# Presentation: 876263

## Relevance of Prostate Cancer Clinical States to Endpoints andPSA Endpoint Application Methodologies For Prostate Cancer 

**Howard I. Scher, M.D.**

## Clinical Trials are ConductedWith Therapeutic Intent

- 1.		Therapeutic goals:		Objectives
- 2.		Patient population:  		Entry criteria
- 3.		Intervention:			Drug, device, procedure
- 4.		Outcome measures:		Endpoints.
- 5.		Conclusions:			Developmental sequence

## Prostate Cancer ManagementDiffers From That of Other Tumors

- Other Cancers
- Untreated history less protracted.
- Treatment is rarely deferred.
- Complete remission is goal.
- Comorbidities have less impact on mortality.

- Prostate Cancer
- Untreated history can span 10 years or more.
- Treatment often “deferred” at diagnosis, at recurrence, or at relapse
- Cancer “control” (slowing growth) may be same as  “cure”.
- Comorbidities produce a high risk of non-prostate cancer death.

## TNM Staging

- Characterizes disease at the time of diagnosis.
- 			Localized disease:  TNM (+PSA)
- 2.	Applies only to the untreated patient
- 3.	Does not inform trial designs for the patient who has failed.

## What is the “STAGE” of a patient with a detectable PSA after a radical prostatectomy?

- Illustrations of Limitations of Staging

## TNM Staging is Not Sufficient to Assess Disease: Why States are Needed

**TNM**
- Characterizes disease at the time of diagnosis
- Applies only to the untreated patient
- Does not inform trial designs for the patient who has failed.

**States**
- Describes patient(s) at any point in the disease **continuum.**
- Applicable to treated and untreated patients
- Provides the framework for **specific issues** and **questions** to be addressed

## Clinical States Describe the Disease Continuum

**Localized **
**Disease**

**Rising PSA**

**Clinical**
** ****Metastases:**
**Castrate**

**Clinical**
**Metastases:**
**Noncastrate**

**Initial Prostate**
**Evaluation: No**
**Cancer Diagnosis**

**Death From**
**Other Causes**

- Death Of
- Disease

**Clinical States Describe the Disease Continuum**
**For Untreated and Treated Patients**

- Urology 55:323, 2000

**         ****230,000       50,000                         29,900**

## Clinical States: A Framework to Determine Prognosis,

**Localized **
**Disease**

**Rising PSA**

**Clinical**
** ****Metastases:**
**Castrate**

**Clinical**
**Metastases:**
**Noncastrate**

**Initial Prostate**
**Evaluation: No**
**Cancer Diagnosis**

**Clinical States: A Framework to Determine Prognosis,**
**Define Therapeutic Objectives, and Assess Outcomes**

- 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_

## Drug Development As A Series of “Go–No Go” Decisions: Treatment Effects (RESPONSE) Can and Should be More Than Tumor Regression or a Decline in PSA

- Consider trials as a sequence:
- 		Phase I		Dose and schedule - PSA
- 		Phase IIa	Treatment effect
- 		Phase IIb	Duration of effect
- 		Phase III
- If endpoint is satisfied, what next?   Or,
- 	do the observed effects justify continuing?

## Prostate Cancer Clinical Trials: The Question Dictates The Outcomes

- What is the objective?  Why is it being offered or tested?
- What are the disease manifestations of the patient group (state) receiving it?
- What change in disease manifestations of the patient group (state) will be used to assess  treatment effects?
- How do we determine that it worked (clinical benefit)?

## OBJECTIVES BY CLINICAL STATE

**INITIAL **
**EVALUATION: NO CANCER DIAGNOSIS**

**LOCALIZED**
**DISEASE**

**CLINICAL METASTASES: **
**NON-CASTRATE**

**PREVENTION**

**MINIMIZE**
**MORBIDITY/**
**MAXIMIZE**
**CURE**

**PREVENT**
**METASTASES**

**        ****ELIMINATE /**
**      ****PREVENT **
**       ****SYMPTOMS**
**DEATH OF**
**  ****DISEASE**

**RISING**
**PSA**

**CLINICAL METASTASES: CASTRATE**

## Outcomes 

- 1.	Assessments should be quantitative and reproducible.
- 2.	A uniform set of ‘outcomes’ will not apply to all states:
- 			e.g.  	Rising PSA only vs.						Symptomatic castrate metastatic disease
- 3.	Any “treatment effect” (response) endpoint must be shown to reflect clinical benefit.
- 4.	Clinical benefit is best demonstrated in prospective randomized comparative trials.

