# Presentation: 182286

## Disease progression endpoints in hormone refractory prostate cancer: experience with the endothelin receptor antagonist, atrasentan

- Perry Nisen MD PhD
- Abbott Laboratories
- June 22nd 2004

## Advanced prostate cancer – key trial design questions to be addressed

- How do you define response and time to progression?
- Role of bone scan
- Role of PSA
- How do you deal with dropouts due to PSA?
- Are symptom endpoints useful?
- Is time to symptomatic progression a practical endpoint?
- Are composite endpoints useful (e.g. skeletal-related events)?

## Today’s presentation

- Endpoints for “cytostatic” vs “cytotoxic” drugs: primary endpoint choices in hormone refractory prostate cancer (HRPC)
- Time to progression (TTP) as a primary endpoint in atrasentan trials – why and how
- What we learned about
- composite endpoints
- bone scans
- PSA bias/dropouts
- biochemical markers of bone disease
- quality of life as a measure of symptomatic progression

## Cytostatic drugs are different

- Atrasentan is an oral, selective, endothelin A receptor antagonist
- Endothelin receptor inhibition monotherapy is cytostatic not cytotoxic
- Tumor shrinkage is not expected
- So how can atrasentan be developed and approved for treatment of HRPC patients?

## Designing a pivotal study for atrasentan in 2000

**Objective: demonstrate efficacy and safety of atrasentan in men with metastatic HRPC**
***Ingoing data:***
- Signal of delay in time to disease progression from phase 2 controlled study in men with asymptomatic, metastatic HRPC
- Positive effects upon PSA and biochemical markers of bone disease

## Three key constraints imposed

- Monotherapy study
- Best for evaluation of novel therapeutic
- Placebo-control arm needed
- Limited understanding of natural history of disease progression
- No approved therapeutic for HRPC at the time
- Necessitates open-label extension – obscures potential survival signal
- Do not expect patients and physicians to wait long for endpoints in placebo-controlled study if PSA is rising
- Alternatives exist: other trials, cytotoxic chemotherapy

## Three classes of primary endpoint to choose from

- Survival
- Symptoms (time to), or Quality of Life
- Time to Disease Progression (TTP)

## Constraints make TTP the only acceptable endpoint

- HRPC

- Death

- M+

- ChemoRx

- Window 3

- Window 2

- Window 1

- Pivotal study
**TTP endpoint**
- Progression = M+

**Pivotal study TTP endpoint**

**Survival endpoint**
- Very advanced patients, not optimizing utility of low toxicity oral drug

**Symptoms endpoint**
- PSA- and scan-driven dropout major concern

## How can disease progression be defined?

| Clinical | Radiographic | Biochemical |
| --- | --- | --- |
| Worse symptoms 
bone pain | Bone lesions dominate clinical picture
Quantification? | PSA
Not acceptable |
|  | Soft tissue lesions
 RECIST | Alkaline phosphatase (bone-specific)  |
|  |  | Hemoglobin |
|  |  | Lactate dehydrogenase |

- Prognostic, but not accepted surrogates

## The disease progression endpoint used in phase 3 atrasentan studies

- Disease progression has occurred when a patient achieves the first of:
***Radiographic progression***
- Bone scan showing 2 or more new skeletal lesions
- Extra-skeletal progression on CT or MRI scan using modified RECIST criteria*
***Clinical progression***
- Pain due to prostate cancer requiring escalated therapy
- Skeletal related event
- Event due to metastatic prostate cancer requiring intervention, e.g. malignant pleural effusion

- *Therasse et al (2000) JNCI 92:205-16

## How can bone scan progression be  reliably quantified?

- Count lesions
- More are bad
- Less may not be good (coalescence)
- Assign threshold for progression (≥2)
- Schedule assessments (Q3 month)
- Independent radiologists decide

## Clinical criteria need to be broad and pain from bone metastases is central

| Manifestation | Frequency* (%) |
| --- | --- |
| Bone pain | 85 |
| Bladder outlet obstruction | 17-72 |
| Ureteric obstruction | 2-51 |
| Spinal cord compression | 1-10 |
| Rectal obstruction | 10 |
| Coagulopathy | <10 |

**Clinical manifestations of advanced prostate cancer**:

- *Mercadante S et al (2000) J Pain Symptom Manage 20:27-34; Surya BV, Provet JA (1989) J Urol 142:921-8

