), pneumonia (n = 2), urinary tract infection (n = 2), hypotension (n = 2), neutropenia (n = 2), fatigue (n = 2) • Efficacy and tolerability demonstrated with TAK-700 administered with or without prednisone, suggesting feasibility of a steroid-free regimen 275 250 225 200 175 150 125 100 PSA Change at 12 Wks (%) 75 50 25 x x x x x x x x x x 0 x x x X x x x x x x X x x -25 -50 -75 -100 -125 Treatment 300 mg BID (n = 23) 400 mg BID + prednisone (n = 24) 600 mg BID + prednisone (n = 26) 600 mg QDAM (n = 24) X Previous ketoconazole therapy Agus DB, et al. ASCO 2011. Abstract 4531.

  25. Novel anti-androgens“Development of Enzalutamide” • Built of the scaffolding of the non-steroidal agonist RU59063 • Screened ~ 200 derivatives • Derivatives were optimized – RD162 and MDV3100 Enzalutamide (MDV3100) Tran et al. Science 324:787-790, 2009

  26. MDV3100 (Enzalutamide) Was Designed to Overcome Deficiencies of Available Anti-Androgens and Has Several Unique Mechanisms of Action and No Agonist Effects 1 T • MDV3100 is an oral investigational drug rationally designed as a new hormonal agent to target androgen receptor (AR) signaling, a key driver of prostate cancer growth. • MDV3100 is the first in a new class of Androgen Receptor Signaling Inhibitors that affects multiple steps in the androgen receptor signaling pathway. T Enzalutamide AR AR Inhibits Binding of Androgens to AR 2 Cell cytoplasm Inhibits Nuclear Translocation of AR Cell nucleus Tumor Death Inhibits Association Of AR with DNA 3 Tran et al. Science 2009;324:787–90.

  27. Bicalutamide vs. Enzalutamide Enzalutamide has a 5-8 fold increased affinity to AR than bicalutamide Enzalutamide does not have agonists effects in castrate resistant setting Enzalutamide suppressed growth and induced apoptosis in cells lines with AR gene amplications Tran et al. Science 324:787-790, 2009

  28. Anti-tumor activity if MDV3100 in castration-resistant prostate cancer: a phase 1-2 study Post-chemotherapy N=75 Pre-chemotherapy N=65 Scher et al. Lancet 375:1437-1446, 2010

  29. AFFIRM: Phase 3 Trial of Enzalutamide vs Placebo in Post-Chemotherapy Castration-Resistant Prostate Cancer (CRPC) RANDOMIZED 2:1 Patient Population: 1199 patients with progressive CRPC * Failed docetaxel chemotherapy Enzalutamide 160 mg daily n = 800 Primary Endpoint: Overall Survival Placebo n = 399 *Glucocorticoids were not required but allowed Tran et al. Science 2009;324:787–90. ASCO June 2012

  30. AFFIRM: Clinical Outcomes De Bono et al. ASCO 2012

  31. Favorable Adverse Risk Profile De Bono et al. ASCO 2012

  32. Association of PSA progression and rPFS AFFIRM COU-AA-301 PSA rPFS De Bono et al. ASCO 2012 de Bono JS et al. N Engl J Med 2011;364:1995-2005

  33. Novel Agents Targeting the Androgen Pathway

  34. Cabazitaxel Microtubule stabilizer Developed in docetaxel-resistant prostate cancer cell lines a favorable pharmacokinetic and safety profile decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance. inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp.

  35. TROPIC – Cabazitaxel vs Mitoxantrone RANDOMIZE Cabazitaxel 25 mg/m2 Q 21 d Prednisone 10 mg daily • CRPC • PD during or after docetaxel N=755 146 Sites / 26 Countries Mitoxantrone Prednisone 10 mg daily Abbreviation: PD=progressive disease. Source: deBono et al. Lancet. 2010;376:1147-1154.

  36. 100 MP CBZP Median OS (months) 12.7 15.1 Hazard Ratio 0.70 80 95% CI 0.59–0.83 P Value <.0001 60 40 20 0 6months 12 months 18 months 24 months 30 months 0 months TROPIC Primary Endpoint – OS (ITT Analysis) Proportion of OS (%) Numberat Risk Abbreviation: ITT=intent-to-treat. Source: deBono et al. Lancet. 2010;376:1147-1154.

  37. Most Frequent Grade ≥3 Treatment-Emergent AEs* *Sorted by decreasing frequency of events grade ≥3 in the CBZP arm. deBono et al. Lancet. 2010;376:1147-1154

  38. Immunotherapy Approaches in PC • Active immunotherapy • tumor associated antigen is directly targeted by loading in that antigen in APC or into vaccine vector at protein or DNA level • Antigen specific immunotherapy • Sipuleucel-T • Poxvirus-based vectors • DNA based vaccines • Passive immunotherapy • Antibodies to specific receptors/antigens • Prostate Specific Membrane Antigen (PSMA) • Immune Checkpoint Inhibitors • Strategies to maintain activated tumor specific T-cells by neutralizing co-inhibitory receptors • Anti-cytotoxic T lymphocyte protein 4 (CTLA 4) • Ipilumimab, tremelimumab • Anti- program death 1 (PD-1) • MDX-1106

  39. Cells infused back into patient (IV) Active Cellular Immunotherapy(Sipuleucel-T) Patient’s white blood cells harvested Short-term culture with protein “cassette” GM-CSF Prostatic acid phosphatase Shipping

  40. Sipuleucel-T in Prostate Cancer Cheever and Higano., Clin Cancer Res 2011;17:3520-3526

  41. CD54 is a surrogate marker of antigen presenting cell activation Serum cytokines or humoral responses by ELISA have limited utility

  42. Second Generation Anti-PSMA Abs: J591 • 2nd generation mAbs • Bind extracellular domain • Bind viable PSMA+ cells • Rapidly internalized • May be conjugated Capromab binding site J591 binding site Liu H et al. Cancer Res 1997; 57: 3629 Liu H et al. Cancer Res 1998; 58: 4055

  43. Tagawa et al, ASCO 2008 177Lu-J591 Rx: Excellent Targeting & PSA Response 30/32 (94%) with accurate targeting of known sites of disease 99mTc-MDP bone scan177Lu-J591 mAb PSADT=3.9 mo 6 months Log scale 90% decline Arithmetic scale Ant Post Ant Post

  44. Defining the Future:Ongoing Immumotherapy Trials

  45. Radioisotopes Targets Bone Metastases Naturally targets new bone growth in and around bone metastases Most acts as a calcium mimic Strontium-89 Samrarium-153 Radium-223 Ca Ra

  46. Radium-223 (AlpharadinTM ) • Based on alpha emitter Radium-223 • ideal half-life of 11.4 days • Excreted via small bowel • Safe and easy to produce, deliver and handle Range of alpha-particle Radium-223 Encouraging Phase II results

  47. 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 Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751.

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