## Questions / Outcomes by State (1) 

-    **State ****	****	**** Objective / Question    ****	****      Outcome / Endpoint**
**No Cancer Diagnosis          Prevent cancer****	****	****       No cancer (Pathology)**
**Localized Disease          ****	****  Maximize cure ****	****	****       PSA NMA (Surgery)**
**	****	****	****	****  ****/ minimize morbidity****	****       PSA <0.5 (RT)**
**	****	****	****	****	****	****	****       ****No cancer:  Pathology**
**Rising PSA:  Noncastrate Prevent metastases****	****       Change in PSA kinetics**
**	****	****	****	****  ****Eliminate Disease****	****	****Undetectable****	****	****	****	****	****	****      ****	****       No metastases****	****	****	****      ****	****	**

## Potential Manifestations That We Aimto Prevent with Treatment

- Recurrence.
- Regrowth in the prostate or prostate bed.
**PSA recurrence or elevations.**
- Nodal/visceral spread.
- Osseous spread.
- New or progressive symptoms.
- Death from disease.

- For a Patient in the State of a Rising PSA:  Preventing Clinical Metastases Prevents a “Transition” to Lethal Disease

***Pound et al. JAMA 281: 1592, 1999; updated 2003.**

**RRP**

**1997 pts**

**PSA**
**>0.2ng/ml**

**Distant**
**metastasis**

**Death**

**329 pts (16%) +14**

**2.3 yrs**

**Median 7.5 yrs**
**63%-5yrs**

**144 pts (44%) +31**

**Median 6.5 yrs**

## Probabilities Estimated with Prognostic Models or Nomograms: Metastasis-free Survival Following PSA Failure After Radical Surgery

- 		     Time to	    Doubling
- 	Grade    Recurrence      Time	3 Yr.	   5 Yr.	    7 Yr.
- 	5-7	      > 2 Yr.   	   >10 Mo.	  95%	    86%      82%
-    8-10 	      < 2 Yr.	         -	 	  53%	     31%     21%

- Pound et al. JAMA, 1999

## Questions / Outcomes by State (2)

-  **Clinical Metastases ****	****     Objective/Question    Outcomes/Endpoint**
**	****	****	****	****	**
- Non-Castrate		Eliminate; control; prevent	    Multiple
-  & Castrate		morbidity or death from cancer

## APPROVED Drugs for Clinical Metastases:  Castrate Disease:  A Range of Clinical Benefit Endpoints

**Relief of symptoms:**  	Androgen ablation, bisphosphonates,
- 				bone seeking 	radiopharmaceuticals,					Chemotherapy:   Mitoxantrone/prednisone
**      ****Delay/prevent****	****	**Bone seeking radioisotopes, bisphosphonates
**	**** ****symptoms**:		   (skeletal related events)
**Survival**:			Taxotere and prednisone
**Reduce toxicity**:		GnRH analogs/DES, Anti-androgens for flare
- 				Bicalutamide, Bisphosphonates bone loss
**    ****None approved solely for tumor regression or for “PSA”**

## Outcomes

- Must be considered on a state by state or question by question basis.
- The outcome for each disease manifestation should be reported separately.
- 3.	Include both the **proportion** of patients showing the outcome (degree and proportion), as well as the **durability.**
- 4.	Avoid global categorizations such as **CR, PR **or** Stable** disease that vary by disease manifestation and by disease state.

