DrDreicer AdvancedProstateCancer(Royal)

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The management of advanced prostate cancer has been revolutionized by the translation of the rapid progress made in understanding the biology of the disease into new therapies. While these developments are unprecedented, many challenges remain, including our need to understand how best to utilize these new treatments, how to integrate them into current treatment paradigms and how to demonstrate the most cost effective ways to use these new drugs. Dr. Dreicer briefly reviews the most important of the new developments, progress to date in integrating these new therapies, and speculates how these developments will translate into improvements in patient outcomes.

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  • Consider revision bullet 2 to remove “new class”
  • TROPIC slide deck. Slide6,10,13
  • TROPIC slide deck. Slide5
  • 140
  • DrDreicer AdvancedProstateCancer(Royal)

    1. 1. Management of Advanced ProstateCancer: Moving Towards A ChronicDisease Robert Dreicer, M.D., M.S., FACP, FASCO Chair Dept of Solid Tumor Oncology Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine
    2. 2. A Brief History of the Management ofAdvanced Prostate Cancer Pre-PSA era (Pre 1989)  Patient presents with de novo metastatic disease  ADT, response, followed by symptomatic progression PSA directed therapy era (1989-)  Rare de novo presentation of metastatic disease  ADT, response assessed by PSA, biochemical progression, followed by secondary hormonal maneuvers (casodex shuffle), chemotherapy
    3. 3. Death from Other Causes Clinically Clinical Clinical Initial Prostate Rising PSA Evaluation: No Localized Metastases MetastasesCancer Diagnosis Salvage Rx Noncastrate Disease Castrate Death From Disease Scher H, et al. Urology 2000
    4. 4. Clinical States In Prostate Cancer Sipuleucel-T Rad 223 Metastatic Disease Cabazitaxel Organ (De novo)Confined Metastases Metastases Metastases Metastases Castrate Castrate Rising PSA Castrate Castrate Resistant Resistant Hormone Resistant Resistant Post Docetaxel Post Asymptomatic Post Abiraterone Cabazitaxel Naive Symptomatic Locally Rising PSA Advanced Castrate Disease MDV-3100 Abiraterone Denosumab Zolendronic Acid Modified from Scher H, et al. Urology 2000
    5. 5. Why Terminology Matters: Hormone-refractory/Androgen-independent: NOT Limits in understanding at the molecular level and in available therapeutics have heavily influenced our view of the disease Clinical utility of “second-line” hormonal therapy Mixed (essentially no) clinical data French-American rule
    6. 6. Testosterone Suppression with CurrentTherapies Bilateral orchiectomy: testosterone, on average, falls to 15 ng/dL (0.5 nmol/L) LHRH agonists average range of suppression in the 30-40 ng/dl range  Escape occurs in a subset of pts
    7. 7. Lymph node Met(i) H&E(ii) Nuclear ARexpression PSA and FKBP5 are(iii) PSA stain with androgencytoplasmic PSA regulatedexpression genes Montgomery BR, et al. Cancer Res 2008;68:4447-4454
    8. 8. Steroid SynthesisCholesterol Low-dose steroid replacement decreases ACTH and minimizes mineralocorticoid-related toxicity DesmolasePregnenolone Progesterone Deoxy- Corticosteron Aldosterone corticosterone e CYP17 X 17α-hydroxylase 17α-OH- 17α –OH- 11-Deoxy- Cortisol ACTH ↓ pregnenolone progesterone cortisol CYP17 X C17,20-lyase 5α-reductase DHEA Androstenedione Testosterone DHT CYP19: aromatase Estradiol Attard G, et al. J. Clin. Oncol. 26: 4563–4571, 2008
    9. 9. Attard G, et al. J. Clin. Oncol. 26: 4563–4571, 2008
    10. 10. PSA Response / Progression in Phase II Trials ofAbiraterone in Docetaxel-Treated CRPC Reid (N = 47) Danila (N = 58) 50% PSA decline – 54.8% 50% PSA decline – 45.2% Danila DC, et al. J Clin Oncol. 2010;28:1496-1501; Reid AH, et al. J Clin Oncol. 2010;28:1489-1495.
