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ASCO Update 2004: Focus on Prostate and Renal Cell Cancers Primo N. Lara, Jr., MD

ASCO Update 2004: Focus on Prostate and Renal Cell Cancers Primo N. Lara, Jr., MD Associate Professor University of California Davis Cancer Center. Development of Hormonal Escape. Androgen-independent cells take over. Deprive androgen. Responsive. Cell numbers. Dependent. Independent.

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ASCO Update 2004: Focus on Prostate and Renal Cell Cancers Primo N. Lara, Jr., MD

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  1. ASCO Update 2004:Focus on Prostate and Renal Cell Cancers Primo N. Lara, Jr., MD Associate Professor University of California Davis Cancer Center

  2. Development of Hormonal Escape Androgen-independentcells take over Depriveandrogen Responsive Cell numbers Dependent Independent Time Prostate Cancer. London, England: Times Mirror International Publishers Ltd;1996:143.

  3. Hormone Refractory Prostate Canceraka Androgen Independent Disease • Practical definition: consecutive series of increasing PSA levels after a nadir is reached with hormone therapy • Must have had a trial of anti-androgen withdrawal • 10-30% of patients will have a PSA response • Must have castrate levels of testosterone

  4. Current Status 2004:Hormone Refractory Prostate Cancer • Benchmark median survival = 18 months • Prognostic factors can predict response and survival independent of therapy received • Survival and quality of life are most important outcome measures

  5. Current Status 2004:Hormone Refractory Prostate Cancer • Chemotherapy results in prolongation of life, symptom control, and enhanced quality of life • Second-line hormonal therapies are generally ineffective • Novel molecular targeted therapies are now being integrated into treatment strategies

  6. Treatment Goals in HRPC Biochemical (PSA-only) disease Metastatic disease: Asymptomatic • Prolong life • Prevent morbidity: skeletal-related events, pain Metastatic disease: Symptomatic • Palliate symptoms • Enhance quality of life • Prolong life

  7. Prognostic factors in HRPC • PSA-related variables • Doubling time • Ratio of pre- and post-treatment slopes • PSA velocity • Prior prostatectomy • Performance status • Gleason score • LDH • Alkaline phosphatase • Hemoglobin • Presence of Visceral Disease

  8. PSA-related variables as prognostic indicators in HRPC • Doubling time • PSADT < 4 months MST = 445 days • PSADT > 4 months MST = 746 days (p<0.001) • Pre-post treatment PSA ratios • Ratio –0.8 to –0.3 Hazard Ratio (survival) = 0.7 • Ratio > -0.3 Hazard Ratio = 1.0 (p=0.09) • PSA velocity • Measured within first 3 months of chemotherapy • Hazard ratio for death = 3.56 (p < 0.0001) for each unit increase of PSA velocity ASCO 2004: Nelson #4554, D’Amico #4506, Crawford #4505

  9. Prognostic Variables for HRPC: CALGB Database Halabi, JCO 2003

  10. Survival Distributions: CALGB Prognostic Model Q1: 7.5months Q2: 13.4 months Q3: 18.9 monthsQ4: 27.2 months

  11. Current Treatment Options: HRPC • Supportive Care • Radioisotopes and Palliative radiation • Second line hormonal therapy • Cytotoxic chemotherapy • Investigational approaches

  12. Cytotoxic Chemotherapy in HRPC: Active Agents • Cyclophosphamide • Anthracyclines (e.g., mitoxantrone) • Antimicrotubule agents • Estramustine phosphate • Taxanes: docetaxel, paclitaxel • Vinca alkaloids: vinblastine

