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

Prostate CancerProstate Cancer

Derek Raghavan MD PhDDerek Raghavan MD PhDCleveland Clinic Taussig Cancer CenterCleveland Clinic Taussig Cancer Center

Cleveland, OH.Cleveland, OH.

PRESENTATION TO ODAC

Important Specific Issues for Prostate CancerImportant Specific Issues for Prostate Cancer

Potentially long natural history – 10+ yearsPotentially long natural history – 10+ years Elderly patientsElderly patients

intercurrent disease intercurrent disease deaths from competing risksdeaths from competing risks

Variable clinical manifestations – the “states” modelVariable clinical manifestations – the “states” model Advanced “conventional” disease – clinical metastasesAdvanced “conventional” disease – clinical metastases Hormone treated – relapsed, resistant, refractoryHormone treated – relapsed, resistant, refractory New imaging techniques used more actively New imaging techniques used more actively earlier stage earlier stage PSA-only disease after treatmentPSA-only disease after treatment

Stage migrationStage migration Changes in imagingChanges in imaging PSA and other tumor markersPSA and other tumor markers Quality of life measurement – new indicesQuality of life measurement – new indices

Changing surrogate measures of outcomeChanging surrogate measures of outcome

ClinicallyLocalized

DiseaseRising PSA

ClinicalMetastases:

Castrate

ClinicalMetastases:Noncastrate

Initial ProstateEvaluation: No

Cancer Diagnosis

1. Assess and reassess for the presence of disease, or probability of a clinically significant event in a given time frame.

2. Treat to eliminate or, depending on probability, to prevent the occurrence of the event(s).

3. Defer treatment if probability is low.

Points of Intervention

CLINICAL STATES: A FRAMEWORK

Important Specific Issues for Prostate CancerImportant Specific Issues for Prostate Cancer

Potentially long natural history – 10+ yearsPotentially long natural history – 10+ years Elderly patientsElderly patients

intercurrent disease intercurrent disease deaths from competing risksdeaths from competing risks

Variable clinical manifestations – the “states” modelVariable clinical manifestations – the “states” model Advanced “conventional” disease – clinical metastasesAdvanced “conventional” disease – clinical metastases Hormone treated – relapsed, resistant, refractoryHormone treated – relapsed, resistant, refractory New imaging techniques used more activelyNew imaging techniques used more actively PSA-only disease after treatmentPSA-only disease after treatment

Stage migrationStage migration Changes in imagingChanges in imaging PSA and other tumor markersPSA and other tumor markers Quality of life measurement – new indicesQuality of life measurement – new indices

Changing surrogate measures of outcomeChanging surrogate measures of outcome

Brief Historical Perspective: 1Brief Historical Perspective: 1

1900-1960’s1900-1960’sAnimal modelsAnimal models

SurvivalSurvival Acid phosphataseAcid phosphatase Huggins & Hodges Huggins & Hodges Nobel Prize: CAP & Castration Nobel Prize: CAP & Castration

Human studiesHuman studies Usually characterized by VERY advanced diseaseUsually characterized by VERY advanced disease Some imprecise endpoints – tried to assess responseSome imprecise endpoints – tried to assess response Acid phosphataseAcid phosphatase SurvivalSurvival

Brief Historical Perspective: 2Brief Historical Perspective: 2

1970’s-1990’s:1970’s-1990’s:Refinement of assessment:Refinement of assessment:

NPCP – “response” and “stable disease”NPCP – “response” and “stable disease”Earlier and more precise diagnosisEarlier and more precise diagnosisEvolving measures of quality of lifeEvolving measures of quality of lifeIntroduction of concept of “PSA RESPONSE”Introduction of concept of “PSA RESPONSE”

Development of PSA Development of PSA (TM Chu (TM Chu et alet al))

Stage migrationStage migrationEducation of the Public regarding treatmentEducation of the Public regarding treatment

Brief History of FDA Approval of Agents Brief History of FDA Approval of Agents

for Prostate Cancerfor Prostate Cancer AGENTAGENT YEARYEAR ENDPT.ENDPT.