## Relevance of Prostate Cancer Clinical States to Endpoints andPSA Endpoint Application Methodologies Prostate Cancer 

## Prostate Specific Antigen

- 1.	Secreted “only” by the prostate.
- 2.	Serine protease that functions to lyse seminal coagulum.
- 3.	Can stimulate tumor growth by activating growth factors.
- 4.	**Clinical applications**:
**	****	****	****	**Early detection and diagnosis.
- 				Staging.
- 				Prognosis.
- 				**Monitor disease.**
**	****	****	****	****Outcomes.**

## PSA Based Outcomes And Endpoints

- Originally proposed because of difficulties assessing outcomes in bone.
- Determinations are reproducible and quantitative.
- Rising values precede other manifestations of progression across the spectrum of disease.
- Allows more patients to be enrolled on trials – not just those with “measurable disease”.
- Early “read out” may accelerate development of promising agents; and discontinuation of inactive ones.

## PSA Change as an Intermediate Endpoint:

- The Central Question

## PSA Based Outcomes And Endpoints

- 1.	Different decision rules needed for trials in different states.
- 2.	Different decision rules needed for drugs with different mechanisms of action.
- 3.	A decision rule is not a stand-alone criterion:  all manifestations of disease must be monitored.
- 4.	The relevance of a “PSA response” is questioned; more important is whether the observed pattern of change - **decline, normalization, disappearance, or modulation in rate of rise,** translates into clinical benefit.

## PSA Based Outcomes For Rising PSA

## Does This Treatment “Work”Mean Change in PSA from Baseline (ng/ml)

**Group****	****   Placebo (n)****	****Therapy (n)   p=**
- Overall		1.78 (49)	1.17 (47)	.0166
- High Risk		3.10 (6)	1.115 (9)	.0003
- Interm. Risk		2.23 (21)	1.47 (14)	.1260
- Low Risk		0.65 (17)	0.82 (18)	ns

**AUA 163:159,  2000**** **

- There is a difference, but values are still rising.

## Post-Therapy PSA Patterns

- Start of Therapy

- Lead In          Post-therapy

- No effect

- Broken Arrow

- Delayed effect

- Rapid decline

## Hormone or Cytotoxic Agent

**Lead In**

**Start Therapy**

**Post-therapy Observation**

**Hormone or Cytotoxic Agent**

## Cytostatic Drug:  Signaling Inhibitor

**Lead In**

**Start Therapy**

**Post-therapy Observation**

**Cytostatic Drug:  Signaling Inhibitor**

## Antimetastatic Agent or Immune Approach

**Lead In**

**Start Therapy**

**Post-therapy Observation**

**Broken Arrow**

**Antimetastatic Agent or Immune Approach**

## Differentiating Agent

**Lead In**

**Start Therapy**

**Post-therapy Observation**

**Differentiating Agent**

## PSA Endpoints for the STATE of A Rising PSA

**Rate of rise (doubling time) is used to assess prognosis.**
**Treated patients should have a high risk of metastases or death from disease. **
**Outcomes variable:****	****	****Slope**
**	****	****	****	****	****	****Change in rate of rise**
**	****	****	****	****	****	****Decline**
**	****	****	****	****	****	****Undetectable**
**4.****	****Post-therapy parameter must be validated for a change in time to metastases or death from disease.**

## Different Definitions of PSA ProgressionAffect Duration of Effect

- JCO, 2004

## Determining “Failure” or “Progression”Is More Difficult if there is No Decline

## Eligibility and Outcomes Reporting Guidelines for Clinical Trials for Patients in the State of a Rising PSA: Recommendations from the Prostate-Specific Antigen Working Group

- 		Howard I. Scher, Mario Eisenberger, Anthony V. D’Amico, Susan Halabi, Eric J. Small,  Michael Morris, Michael W. Kattan, Mack Roach, Philip Kantoff, Kenneth J. Pienta, Michael A. Carducci, Susan F. Slovin, Glenn Heller, Wm Kevin Kelly, Paul H. Lange, Daniel Petrylak, William Berg, George Wilding,  Judd W. Moul, Alan N, Partin, Christopher Logothetis, Howard R. Soule
- 		Memorial Sloan-Kettering Cancer Center, New York, NY; Brigham Women’s Hospital, Boston, MA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; University of California San Francisco, San Francisco, CA; Duke University, Durham, NC; Dana Farber Cancer Institute, Boston, MA; University of Michigan, Ann Arbor, MI, Columbia Presbyterian Medical Center, New York, NY; University of Washington, Seattle, WA; Aventis Pharmaceuticals, Bridgewater, NJ; University of Wisconsin Comprehensive Cancer Center,  Madison, WI; Uniformed Services University, Rockville, MD; The Johns Hopkins Hospital, Baltimore, MD; (ANP); M.D. Anderson Cancer Center, Houston Texas; Prostate Cancer Foundation (CaP CURE), Santa Monica, CA;
- 		Additional participants are listed in Appendix B
**JCO, February, 2004**