  13. Randomized Trials of Mitoxantrone + Steroid vs. Steroid Alone in HRPC

  14. Randomized Phase II Trial of Docetaxel/Estramustine/Prednisone vs. Mitoxantrone/Prednisone Oudard, pASCO 2003 #706

  15. Randomized Phase II Trial of Docetaxel/Estramustine/Prednisone vs. Mitoxantrone/Prednisone Oudard, pASCO 2003 #706

  16. A multicenter comparison of docetaxel given weekly or every three weeks + prednisone with mitoxantrone + prednisone in patients with hormone-refractory prostate cancer:Study TAX-327 Ronald De Wit M.D. PhD Mario A.Eisenberger M.D. Ian Tannock M.D. PhD and TAX-327 investigators ASCO 2004 Abstract #4

  17. TAX327 Study Design Docetaxel 75 mg/m2 Q3 wks + Prednisone 5 mg bid Stratification: Pain level PPI ≥ 2 or AS ≥ 10 vs. PPI < 2 or AS < 10 KPS ≤70 vs. ≥ 80 R A N D O M I Z E Docetaxel 30 mg/m2 wkly 5 of 6 wks + Prednisone 5 mg bid Mitoxantrone 12 mg/m2 Q3 wks + Prednisone 5 mg bid Premedication: weekly docetaxel arm-dexamethasone 8 mg 1 hr prior to infusion; q3week docetaxel arm: dexamethasone 8 mg 12, 3, and 1 hour prior to infusion Treatment duration in all 3 arms = 30 weeks

  18. Grade 3-4 Hematologic Toxicity (%)

  19. Non-hematological Toxicity(%) Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Toxicity All grades3/4 All grades 3/4 All grades 3/4 Alopecia 65 NA 50 NA 13 NA Fatigue 53 4.5 49 5.5 35 5.1 Nausea 41 2.7 36 2.4 36 1.5 Diarrhea 32 2.1 344.8 10 1.2 Neuro-Sensory 30 1.8 24 0.9 7 0.3 37 NA 7 NA Nail change 30 NA Constipation 25 2.1 17 1.5 17 0.6 * NA = not applicable

  20. Overall Survival 1.0 Docetaxel 3 wkly 0.9 Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 Probability of Surviving 0.5 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–– 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Months

  21. Overall Survival 1.0 Docetaxel 3 wkly 0.9 Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 Probability of Surviving 0.5 Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4–– 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Months

  22. Quality of Life Response> 16 points FACT-P score compared to baseline *Compared to mitoxantrone

  23. ASCO 2004 Abstract #3 Docetaxel and Estramustine versus Mitoxantrone and Prednisone in Men with Androgen Independent Prostate Cancer: Results of Southwest Oncology Group Intergroup Protocol 99-16 Daniel P. Petrylak, M.D.1, Catherine M. Tangen, Dr.PH.2, Maha A. Hussain, M.D.3, Primo N. Lara Jr., M.D.4, Jeffrey A. Jones, M.D.5, Mary Ellen Taplin, M.D.6, Patrick A. Burch, M.D.7, Graham F. Greene, M.D.8, Mitchell C. Benson, M.D.,1 Eric J. Small, M.D.9, Derek Raghavan, M.D., Ph.D,10 E. David Crawford, M.D.11 1Columbia University, New York, NY 2Southwest Oncology Group Statistical Center, Seattle, WA 3University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 4University of California, Davis, Sacramento, CA 5Baylor College of Medicine, Houston, TX 6University of Massachusetts Medical Center, Worcester, MA 7Mayo Clinic, Rochester, MN 8University of Arkansas for Medical Science, Little Rock, AR 9University of California San Francisco Cancer Center, San Francisco, CA 10Cleveland Clinic Foundation, Cleveland, OH 11University of Colorado Health Science Center, Denver, CO

  24. Schema: S9916 D/E* Docetaxel 60 mg/m2 IV D2 every 21 days Estramustine 280 mg po TID, D1-5 Premedication: Dexamethasone 20 mg PO TID starting evening of D1 R Patient Stratification: Type of progression (progression of measurable or evaluable disease vs. increasing PSA only; NCI CTC pain scale grade < 2 vs > 2; SWOG PS status 0-1 vs 2-3 M/P Mitoxantrone 12 mg/m2 IV every 21 days Prednisone 5 mg po BID continuously *Per protocol amendment January 15, 2001: Coumadin 2 mg PO daily + ASA 325 mg PO daily was added Docetaxel and mitoxantrone doses could be increased to 70 mg/m2 and 14 mg/m2, respectively, if no grade 3 or 4 toxicities were seen in cycle 1