DocetaxelDocetaxel 20042004 survivalsurvivalZolidronic AcidZolidronic Acid 20032003 QOLQOLMitoxantroneMitoxantrone 19961996 QOLQOL

EstramustineEstramustine 19811981 old old rulesrules

Current StatusCurrent Status

Impact of Community Pressure & Patient AdvocacyImpact of Community Pressure & Patient Advocacy Stage MigrationStage Migration

New imaging – PET scans, tomographic scansNew imaging – PET scans, tomographic scans Super-sensitive assays of PSA, etc.Super-sensitive assays of PSA, etc. Refinement of “PSA response”Refinement of “PSA response”

New Endpoints presented:New Endpoints presented: Refined measurement of quality of lifeRefined measurement of quality of life Absence of progression – the “static” agentsAbsence of progression – the “static” agents PSA and other antigens – time dependent fluxesPSA and other antigens – time dependent fluxes

““Response” – PSA, symptoms, objectiveResponse” – PSA, symptoms, objective Is survival still THE standard?Is survival still THE standard?

KEY QUESTION FOR APPROVAL: KEY QUESTION FOR APPROVAL: Does New Therapy ALTER True Outcomes?Does New Therapy ALTER True Outcomes?

Is survival the “ultimate” test?Is survival the “ultimate” test? Confounded by death from other causesConfounded by death from other causes Confounded by a series of “salvage” therapiesConfounded by a series of “salvage” therapies

What about quality of life & toxicity of treatment?What about quality of life & toxicity of treatment? Do surrogates reflect real changes in outcome?Do surrogates reflect real changes in outcome? Do measures of outcome change with the Do measures of outcome change with the

clinical states of the disease?clinical states of the disease?

Goals of Treatment vs. StatesGoals of Treatment vs. States

Clinical StateClinical State AimAim OutcomeOutcome

No CancerNo Cancer Prevent CancerPrevent Cancer No cancerNo cancer

Localized DiseaseLocalized Disease Delay recurrenceDelay recurrence

Maximize cureMaximize cure

Minimize toxicityMinimize toxicity

PSA levelPSA level- after surgeryafter surgery

- after radiotherapyafter radiotherapy

Rising PSARising PSA Prevent clinical Prevent clinical metastasesmetastases

Absolute PSA level?Absolute PSA level?

Altered kinetics?Altered kinetics?

OBJECTIVES BY CLINICAL STATE

INITIAL EVALUATION:

NO CANCER DIAGNOSIS

LOCALIZEDDISEASE

CLINICAL METASTASES:

NON-CASTRATE

PREVENTION MINIMIZEMORBIDITY/MAXIMIZE

CURE

PREVENTMETASTASES

ELIMINATE /PREVENT

SYMPTOMS

DEATH OFDISEASE

RISINGPSA

CLINICAL METASTASES:

CASTRATE

Presentation of Advanced Prostate Presentation of Advanced Prostate Cancer: SyndromesCancer: Syndromes

Bone painBone painConstitutional symptoms – the great mimicConstitutional symptoms – the great mimicUrinary obstructionUrinary obstruction

Slow stream, nocturia, frequency, hematuriaSlow stream, nocturia, frequency, hematuriaAcute/chronic renal failureAcute/chronic renal failure

Bone marrow failureBone marrow failureUnusual sites – liver, lungs, nodes, skinUnusual sites – liver, lungs, nodes, skinPSA only diseasePSA only disease ““Imaging only” diseaseImaging only” disease

Hormone Refractory Prostate Cancer: Hormone Refractory Prostate Cancer: Median Time from Progression to DeathMedian Time from Progression to Death

PARAMETERPARAMETER WeeksWeeks

PSA increasePSA increase 5252

Bone scan changeBone scan change 4141

Alkaline phos increaseAlkaline phos increase 3535

Pain increasePain increase 3232

Performance status declinePerformance status decline 2424

Hemoglobin declineHemoglobin decline 2222

Weight lossWeight loss 1212

Liver metastasesLiver metastases 1010

Newling, et al. Cancer. 1993;72:3793-3798.