    11. 11. COU-AA-301 Study Design Efficacy endpoints (ITT) R Patients A Abiraterone1000 mg daily• 1195 patients with Primary end point: N Prednisone 5 mg BID progressive, mCRPC D N=797 • OS (25% improvement; HR• Failed 1 or O 0.8) 2 chemotherapy M I Secondary end points (ITT): regimens, one of Z Placebo daily • TTPP which contained E docetaxel Prednisone 5 mg BID • rPFS D 2:1 n=398 • PSA response  Phase 3, 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) Clinicaltrials.gov identifier: NCT00638690.
    12. 12. COU-AA-301: Abiraterone Acetate Improves Overall Survival in mCRPC 100 HR = 0.646 (0.54-0.77) P< 0.0001 Abiraterone acetate: 80 14.8 months (95%CI: 14.1, 15.4)Survival (%) 60 40 Placebo: 10.9 months (95%CI: 10.2, 12.0) 20 2 Prior Chemo OS: 1 Prior Chemo OS 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo 0 0 100 200 300 400 500 600 700 Days from Randomization de Bono J et al: N Engl J Med 364:1995- 2005, 2011
    13. 13. Adverse Events of Special Interest Placebo Abiraterone Acetate Plus Prednisone Plus Prednisone (n=791) (n=394)Adverse Event, no. All Grade Grade All Grade Gradepatients (%) Grades 3 4 Grades 3 4Fluid retention and 241 (31) 16 (2) 2 (<1) 88 (22) 4 (1) 0edemaHypokalemia 135 (17) 27 (3) 3 (<1) 33 (8) 3 (1) 0Cardiac disorders 106 (13) 26 (3) 7 (1) 42 (11) 7 (2) 2 (<1)LFT abnormalities 82 (10) 25 (3) 2 (<1) 32 (8) 10 (3) 2 (<1)Hypertension 77 (10) 10 (1) 0 31 (8) 1 (<1) 0 • Adverse events associated with elevated mineralocorticoid levels, cardiac events, and LFT abnormalities were deemed of special interest • These events were more common in the abiraterone acetate group (55% vs 43%; P<0.001) but were largely mitigated by the use of low-dose prednisone deBonoJS et al. N Engl J Med. 2011;364(21):1995-2005.
    14. 14. Overall Study Design of COU-AA-302 R R Efficacy end points Patients A A N N AA 1000 mg daily AA 1000 mg daily Co-Primary:• Progressive chemo- D D Prednisone 5 mg BID Prednisone 5 mg BID • rPFS by central review naïve mCRPC O O (Actual n = 546) (Actual n = 546) M M • OS patients II (Planned N = 1088) Z Secondary: Z• Asymptomatic or E E Placebo daily Placebo daily • Time to opiate use mildly symptomatic D D Prednisone 5 mg BID Prednisone 5 mg BID (cancer-related pain) (Actual n = 542) (Actual n = 542) • Time to initiation of 1:1 1:1 chemotherapy • Time to ECOG-PS deterioration • TTPP • 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
    15. 15. Statistically Significant Improvement in rPFS Primary End Point 100 AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 (0.35-0.52) 80 P value: < 0.0001 Progression-Free (%) 60 40 20 AA + P PL + P 0 0 3 6 9 12 15 18 Time to Progression or Death (Months) AA 546 489 340 164 46 12 0 PL 542 400 204 90 30 3 0Data cutoff 12/20/2010.NR, not reached; PL, placebo. Ryan CJ . J Clin Oncol 30, 2012 (suppl; LBA 4518)
    16. 16. Strong Trend in OS Primary End Point 100 80 Survival (%) 60 40 AA + P (median, mos): NR PL + P (median, mos): 27.2 20 HR (95% CI): 0.75 (0.61-0.93) AA + P P value: 0.0097 PL + P 0 0 3 6 9 12 15 18 21 24 27 30 33 Time to Death (Months) AA 546 538 524 503 482 452 412 258 120 27 0 0 PL 542 534 509 493 465 437 387 237 106 25 2 0Data cutoff 12/20/2011.Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008. Ryan CJ . J Clin Oncol 30, 2012 (suppl; LBA 4518)