## Bone pain escalates– hard endpoint threshold is needed

- Pain intensity

- No pain

- Pain requiring regular opioids

- Patient Baseline

- NSAIDs for bone pain

- Time

- Endpoint

- Patients here may achieve radiographic endpoint – pain data can be collected from QoL and AE data

- Lo

- Hi

## Abbott clinical progression criteria

***Clinical progression defined as:***
- Pain due to prostate cancer* requiring one or more palliative interventions:
- Opioids, glucocorticoids, radionuclides, radiation or chemotherapy
- Opioid use defined as single dose parenteral opioid or >10 of 14 consecutive days oral/transdermal therapy
- Skeletal related event*
- Non-traumatic fracture, cord compression or intervention for impending fracture
- Event due to metastatic prostate cancer* requiring intervention, e.g. urinary tract obstruction, brain metastases, malignant pleural effusion

- * Evidence of metastasis required at site

## Abbott process for endpoint adjudication

- Investigator

- Central radiology

- 1

- No progression seen – routine imaging

- Abbott

- 2

- Investigator sees progression – data packet sent in

- 3

- Abbott ensures packet complete

- Endpoint reviewer

- 4

- 5

- 6*

- * Endpoint confirmation/denial sent to investigator via Abbott

## Secondary and tertiary endpoints support individual elements of primary endpoint

**Primary endpoint element**

**Secondary/tertiary endpoint**

- Bone scan

- CT/MRI scan

- Pain

- Skeletal related event

- Intervention required

- PSA

- Alkaline phosphatase

- Quality of life

- (Survival)

- Study not powered to determine individual elements of composite endpoint significantly benefiting from drug therapy

## Pivotal study of atrasentan in asymptomatic, metastatic HRPC

- 809 men with M+ HRPC

- Randomize 1:1 to atrasentan 10mg QD PO or placebo

- Primary endpoint of time to disease progression

- Open-label extension for progressing patients

## Primary endpoint analysis (intent to treat)

- The “cliff”

## Decomposing the primary endpoint: bone scans and (bone) pain predominate

- 	177 	(43.4)

- 	181 	(45.1)

- Bone scan

- 	299 	(73.3)

- 	311	(77.6)

- Total

- 	9	(2.2)

- 	9	(2.2)

- Skeletal-related event

- 	9   	(2.2)

- 	48 	(11.7)

- 	56  	(13.7)

**Atrasentan 10 mg**
**n      (%)**

**Placebo**
**n       (%)**

**Progression event**

- 	68  	(17.0)

- Pain

- 	6	(1.5)

- Other metastasis-related event

- 	47  	(11.7)

- CT/MRI scan

## Biochemical endpoints demonstrate relevant biological activity 

**Mean change from baseline to final visit**

- -90

- -63.3

- -20.7

**Treatment difference**

- 0.001

- 13.2

- 33.9

- Bone ALP
- (ng/mL)

- 0.025

- 199

- 289

- PSA
- (ng/mL)

- 0.001

- 39.4

- 102.7

- Total ALP
- (IU/L)

***p***** value**
**(ANCOVA)**

**Atrasentan**

**Placebo**

**Variable**

- Is a PSA effect necessary but not sufficient for a drug treating prostate cancer to be approved?

## Endpoint takeaways

- Two or more new bone scan lesions appear very quickly, especially if extensive baseline bone disease
- Secondary and tertiary endpoints useful to support individual elements of composite endpoint
- Independent radiologists and separate oncology endpoint reviewers are critical, with clear hierarchy of which opinion counts

## Study conduct takeaways

- High level of diligence and planning required to conduct studies with composite endpoints, extensive radiological assessment, independent radiologists and independent endpoint reviewers
- Urologists are major recruiters of asymptomatic HRPC patients
- Global studies are feasible, although frequent isotopic bone scans present concern in some countries

## Key questions – some answers

| Question | Abbott Perspective |
| --- | --- |
| How can disease progression be defined? | TTP endpoint–clinical and radiographic criteria |
| How do you deal with dropouts from PSA? | Use definition of progression that pre-empts PSA-driven dropout but is still clinically meaningful
Keep patient on study assessment protocol, even if off study drug |
| Are symptom endpoints useful? | Not as primary endpoint for monotherapy study in patients prior to chemotherapy |
| Are composite endpoints useful? | Yes, but secondary/tertiary endpoints important for substantiation |