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Towards a Consensus in Measuring Outcomes in New Agents for Prostate Cancer

PRESENTATION TO ODAC. Towards a Consensus in Measuring Outcomes in New Agents for Prostate Cancer. Derek Raghavan MD PhD Cleveland Clinic Taussig Cancer Center Cleveland, OH. Important Specific Issues for Prostate Cancer. Potentially long natural history – 10+ years Elderly patients

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Towards a Consensus in Measuring Outcomes in New Agents for Prostate Cancer

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  1. PRESENTATION TO ODAC Towards a Consensus in Measuring Outcomes in New Agents for Prostate Cancer Derek Raghavan MD PhD Cleveland Clinic Taussig Cancer Center Cleveland, OH.

  2. Important Specific Issues for Prostate Cancer • Potentially long natural history – 10+ years • Elderly patients • intercurrent disease • deaths from competing risks • Variable clinical manifestations – the “states” model • Advanced “conventional” disease – clinical metastases • Hormone treated – relapsed, resistant, refractory • New imaging techniques used more actively  earlier stage • PSA-only disease after treatment • Stage migration • Changes in imaging • PSA and other tumor markers • Quality of life measurement – new indices • Changing surrogate measures of outcome

  3. Important Specific Issues for Prostate Cancer • Potentially long natural history – 10+ years • Elderly patients • intercurrent disease • deaths from competing risks • Variable clinical manifestations – the “states” model • Advanced “conventional” disease – clinical metastases • Hormone treated – relapsed, resistant, refractory • New imaging techniques used more actively • PSA-only disease after treatment • Stage migration • Changes in imaging • PSA and other tumor markers • Quality of life measurement – new indices • Changing surrogate measures of outcome

  4. Brief Historical Perspective: 1 • 1900-1960’s • Animal models • Survival • Acid phosphatase • Huggins & Hodges  Nobel Prize: CAP & Castration • Human studies • Usually characterized by VERY advanced disease • Some imprecise endpoints – tried to assess response • Acid phosphatase • Survival

  5. Brief Historical Perspective: 2 • 1970’s-1990’s: • Refinement of assessment: • NPCP – “response” and “stable disease” • Earlier and more precise diagnosis • Evolving measures of quality of life • Introduction of concept of “PSA RESPONSE” • Development of PSA (TM Chu et al) • Stage migration • Education of the Public regarding treatment

  6. Brief History of FDA Approval of Agents for Prostate Cancer AGENT YEAR ENDPT. • Docetaxel 2004 survival • Zolidronic Acid 2003 QOL • Mitoxantrone 1996 QOL • Estramustine 1981 old rules

  7. Current Status • Impact of Community Pressure & Patient Advocacy • Stage Migration • New imaging – PET scans, tomographic scans • Super-sensitive assays of PSA, etc. • Refinement of “PSA response” • New Endpoints presented: • Refined measurement of quality of life • Absence of progression – the “static” agents • PSA and other antigens – time dependent fluxes • “Response” – PSA, symptoms, objective • Is survival still THE standard?

  8. KEY QUESTION FOR APPROVAL: Does New Therapy ALTER True Outcomes? • Is survival the “ultimate” test? • Confounded by death from other causes • Confounded by a series of “salvage” therapies • What about quality of life & toxicity of treatment? • Do surrogates reflect real changes in outcome? • Do measures of outcome change with the clinical states of the disease?

  9. Goals of Treatment vs. States

  10. Presentation of Advanced Prostate Cancer: Syndromes • Bone pain • Constitutional symptoms – the great mimic • Urinary obstruction • Slow stream, nocturia, frequency, hematuria • Acute/chronic renal failure • Bone marrow failure • Unusual sites – liver, lungs, nodes, skin • PSA only disease • “Imaging only” disease

  11. Hormone Refractory Prostate Cancer: Median Time from Progression to Death PARAMETERWeeks PSA increase 52 Bone scan change 41 Alkaline phos increase 35 Pain increase 32 Performance status decline 24 Hemoglobin decline 22 Weight loss 12 Liver metastases 10 Newling, et al. Cancer. 1993;72:3793-3798.

  12. Changing Endpoints in Prostate Cancer Therapy • Impact of stage migration • PSA only disease • Rising after radiotherapy or surgery • Asymptomatic disease with known metastases • New PSA targets – e.g. rate of rise or fall • Earlier intervention for +ve bone scans and refinement in measurement of changes in scans • Measurement of quality of life • Measurement of time to progression • Adjuvant trials

  13. (SWOG 9916)

  14. (50% Decrease in PSA during first 3 months)

  15. Changing Endpoints in Prostate Cancer Therapy • Impact of stage migration • PSA only disease • Rising after radiotherapy or surgery • Asymptomatic disease with known metastases • New PSA targets – e.g. rate of rise or fall • Earlier intervention for +ve bone scans and refinement in measurement of changes in scans • Measurement of quality of life • Measurement of time to progression • Adjuvant trials