Changing Endpoints in Prostate Changing Endpoints in Prostate Cancer TherapyCancer Therapy

Impact of stage migrationImpact of stage migration PSA only diseasePSA only disease

Rising after radiotherapy or surgeryRising after radiotherapy or surgery Asymptomatic disease with known metastasesAsymptomatic disease with known metastases New PSA targets – e.g. rate of rise or fallNew PSA targets – e.g. rate of rise or fall

Earlier intervention for +ve bone scans and Earlier intervention for +ve bone scans and refinement in measurement of changes in scansrefinement in measurement of changes in scans

Measurement of quality of lifeMeasurement of quality of life Measurement of time to progressionMeasurement of time to progression Adjuvant trialsAdjuvant trials

0%

20%

40%

60%

80%

100%

0 12 24 36 48Months

D+EM+P

# at Risk338336

# of Deaths

217235

Medianin Months

1816

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

Overall Survival (SWOG 9916)

PSA Response Rate

50%

27%

0%

10%

20%

30%

40%

50%

Docetaxel/estramustinen = 303

Mitoxantrone/prednisonen = 303

% o

f p

atie

nts

wit

h a

>50

% d

ecre

ase

in P

SA

p < 0.0001

0%

20%

40%

60%

80%

100%

0 12 24 36 48Months After Registration

no 50% dec50% dec

At Risk291238

Deaths214130

Medianin Months

1421

P < .0001

Criterion 1b: Survival by Surrogate(50% Decrease in PSA during first 3 months)

0%

20%

40%

60%

80%

100%

0 12 24 36 48Months After Registration

D + E, no 50% decD + E, 50% decM + P, no 50% decM + P, 50% dec

At Risk9916219276

Deaths719114339

Medianin Months

15211421

P < .0001

Criterion 1c: Survival by Treatment and Surrogate

Changing Endpoints in Prostate Changing Endpoints in Prostate Cancer TherapyCancer Therapy

Impact of stage migrationImpact of stage migration PSA only diseasePSA only disease

Rising after radiotherapy or surgeryRising after radiotherapy or surgery Asymptomatic disease with known metastasesAsymptomatic disease with known metastases New PSA targets – e.g. rate of rise or fallNew PSA targets – e.g. rate of rise or fall

Earlier intervention for +ve bone scans and Earlier intervention for +ve bone scans and refinement in measurement of changes in scansrefinement in measurement of changes in scans

Measurement of quality of lifeMeasurement of quality of life Measurement of time to progressionMeasurement of time to progression Adjuvant trialsAdjuvant trials

Measures of Quality of LifeMeasures of Quality of Life

Difficulty of assessing response within “stable” Difficulty of assessing response within “stable” disease categorydisease category

Use of patient reported symptom response Use of patient reported symptom response widens the goalpostswidens the goalposts

Contrast:Contrast: symptoms of age symptoms of age symptoms of cancersymptoms of cancer side effects of therapyside effects of therapy

DichotomyDichotomy between between objectiveobjective vs. vs. subjectivesubjective vs. vs. PSA PSA responseresponse

Optimal technology not definedOptimal technology not defined

Patient Reporting DomainsPatient Reporting Domains

Non-specificNon-specific Fevers, sweatsFevers, sweats PruritisPruritis MalaiseMalaise

Well-beingWell-being MoodMood ActivitiesActivities Quality of lifeQuality of life SexualitySexuality

Tumor-relatedTumor-related PainPain WeightWeight Performance statusPerformance status MetastasesMetastases

