Initial Androgen Treatment for Progressive, Metastatic or Recurrent Prostate Cancer

Andrew Loblaw BSc, MD, MSc, FRCPC, CIPDepartment of Radiation OncologySunnybrook Health Sciences Centre

January 28, 2011

Objectives

1. To review the standard initial hormonal interventions for prostate cancer

2. To discuss the evidence behind the use of AA monotherapy

3. To review the published literature on the benefit of combined androgen blockade

4. To review emerging evidence on the benefit of bicalutamide CAB for prostate cancer

5. To review the evidence behind the timing of ADT6. To review the pros/cons of intermittent

androgen blockade

Standard ADT

Standard ADT*

Seidenfeld J Ann Int Med 2002; 132(7):566-77

(aberelix)

***

*

Combined Androgen Blockade

PCTCGIndiv Pt DataMeta-Analysis

8275 men, 27 trials88% D2

Overall Death Rate70.4 vs 72.4%ARR 2%

NSAA Death Rate72.4 vs 75.3%ARR 2.9%(p<0.005)

PCTCG. Lancet 2000;355:1491-8

Schmitt et al Meta-Analysis

• 20 RCTs, 6320 men with prostate cancer

• Efficacy• 2 y OS: OR 1.16 (95% CI 1.00 – 1.33)• 5 y OS: OR 1.29 (95% CI 1.11 – 1.50)

• Toxicity • diarrhea (10% v 2%)• gastrointestinal pain (7% v 2%)• non-specific ophthalmologic events (29% v 5%)

Schmitt et al Urology 57:727-32, 2001

Anti-androgen Use Today

• Steroidal Antiandrogens• Ketoconazole• Cyproterone acetate• Non-steroidal Antiandrogens• Flutamide• Nilutamide• Bicalutamide

CCO MAB Guideline

SideEffects

Patient Decision Making

n = 10 men with prostate cancer on RT

“What potential survival advantage (at 5 years) would you expect to justify these additional side effects and the inconvenience of taking a daily pill”

1 (10%) < 1 % survival benefit at 5 y

5 (50%) 1-5% survival benefit at 5 y

3 (30%) 5-10% survival benefit at 5 y

1 (10%) 10-15% survival benefit at 5 y

New Data

• Klotz et al.• Combined data from PCTCG and Schellhammer’s

RCT of bicalutamide + LHRH vs flutamide + LHRH– Same methods used to get FDA approval of capecitabine

in colon CA

RHR = HR (PCTCG) * HR (Schell)= HR(flut vs castration) * HR (bical vs flut)= HR (bical vs castration)= .80 (95% CI 0.66 - 0.98)

Klotz L, Schellhammer P. Clin Prostate Cancer. 2005 Mar;3(4):215-9.

Docetaxel for HR Prostate Cancer

Tannock NEJM 2004 Petrylak NEJM 2004

HR 0.76 HR 0.80

16.5 mo

18.9 mo

Relative Benefit vs Accepted Treatments

Potential benefit of bicalutamide CAB• Pound Series 5 year median survival from

diagnosis of metastatic disease• Bicalutamide CAB would increase median

OS 1.25y over castrate therapies alone (with HR 0.80)

Potential Costs• CAB pack $(3900) per 6 months• Docetaxel $20 000 per 6 months

ASCO 2006 Update

An interim analysis of an RCT2 and a study that combined

data from an individual patient data metaanalysis and a

randomized active control study,3 were published since the

last guideline. Overall survival is greater with the addition of

an NSAA to medical or surgical castration, but increased

adverse effects may occur as a result.

Loblaw DA et al., JCO April 2007

Akaza update• Double-blind RCT, N=205, 40% D2• CAB vs LHRHa (or CAB at progression)• Median F/U 5.2y

HR 0.78 (0.60 – 0.99)p=0.0498 or 0.0425y OS 75 vs 63%

CSS HR 0.79 (.55 – 1.11)

Akaza H et alCancer 115: 3437-45; 2009

Summary CAB• Several meta-analyses have shown

small to moderate improvements in overall survival with CAB

• Two recent clinical practice guidelines recognize these improvements but are concerned about additive toxicity

• All studies in MA used older AA which are rarely used today

• Bicalutamide CAB has very tolerable side effects and has a large OS benefit

Clinical Practice

“I think there is a compelling survival advantage with bicalutamide CAB and I will speak to my patients about that option”

or

“I am not convinced that there is a compelling survival advantage with bicalutamide CAB and a clinical trial should be designed to address the issue”

Timing of ADTi) Watchful Waiting Patients

• 1960-1975, n=954 locally advanced or metastatic disease

• Randomized to one of four arms: placebo, orch+placebo, DES (5mg), or orch+DES

• Patients with metastatic disease in the placebo arm were allowed active treatment upon progression