## Clinical Metastases:  Castrate

## Clinical Metastases:  Castrate Disease 

- Kelly et al., JCO, 1993

- Clinical Metastases:  Castrate Disease
- Post-therapy PSA Change and Survival:
- Landmark Analysis with Independent Data Set

- Scher et al., JNCI, 1999

- >**50% Decline and No 50% Decline**

- No Change vs. Rise

**No rise and Any rise at 12 weeks**

## Prognostic Significance Explored in A Multivariate Model for Survival:  MSKCC

- Variables	Parameter	Risk Ratio (95% CI)	p value
- PSA Decline  in 12 weeks
- No decline	    0.83		2.31  	(1.39-3.81)	0.0012
- LDH Baseline	    0.003	1.003 	(1.001-1.004)	0.0001
- HGB Baseline	   -0.19		0.82  	(0.75 -0.90)	0.0001
- Age		   -0.02		0.97  	(0.96-0.99)	0.043

- JNCI, 1999

## 1.	Surrogacy could not be established:  the 	comparative trial did not show survival benefit. 2.	Two taxotere based trials did show a survival 	benefit in comparison to mitoxantrone/prednisone.

- Post-Therapy PSA Decline in Castrate Metastatic Disease

## Association Between Time Dependent PSA Levels and Relative Risk of Death

- Verbel et al., Clin. Cancer Res, 2002.

## Strength of Association (R2)

- 	MSKCC					17%
- A significant proportion remains unexplained simply on basis of PSA.

- Verbel et al., Clin Cancer Res, 2002

## PSA Changes Are Not Stand Alone Criterion:

**Lead In**

**Start Therapy**

**Post-therapy Observation**

**No effect**

- A Continued Rise Does Not Exclude Clinical Benefit:
-  Anti-metastatic or Anti-Angiogenic Drugs

## Clinical Event at Fixed Time Point

- 1.	  More precise estimation of treatment effects.
- 2.	  Applicable to agents of diverse mechanisms.
- 3.	  Circumvents the need for surrogates that have not     	been validated.

## 

- *0

- Sufficient Level
- of Activity

- Insufficient Level
- of Activity

- [                                          ]
- 95% LCL                      95% UCL

- (A)

- (B)

- The Phase II/III Transition:
- Focus on **Durability** of Effect and Not **Just the Rate:**
**Clinical Event at a Fixed Time Point**

- (shifts right)

-    [                     ]
- 95% LCL    95% UCL

- Trial accrual:
-      Small
-      Large

- Fazzari, Cont Clin Trials, 2000

## Reducing the Impact of The Cancer In Bone:Clinical Metastases Castrate DiseaseStandard Therapy +/- Zoledronate

- 					Zoledronate       Placebo
- Skeletal Related		       33%                44%      p=.021
-     Events at 15 months
- Time to SRE		      	       NYR              321 d     p=.011
**PSA Progression****	****	****      No difference**
- Survival			      Trend	  	        p=.091

## PSA CHANGE:  PATIENT CARE,
CLINICAL RESEARCH, AND DRUG APPROVAL

Has a post-therapy PSA kinetics endpoint circumvented the difficulties assessing “outcomes” in this disease?

2.	Can and should we assess efficacy solely on the basis of early PSA changes?

3.	Should we abandon other outcome measures?

**CLINICAL RESEARCH, AND DRUG APPROVAL**
- Has a **post-therapy PSA kinetics** endpoint **circumvented** the difficulties assessing “outcomes” in this disease?
- 2.	Can and should we assess efficacy solely on the basis of early PSA changes?
- 3.	Should we abandon other outcome measures?