    17. 17. MDV3100/Enzalutamide1. MDV3100 is an oral investigational drug T rationally designed as a new hormonal agent to target androgen receptor (AR) signaling, a key driver of prostate cancer growth. T2. MDV3100 is the first in a Inhibits Binding of MDV3100 new class of Androgen Receptor 1 Androgens to AR Signaling AR Inhibitors that affects multiple steps in the Cell cytoplasm androgen receptor signaling pathway. 2 Inhibits Nuclear Translocation of AR Cell nucleus AR Inhibits Association 3 Of AR with DNA Scher H, et al. J Clin Oncol 30, 2012 (suppl 5; abstr LBA1)
    18. 18. Antitumor activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study Scher HI, et al. Lancet 375: 437 - 1446,2010
    19. 19. MDV3100 Prolonged Survival by a Median of 4.8 Months in the Phase 3 AFFIRM Trial 100 HR = 0.631 (0.529, 0.752) P < 0.0001 37% Reduction in Risk of Death 90 80 MDV3100: 18.4 months (95% CI: 17.3, NYR) Survival (%) 70 60 50 40 30 20 Placebo: 13.6 months (95% CI: 11.3, 15.8) 10 0MDV3100 800 775 701 627 400 211 72 7 0Placebo 399 376 317 263 167 81 33 3 0 Scher H, et al. 2012 Genitourinary Cancers Symposium
    20. 20. Adverse Events of Interest All Grades Grade ≥ 3 Events MDV3100 Placebo MDV3100 Placebo (n = 800) (n = 399) (n = 800) (n = 399)Fatigue 33.6% 29.1% 6.3% 7.3%Cardiac Disorders 6.1% 7.5% 0.9% 2.0% Myocardial Infarction 0.3% 0.5% 0.3% 0.5%LFT Abnormalities* 1.0% 1.5% 0.4% 0.8%Seizure 0.6% 0.0% 0.6% 0.0%*Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased. Scher H, et al. 2012 Genitourinary Cancers Symposium
    21. 21. Second-line Hormonal Therapy: Thistime with drugs that actually work Many issues remain  Optimal timing  Role of combination therapy  When to stop androgen biosynthesis inhibitors  Major issue in the pre-chemotherapy setting  Optimal dose of steroids for ABI’s  Issues of divergent practice urology vs. oncology
    22. 22. Randomized Phase 3 IMPACT Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment) P P Treated at Treated at Asymptomatic or Asymptomatic or Sipuleucel-T Sipuleucel-T R R Physician Physician S Minimally Q2 Q2 OO discretion S Minimally discretion weeks x 3 weeks x 3 G U U Symptomatic Symptomatic G R R R Metastatic Metastatic R 2:1 V V Castrate Castrate E E S II Resistant Resistant S Treated at Treated at S V V Prostate Cancer Prostate Cancer Placebo Placebo Placebo S Physician Physician II discretion A A (N=512) (N=512) Q 2 Q 2 weeks weeks x 3 Q 2 weeks discretion O and/or Salvage and/or Salvage L L x3 x3 O N Protocol Protocol NPrimary endpoint: Overall SurvivalSecondary endpoint: Time to Objective Disease Progression
    23. 23. Kantoff, P et al. N Engl J Med 363;5 2010
    24. 24. The Sipuleucel-T Conundrum What sipuleucel-T appears to provide patients  improvement in survival What sipuleucel-T DOES NOT DO  It is not a therapeutic replacement for therapy in patients in need of an objective anti tumor response in real time Unprecedented development and integration of a novel therapy  No improvement in OR/PFS  Limited access dampens learning curve  Cost
    25. 25. TROPIC: Phase III Registration Study mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles + prednisone* for 10 cycles (n=378) (n=377) *Oral prednisone/prednisolone: 10 mg daily.Primary endpoint: OS Inclusion: Patients with measurableSecondary endpoints: Progression-free disease must have progressed by RECIST;survival (PFS), response rate, and safety otherwise must have had new lesions or PSA progression
    26. 26. TROPIC: Overall Survival 100 MP CBZP Median OS, mos 12.7 15.1 Patients remaining alive, % 80 HR 0.72 60 95% CI 0.61-0.84 P value < .0001 40 Censored MP CBZP 20 Combined median follow-up: 13.7 mos 0 0 6 12 18 24 30 MosPatients at Risk, n MP 377 299 195 94 31 9 CBZP 378 321 241 137 60 19 de Bono JS, et al. Lancet. 2010;376:1147-1154.