Jordan WP. South Med J 1977;70(12):1411-1413

VACURG I Study

12 year survival P Orch+P

DES Orch+DES

Cause specific (%) Overall (%)

6510

7012

7713

7613

T3/4 or M1

Prostate Cancer

RANDOMIZE

n=934

MRC Prostate Cancer Working Party Investigators Group Br J Urol 1997;79:235-246

Immediate ADT

Deferred ADT (at symptom

onset)

n=469

n=465

•Distant Progression•Overall survival•Cause specific

survival•Pain-free survival•TURP•Ureteric obstruction•Metastatic

complication

Outcomes

MRC Study Schema

Minimum follow-up of 2.7 years

3847267

4258

598645123746

Deferred(%) 2p

Immediate(%)

<0.001<0.001<0.001<0.025

0.020.001

n =934, T3/4 or M1

Distant progressionPainful metastasesTURPUrinary obstruction5 yr OS5 yr CSS

MRC Study Outcomes

MRC Prostate Cancer Working Party Investigators Group Br J Urol 1997;79:235-246

Minimum follow-up of 9.5 years

74258

123746

Deferred(%) 2p

Immediate(%)

0.090.250.26

n =934, T3/4 or M1

Overall survivalExtraskeletal metastasesUrinary obstruction

MRC Study Outcomes

Kirk, 2004

•No standardized follow-up schedule- 29 patients (6.2%) randomized to deferred arm

died of prostate cancer before receiving treatment

•Minority of patients had PSA measured on follow-up

•Generalizability?- Results from locally advanced or M1 tumors may not reflect biology of biochemical failures post-RT

MRC Criticisms

LocalizedProstate Cancer

•Too unwell for

radical therapy

RANDOMIZE

Immediate Orchiectomy

Deferred Orchiectomy

(at symptom onset)

n=197

Studer et al. J Clin Oncol 2004;22:4109-4118

n=96

n=92

SAKK 08/88 Study Schema

•Cause specific survival

•Overall survival•First pain•Symptom-free

survival•Ureteric obstruction•New metastases

Outcomes

OverallSurvival

Cause SpecificSurvival

Time to HormoneResistant Disease

SAKK 08/88 Results

T0-4 N0-2 M0ProstateCancer

n=985

Studer UE et al. J Clin Oncol 2006;24:1868-76

n=493

n=492

Too unwell for radical therapy

ExcludedAge > 80 yrOther CA (non-BCC)Symptomatic Pr CA“juxtaregional LN”

Immediate ADT

Deferred ADT (at symptom

onset)

RANDOMIZE

EORTC 30891 Study Schema

•Overall survival•Cause specific

survival•Non-PC survival•Symptom-free

survival•Time to Dist Mets•Symptomatic AIPC•Castrate

Metastases•TURP

Outcomes

Overall Hazard Ratio 1.25 (1.05-1.48)

Non-inferiority p = 0.47

36%

25%

68%

61%

SURVIVAL

p = 0.44

p = 0.062

925

1326

Deferred(%)

Immediate(%)

5 yr10 yr

Cause specificMortality

2339

2646

Deferred(%)

Immediate(%)

5 yr10 yr

All causeMortality

Cause-Specific Mortality

Studer UE et al. Eur Urol 2008;53:914-9

Immediate Arm

Deferred Arm

By PSAdt in deferred arm

Timing of ADTiii) N+ Post-Radical Prostatectomy Patients

ECOG 3886N+ post rP

Messing E et al. N Engl J Med 1999;341:1781-8

EORTC 30846N+, no rP

OS HR 1.23 [0.88-1.71]medOS 7.8 vs 6.2 y

CSS no difference

Difference w/ ECOG 3886• More T3 (66%)• No local treatment

Timing of ADTiii) Recurrent Cancer Post-RT

SathyaJCO

2005

PeetersJCO

2006

n=305

Dose Escalated Radiation Therapy

Pollack IJROBP 2002

Zeitman

JAMA2005

Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006

Burden of Problem

Extent of disease Incidence

Localized 17,225 (85%)

Metastatic 3,151 (15%)

Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006

97019411745

485970873

5 yr Biochemical Failure

Localized disease At risk(n)

Post-RT(n)

Burden of Problem

Low riskIntermediateHigh risk

Incidence

53914852 6982

(31%)(28%)(41%)

30% overall (2570 post-RT)

Post-Radiotherapy Failure

• Local therapies– Radical prostatectomy– Cryotherapy– HiFU– Seed brachytherapy*

• ANDROGEN DEPRIVATION THERAPY– ASCO Androgen Sensitive Guideline

2006 Update available Jan 29th, 2007

TROG Timing of Androgen Deprivation (TOAD)•ongoing

RCTs Timing of ADT Post Radical RT

Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006

<1010-2020-50>50

20183224

2850202

2000USA

5336110

1994Canada

2004Canada

Trigger PSA (ng/mL)for starting ADT

Patterns of Care Survey

Oncologists Survey (%)

Hormone-Sensitive Prostate Cancer (2004)

• Timing of ADT • Systematic review of literature

– 1 meta-analysis– 1 Markov model

Loblaw DA et al. J Clin Oncol 2004;14:2927-41

ASCO Guidelines

“...antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical

tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the

question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.”

