# Presentation: 894876

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

- Derek Raghavan MD PhD
*Cleveland Clinic Taussig Cancer Center*
*Cleveland, OH.*

-   PRESENTATION TO ODAC

## 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

## Slide 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

## 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

## 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

## 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

## 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?

## 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?

## Goals of Treatment vs. States

| Clinical State | Aim | Outcome |
| --- | --- | --- |
| No Cancer | Prevent Cancer | No cancer |
| Localized Disease | Delay recurrence
Maximize cure
Minimize toxicity | PSA level
 after surgery
 after radiotherapy
 |
| Rising PSA | Prevent clinical metastases | Absolute PSA level?
Altered kinetics? |

## Slide 11

## 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

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

- _PARAMETER_				      _Weeks_
- 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.

## 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

## (SWOG 9916)

## Slide 16

## (50% Decrease in PSA during first 3 months)

## Slide 18

## 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

## 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

## Patient Reporting Domains

- 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

## 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

## 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

## Chemotherapy for Prostate Cancer

- Impact of Patient-Reported
- Outcomes
- (usually added to hormone effects)

## Mitoxantrone Phase III Canadian Trial:  Study Design

- Symptomatic
- HRPC

**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:Overall Survival

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

## Mitoxantrone for Advanced Prostate Cancer: Quality of LIfe

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

## 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*

## 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)

## TAX 327:  Secondary Objectives Response Rates

|  | Docetaxel3 wkly | Docetaxel wkly |  Mitoxantrone  |
| --- | --- | --- | --- |
| Pain Response Rate* |  |  |  |
| 	 n, evaluable | 153 | 154 | 157 |
| 	 Response rate (%) | 35 | 31 | 22 |
| 	 P-value (vs. mitoxantrone) | 0.01 | 0.07 | - |
| PSA Response Rate* |  |  |  |
| 	 n, evaluable | 291 | 282 | 300 |
| 	 PSA response rate (%) | 45 | 48 | 32 |
| 	 P-value (vs. mitoxantrone) | 0.0005 | <0.0001 | - |
| Tumor Response Rate* |  |  |  |
| 	 n, evaluable | 141 | 134 | 137 |
| 	 Response rate (%) | 12 | 8 | 7 |
| 	 P-value (vs. mitoxantrone) | 0.1 | 0.5 | - |

**TAX 327:  Secondary Objectives ****Response Rates**

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

## 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

## 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)

## 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

## 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