  16. Measures of Quality of Life • Difficulty of assessing response within “stable” disease category • Use of patient reported symptom response widens the goalposts • Contrast: • symptoms of age • symptoms of cancer • side effects of therapy • Dichotomy between objective vs. subjective vs. PSA response • Optimal technology not defined

  17. Non-specific Fevers, sweats Pruritis Malaise Well-being Mood Activities Quality of life Sexuality Tumor-related Pain Weight Performance status Metastases Treatment-related Hormone effects RT effects Surgical effects Chemotherapy impact Patient Reporting Domains

  18. Examples of Patient Report Instruments • McGill Melzack – Present Pain Intensity • What is optimal measure of reduction? • Significance of 2 point reduction? • Impact of baseline severity? • EORTC QLQ 30 • EORTC Prostate Cancer Specific Module • PROSQOLI

  19. Methodological Problems • Impact of baseline variables – e.g. pain • How to score • Dealing with missing data • Statistical analysis • Area under curve • Kaplan Meier vs. Wilcoxson • ROC curves • Confounding variables • e.g. Patient knowledge of PSA fluxes – impact? • e.g. Race and socio-demographic factors

  20. Chemotherapy for Prostate Cancer Impact of Patient-Reported Outcomes (usually added to hormone effects)

  21. Mitoxantrone Phase III Canadian Trial: Study Design Mitoxantrone + Prednisone Prednisone* RANDOMIZE N=80 Primary Endpoint: Palliation Symptomatic HRPC N=81 *Crossover on progression (N=50) Tannock, et al. J Clin Oncol. 1996;14:1756-1764.

  22. Mitoxantrone for Advanced Prostate Cancer:Overall Survival Tannock et al, J. Clin. Oncol., 1996

  23. Mitoxantrone for Advanced Prostate Cancer: Quality of LIfe Tannock et al, J. Clin. Oncol., 1996

  24. PSA, Palliative Response & Survival(Dowling et al, Ann. Oncol., 2001, 12: 773-8) • Retrospective analysis of MP vs P trial • Cox proportional hazards model & landmark analysis at 9 weeks • Absence of PSA data = “non-responders” • 34% of M+P  PSA response • 11% of P  PSA response • 53% with PSA response  palliative response • 29% without PSA response  palliative response • Multivariate factors: PS, high Hb, PSA response • Palliative response did NOT predict survival

  25. Summary of Estramustine-Based Chemotherapy: Nonrandomized Trials Number PR/ Imp. Median Agents Combined Number N (%)  Pain Survival Study Phase with EMP N Measured 50% PSA  N (%) (Months) Amato II vinblastine 22 3/7 11/22 (50) — — Seidman II vinblastine 25 2/5 13/24 (54) 6/9 (66) — Hudes II vinblastine 36 1/7 11/36 (31) 12/28 (43) 11.5 Hudes I+II paclitaxel 38 6/12 19/35 (54) — 17 Petrylak I docetaxel 32 5/16 20/32 (63) 8/15 (53) — Amato, et al. Proc Am Assoc Cancer Res. 1999. Seidman, et al. J Urol. 1992;147:931-934. Hudes, et al. J Clin Oncol. 1992;10:1754-1761. Hudes, et al. J Clin Oncol. 1997;15:3156-3163. Petrylak, et al. Proc Am Soc Clin Oncol. 1997. (Courtesy of Maha Hussain, MD)

  26. TAX 327: Secondary Objectives Response Rates * Determined only for patients with pain or PSA 20 or measurable disease at baseline, respectively

  27. Taxotere-Calcitriol(Beer et al, J Clin Oncol, 2004, 100: 758-763) • Indices: • 2 point reduction on PPI (or 0 if PPI=1) • 50% reduction in analgesic use • Other measures of QOL • Analgesic response in 48% • BUT worse QOL on QLQ-C30QOL • Physical and role functioning • Fatigue • Appetite • Global health status

  28. Placebo Effects in Oncology(Chvetzoff & Tannock, JNCI, 2003, 95: 19-29) • Reviewed 37 placebo-controlled trials & 10 with best supportive care • Studies not all double blinded • Improved pain with placebo in 2/6 trials • (0%  21% of individual patients) • Improved appetite in 1/7 trials • (8%  27% of individual patients) • No improvement in weight with placebo • No improvement in QOL in 10 trials (assessed by pt’s) • No improvement in ECOG performance status in 9 trials (via MD’s)

  29. Patient Reports of Symptoms • Assessment of symptomatic response leads to stage/response migration – c.f. “objective” response • Measures of Quality of Life and Symptom Response still being developed and validated • PSA response vs. Symptom Response vs. Toxicity of Treatment  “disconnect” • Discordant QOL results – which should “dominate”? • Confounding symptoms: • Toxicity of treatment • Age-related disorders – BPH, arthritis, anemia • This area should be regarded as “work in progress” by FDA

  30. SUMMARY • Survival has been the standard • Surrogates under evaluation • Quality of Life and Patient Reporting • PSA response • PSA time dependent kinetics • Markers of bone turnover • New agents that cause cytostatic effects • Need for new parameters? • Are they really useful? • Definition of a “new era” – insufficient data in 2005

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