  25. 20 18 16 14 12 D/E 10 M/P 8 6 4 2 0 Pain Neurologic Metabolic Infection Hematologic GI Flu-like symptoms Cardiovascular Grade > 3 toxicity % of patients - there was no difference in toxic deaths between treatment arms

  26. PSA Response Rate p < 0.0001 50% 40% 50% 30% % of patients with a > 50% decrease in PSA 20% 27% 10% 0% Docetaxel/estramustine n = 303 Mitoxantrone/prednisone n = 303

  27. Progression Free Survival Stratified by Treatment Arm # at Risk # of Events 100% Median in Months D+E 324 297 6 80% M+P 324 300 3 HR: 0.73 (95% CI 0.63, 0.86), p < 0.0001 60% 40% 20% 0% 0 12 24 36 48 Months

  28. 100% 80% 60% 40% 20% 0% 0 12 24 36 48 Months Overall Survival # at Risk # of Deaths Median in Months D+E 338 217 18 M+P 336 235 16 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

  29. Conclusions: TAX 327 & SWOG 9916 • Docetaxel-based chemotherapy improves • Overall survival • Progression-free survival • Quality of life (Tax 327) • Contribution of estramustine is questionable • Reference standard for future studies in metastatic HRPC should be docetaxel

  30. Bortezomib Bortezomib and Proteasome Inhibition 26S Proteasome b1 b2 Post- GlutamylSite TrypticSite 19SCap b7 b3   20SSubunit b6 b4 19SCap Chymo- trypticSite b5 • Degrades ubiquitinated proteins • Proteolysis is ATP-dependent • Chymotryptic site is rate-limiting in protein degradation J Bio Chem. 1999; 274(32): 22123-22126; Science. 1995; 268(5210) 579-582; Bioorg Med Chem Lett. 1998; 8(4): 333-338.

  31. Bortezomib in Combination with Docetaxel • In vitro • Showed additive growth inhibition and apoptosis in LNCaP and PC-3 prostate cancer cells • In vivo • In pancreatic xenograft models, bortezomib + docetaxel demonstrated enhanced: • Reduction of tumor mass • p21 accumulation • Inhibition of tumor cell proliferation • Increased apoptosis • Reduced tumor microvessel density

  32. ASCO 2004, Abstract #4654 Phase I/II Trial of Bortezomib Plus Docetaxel in Patients With Advanced Androgen-Independent Prostate Cancer R. Dreicer,1 B. Roth,2 D. Petrylak,3 D. Agus,4 M. Meyers,5 D. Esseltine,6 D. Rodriguez,6 P. Oppedisano,6 K. Wang,6 A. Boral61Cleveland Clinic Foundation, Cleveland, OH; 2Vanderbilt-Ingram Cancer Center, Nashville, TN; 3Columbia University, New York, NY; 4Cedars-Sinai Prostate Cancer Center, Los Angeles, CA; 5Aventis Oncology, Bridgewater, NJ; 6Millennium Pharmaceuticals, Cambridge, MA

  33. Treatment Schedule D B D B Rest • Docetaxel 1x/wk (days 1 and 8), bortezomib 1x/wk (days 2 and 9) every 21 days • 24 hours between docetaxel and bortezomib • Dexamethasone 8 mg night before, morning of, and evening after each docetaxel infusion 1 Cycle Day 1 2 8 9 21 D = docetaxel B = bortezomib Dreicer et al, ASCO 2004 Abstract 4654