Treatment-relatedTreatment-related Hormone effectsHormone effects RT effectsRT effects Surgical effectsSurgical effects Chemotherapy impactChemotherapy impact

Examples of Patient Report Examples of Patient Report InstrumentsInstruments

o McGill Melzack – Present Pain IntensityMcGill Melzack – Present Pain Intensityo What is optimal measure of reduction?What is optimal measure of reduction?o Significance of 2 point reduction?Significance of 2 point reduction?o Impact of baseline severity?Impact of baseline severity?

o EORTC QLQ 30EORTC QLQ 30o EORTC Prostate Cancer Specific ModuleEORTC Prostate Cancer Specific Moduleo PROSQOLIPROSQOLI

Methodological ProblemsMethodological Problems

Impact of baseline variables – e.g. painImpact of baseline variables – e.g. painHow to scoreHow to scoreDealing with missing dataDealing with missing dataStatistical analysisStatistical analysis

Area under curveArea under curveKaplan Meier vs. WilcoxsonKaplan Meier vs. WilcoxsonROC curvesROC curves

Confounding variablesConfounding variablese.g. Patient knowledge of PSA fluxes – impact?e.g. Patient knowledge of PSA fluxes – impact?e.g. Race and socio-demographic factorse.g. Race and socio-demographic factors

Chemotherapy for Prostate Chemotherapy for Prostate CancerCancer

Impact of Patient-ReportedImpact of Patient-Reported

OutcomesOutcomes(usually added to hormone effects)(usually added to hormone effects)

Mitoxantrone Phase III Mitoxantrone Phase III Canadian Trial: Study DesignCanadian Trial: Study Design

SymptomaticHRPC

RANDOMIZE

Mitoxantrone

+

Prednisone

Prednisone*

N=80

N=81

Primary Endpoint: Palliation

*Crossover on progression (N=50)

Tannock, et al. J Clin Oncol. 1996;14:1756-1764.

Mitoxantrone for Advanced Prostate Cancer:Mitoxantrone for Advanced Prostate Cancer:Overall SurvivalOverall Survival

Tannock et al, J. Clin. Oncol., 1996

Mitoxantrone for Advanced Prostate Mitoxantrone for Advanced Prostate Cancer: Quality of LIfeCancer: Quality of LIfe

Tannock et al, J. Clin. Oncol., 1996

PSA, Palliative Response & SurvivalPSA, Palliative Response & Survival(Dowling et al, (Dowling et al, Ann. OncolAnn. Oncol., 2001, 12: 773-8)., 2001, 12: 773-8)

Retrospective analysis of MP vs P trialRetrospective analysis of MP vs P trial Cox proportional hazards model & landmark analysis Cox proportional hazards model & landmark analysis

at 9 weeksat 9 weeks Absence of PSA data = “non-responders”Absence of PSA data = “non-responders” 34% of M+P 34% of M+P PSA response PSA response 11% of P 11% of P PSA response PSA response 53% with PSA response 53% with PSA response palliative response palliative response 29% without PSA response 29% without PSA response palliative response palliative response Multivariate factors: PS, high Hb, PSA responseMultivariate factors: PS, high Hb, PSA response Palliative response did NOT predict survivalPalliative response did NOT predict survival

Summary of Estramustine-Based Summary of Estramustine-Based Chemotherapy: Nonrandomized TrialsChemotherapy: Nonrandomized Trials

Number PR/ Imp. MedianAgents 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)

DocetaxelDocetaxel3 wkly3 wkly

Docetaxel Docetaxel wklywkly

Mitoxantrone Mitoxantrone

Pain Response Rate*Pain Response Rate*

n, evaluablen, evaluable 153153 154154 157157

Response rate (%)Response rate (%) 3535 3131 2222

P-value (vs. mitoxantrone)P-value (vs. mitoxantrone) 0.010.01 0.070.07 --

PSA Response Rate*PSA Response Rate*

n, evaluablen, evaluable 291291 282282 300300

PSA response rate (%)PSA response rate (%) 4545 4848 3232

P-value (vs. mitoxantrone)P-value (vs. mitoxantrone) 0.00050.0005 <0.0001<0.0001 --