    27. 27. Skeletal Complications in ProstateCancer: Issues Prevention of osteoporosis and related complications Prevention of bone metastases Impact of disease related complications (SRE) Impact on survival
    28. 28. Approved Agents Zolendronic acid  Prevention of osteoporsis  Decrease in SRE Denosumab  Prevention of osteoporsis  Decrease in SRE  Delay in time to metastatic bone disease
    29. 29. Fizazi, K, et al. Lancet 2011; 377: 813–22
    30. 30. Radium-223 Targets Bone Metastases• Radium-223 acts as a calcium mimic• Naturally targets Ca new bone growth in and around bone Ra metastases• Radium-223 is excreted by the small intestine
    31. 31. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS 6 injections at R 4-week intervals STRATIFICATION • Confirmed A symptomatic N Radium-223 (50 kBq/kg) CRPC D + Best standard of care • ≥ 2 bone • Total ALP: O metastases < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: M • No known I Yes vs No visceral S • Prior docetaxel: Placebo (saline) metastases Yes vs No E • Post- + Best standard of care D docetaxel or unfit for 2:1 docetaxel N = 922Planned follow-up is 3 yearsClinicaltrials.gov identifier: NCT00699751.
    32. 32. ALSYMPCA Overall Survival 100 90 HR 0.695; 95% CI, 0.552-0.875 80 P = 0.00185 70 60 Radium-223, n = 541 % 50 Median OS: 14.0 months 40 30 20 Placebo, n = 268 Median OS: 11.2 months 10 0 Month 0 3 6 9 12 15 18 21 24 27Radium- 223 541 450 330 213 120 72 30 15 3 0 Placebo 268 218 147 89 49 28 15 7 3 0 Parker C . J Clin Oncol 30, 2012 (suppl; LBA 4512)
    33. 33. ALSYMPCA Time to First Skeletal-Related Event 100 90 HR 0.610; 95% CI, 0.461-0.807 80 P = 0.00046 70 % Without SRE Radium-223, n = 541 60 Median: 13.6 months 50 40 Placebo, n = 268 30 Median: 8.4 months 20 10 0 Month 0 3 6 9 12 15 18 21Radium-223 541 379 214 111 51 22 6 0 Placebo 268 159 74 30 15 7 2 0 Parker C . J Clin Oncol 30, 2012 (suppl; LBA 4512)
    34. 34. Agent/Trial/Year Disease State Comparator Hazard Ratio P ValueDocetaxel/Tax 327 Chemo naïve Mitoxantone/ 0.76 0.009(2004) mCRPC PrednisoneSipuleucel T/ Chemo naïve Placebo 0.775 0.032Impact ( 2010) mCRPCAbiraterone Cougar Chemo naïve Placebo/ 0.43 (PFS) < 0.0001301 (2012) mCRPC PrednisoneAbiraterone Cougar Post docetaxel Placebo/ 0.65 < 0.001302 (2010) mCRPC PrednisoneCabazitaxel Tropic Post docetaxel Mitoxantone/ 0.7 < 0.001(2010) mCRPC prednisoneRadium 223 Bone metastases Placebo + best 0.695 0.00185ALSYMPCA (2011) mCRPC supportive careMVD 3100 AFFIRM Post docetaxel Placebo 0.631 < 0.001(2012) mCRPC
    35. 35. Normalization of Bone Scan With XL-184 Docetaxel-pretreated (n=10) Baseline Week 12 Evidence of bone scan resolution (partial or complete) Yes Maximum tumor change, per mRECIST -41% Change in bone pain Improvement 1000 tALP 5000 800 PSA 400 tALP PSA Change in tALP 600 300 and PSA 400 200 200 100 0 0 Scr 0 5 10 15 20 Weeks on Study Maximum change in -88% plasma CTx Bone scans at baseline and during therapy with XL184 Best change in hemoglobin NE Smith et al. EORTC; 2010.
    36. 36. Clinical States In Prostate Cancer Sipuleucel-T Rad 223 Metastatic Disease Cabazitaxel Organ (De novo)Confined Metastases Metastases Metastases Metastases Castrate Castrate Rising PSA Castrate Castrate Resistant Resistant Hormone Resistant Resistant Post Docetaxel Post Asymptomatic Post Abiraterone Cabazitaxel Naive Symptomatic Locally Rising PSA Advanced Castrate Disease MDV-3100 Abiraterone Denosumab Zolendronic Acid Modified from Scher H, et al. Urology 2000
    37. 37. “Everyone has aphotographic memorySome just don’t have film” - Steven Wright

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