  34. Results From Phase I: Dose-Escalation Summary • No DLTs have been reported • MTD not reached • Cohort 4 (40 mg/m2 docetaxel + 1.3 mg/m2 bortezomib) expanded to further assess safety, tolerability, and efficacy • Data on phase II assessment of cohort 4 to be presented (N = 32) Dreicer et al, ASCO 2004 Abstract 4654

  35. Conclusions: Bortezomib + Docetaxel • Combination bortezomib and docetaxel at doses below MTD demonstrated promising activity • PR rate 23% • PSA decrease by ≥ 50% confirmed in 24% of patients • All measurable tumor responses and the majority of PSA responses were observed in patients who received prior chemotherapy • Measurable tumor response was observed in 1 patient who had received prior taxane therapy • Combination of docetaxel and bortezomib was well tolerated at doses assessed; adverse events were primarily low grade and manageable Dreicer et al, ASCO 2004 Abstract 4654

  36. A Phase II Trial of Epothilone-B Analogue BMS-247550 (NSC #710428) Administered Every 21 Days in Patients with Hormone Refractory Prostate Cancer: Southwest Oncology Group Study S0111 M. Hussain, J. Faulkner, U. Vaishampayan, P. Lara, D. Petrylak, D. Colevas, W. Sakr, E.D. Crawford ASCO 2004 Abstract # 5410

  37. SWOG- 0111Rationale • Epothilone-B Analogue BMS-247550: • New class of non-taxane tubulin polymerizing agents resulting in mitotic arrest at G2/M transition. • High level of anti-tumor activity against in-vitro and in-vivo tumor models that are naturally resistant or acquired resistance to paclitaxel. • More potent than paclitaxel in tumor models. • Taxanes have demonstrated activity in patients with hormone refractory prostate cancer.

  38. SWOG- 0111Treatment Plan Registration • Premedication: 1hr prior to BMS-247550: Diphenhydramine 50 mg PO Ranitidine 150 mg PO • BMS-247550: 40 mg/m2 IV over 3hrs Q 21 days. • PSA was monitored prior to each course. • Objective response was assessed after every 2 courses

  39. SWOG- 0111PSA Response Confirmed PSA response = 34% (95% CI: 20% to 51%)

  40. SWOG- 0111Conclusions • In a cooperative group setting single agent Epothilone-B analogue (BMS-247550) is active in patients with metastatic hormone refractory prostate cancer. • The most frequent high grade toxicities were hematologic and neurotoxicities. • There were no G5 toxicities • 31% of patient were removed from study due to toxicity. • Measures to counteract the neuropathy effects are needed. • Further studies are warranted to define this agent’s activity: • in first line treatment relative to standard therapy. • in the second line setting.

  41. SUMMARY: HRPC • HRPC is a virulent, incurable disease • Aggressive palliative care must be pursued in the absence of cure • Although docetaxel-based chemotherapy can now be considered standard treatment for metastatic HRPC, the results remain suboptimal • Whenever possible, the “standard of care” for HRPC should still be clinical trial participation

  42. Renal Cell Carcinoma 2004 • ~32,000 new cases; ~12,000 deaths • Five year survival rate for metastatic disease is 0-10% • Immunotherapy with interleukin-2 or interferon-alfa has generally yielded modest clinical benefits • New agents with unique mechanisms of action are needed Image from urotext.com

  43. ECOG 3898: Low Dose Interferon +/- Thalidomide in Advanced RCCGordon, et al. ASCO 2004, Abstract 4516 RANDOMIZE Interferon alfa 2B 1M units SQ BID N=353 Metastatic or locally advanced RCC PS 0-2 (84% power to detect a 50% increase in MST from 12 to 18 months) Interferon alfa 2B 1M units SQ BID Thalidomide 200 mg q HS (escalated to max of 1 g)

  44. From: Kaelin, ASCO 2004

  45. From: Kaelin, ASCO 2004

  46. #4502

  47. Bevacizumab + Erlotinib in RCC Hainsworth, et al ASCO 2004

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