Tumor Response Rate*Tumor Response Rate*

n, evaluablen, evaluable 141141 134134 137137

Response rate (%)Response rate (%) 1212 88 77

P-value (vs. mitoxantrone)P-value (vs. mitoxantrone) 0.10.1 0.50.5 --

TAX 327: Secondary Objectives TAX 327: Secondary Objectives Response RatesResponse Rates

* Determined only for patients with pain or PSA 20 or measurable disease at baseline, respectively

Taxotere-CalcitriolTaxotere-Calcitriol(Beer et al, J Clin Oncol, 2004, 100: 758-763)(Beer et al, J Clin Oncol, 2004, 100: 758-763)

Indices:Indices:2 point reduction on PPI (or 0 if PPI=1)2 point reduction on PPI (or 0 if PPI=1)50% reduction in analgesic use50% reduction in analgesic useOther measures of QOLOther measures of QOL

Analgesic response in 48%Analgesic response in 48%BUT worse QOL on QLQ-C30QOLBUT worse QOL on QLQ-C30QOL

Physical and role functioningPhysical and role functioning FatigueFatigue AppetiteAppetite Global health statusGlobal health status

Placebo Effects in OncologyPlacebo Effects in Oncology(Chvetzoff & Tannock, JNCI, 2003, 95: 19-29)(Chvetzoff & Tannock, JNCI, 2003, 95: 19-29)

Reviewed 37 placebo-controlled trials & 10 with best Reviewed 37 placebo-controlled trials & 10 with best supportive caresupportive care

Studies not all double blindedStudies not all double blinded Improved pain with placebo in 2/6 trialsImproved pain with placebo in 2/6 trials

(0% (0% 21% of individual patients) 21% of individual patients) Improved appetite in 1/7 trialsImproved appetite in 1/7 trials

(8% (8% 27% of individual patients) 27% of individual patients) No improvement in weight with placeboNo improvement in weight with placebo No improvement in QOL in 10 trials (assessed by pt’s)No improvement in QOL in 10 trials (assessed by pt’s) No improvement in ECOG performance status in 9 trials No improvement in ECOG performance status in 9 trials

(via MD’s)(via MD’s)

Patient Reports of SymptomsPatient Reports of Symptoms

Assessment of symptomatic response leads to Assessment of symptomatic response leads to stage/response migrationstage/response migration – c.f. “objective” response – c.f. “objective” response

Measures of Quality of Life and Symptom Response Measures of Quality of Life and Symptom Response still being developed and validatedstill being developed and validated

PSA response vs. Symptom Response vs. Toxicity of PSA response vs. Symptom Response vs. Toxicity of Treatment Treatment “disconnect” “disconnect”

Discordant QOL results – which should “dominate”?Discordant QOL results – which should “dominate”? Confounding symptoms:Confounding symptoms:

Toxicity of treatmentToxicity of treatment Age-related disorders – BPH, arthritis, anemiaAge-related disorders – BPH, arthritis, anemia

This area should be regarded as “work in progress” This area should be regarded as “work in progress” by FDAby FDA

SUMMARYSUMMARY

Survival has been the standardSurvival has been the standard Surrogates under evaluationSurrogates under evaluation

Quality of Life and Patient ReportingQuality of Life and Patient Reporting PSA responsePSA response PSA time dependent kineticsPSA time dependent kinetics Markers of bone turnoverMarkers of bone turnover

New agents that cause cytostatic effectsNew agents that cause cytostatic effects Need for new parameters?Need for new parameters? Are they really useful?Are they really useful?

Definition of a “new era” – insufficient data in Definition of a “new era” – insufficient data in 20052005