Loblaw DA et al J Clin Oncol 2004;14:2927- 41

ASCO Guidelines

Meta-Analysis of Literature

Inclusion criteria– RCTs on patients with metastatic or untreated localized prostate cancer– ADT Intervention

Literature search– Medline 1966 – Mar 2006– Cochrane Database of Systemic Reviews

Exclusion Criteria– Patients previously treated with ADT– Patients undergoing primary RT with ADT

Meta-Analysis of Literature

Methods of analysis– Outcomes: all cause death, prostate cancer mortality

– RevMan 4.2.8

– Visual and statistical evaluation of heterogeneity

– Combined Relative Ratio, 95% confidence intervals

– Sensitivity analyses performed for methodological weakness, heterogeneity

Prostate Cancer Mortality

Overall Mortality

“Until data from studies using modern medical diagnostic/ biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.”

Loblaw DA et al J Clin Oncol 2004;14:2927- 41

ASCO Guidelines

Loblaw DA et al J Clin Oncol April 2006

“In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non–PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation.… For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated.”

1. What are the benefits of immediate

ADT following radiation therapy

Unanswered Questions

−Can we extrapolate from

Watchful Waiting / Metastatic

patient data?2. What is the magnitude of detriment on QOL?

• Vasomotor symptoms

• Decreased libido erectile

dysfunction

• Decreased muscle mass

• Decreased energy

• Metabolic syndrome

• Osteopenic effects

ADT Side Effects

• 50,613 men with Prostate Cancer in SEERdatabase 1992-1997

• 19% vs 12% had (any) fracture (living >5 yr)─ bone metastases not excluded

• 73,197 men > 66 yr in SEER, Medicare• 1/3 had LHRH agonist• Excluded prevalent M1, DM, CAD

In 10 years 9% 11% 3% 4%

Prognostic Factors

OverallMortality

DistantMetastases

PredictorsCause specific

Mortality

D’Amico2006

PSAdt (< 6months)

Gleason Score (8-10)

PSA response to ADT

Age < 75yr

Kim-Sing2004

Pound1999

Pound1999

D’Amico2006

D’Amico2006

3. Does the effect of timing of ADT differ by PSAdt, Gleason?

Timing of ADT for Recurrent Prostate

Cancer

96 Canadian Specialists – 42 GU Radiation Oncologists– 50 Urologists– 4 Medical Oncologists

ELAAT Survey

Current Practice– Trigger: PSAdt (28%), PSA (3%), both (69%)– Start treatment if PSAdt < 12months (95%) – Start treatment if PSA (ng/mL) <10 (53%), 10-20

(36%)– Orchiectomy (0%)

Trial comfort zones to start ADT– Lowest PSA to start ADT: 4ng/mL (58%)

5ng/mL (86%)

– Highest PSA to withhold ADT: 25ng/mL (61%)

– PSAdt trigger: < 12 months (71%)

ELAAT Survey

Need for Trial– Moderate to very important (86%)– Very important (51%)– Number of patients per year: 1500+

Andrew Loblaw, Sergio Faria, Himu Lukka, Tom Pickles,

Patrick Cheung, Lawrence Klotz, Kathy Pritchard,

Martin Gleave, Tulay Koru-Singul, Mark Levine

A Randomized Comparison of Immediate versusDeferred Androgen Deprivation Therapy using

Goserelin for Recurrent Prostate Cancer after Radical Radiotherapy

ELAAT STUDY

LocalizedProstate Cancer

Asymptomatic biochemical failure post RT

RANDOMIZE

Immediate LHRH

Deferred LHRH

(at symptom onset)

(or PSA>25ng/mL)

•Time to Androgen Independent Disease

•Cause specific survival

•Overall survival•Quality of Life•Complications of

Advanced Malignancy•Bone Fractures

Outcomes

ELAAT Study Schema

ELAAT Enrolment

PSAdt

Gleason Score

Immediate LHRH

Deferred LHRH

Randomization

n= 1100

Clinical Trial Centre

≤12months >12months

2-7 8-102-7 8-10

Centre

1. Adults (> 18 years old) with histopathologically confirmed adenocarcinoma of the prostate

2. Patients who have failed biochemically after radical radiation therapy (total prostate dose ≥52 Gy)

3. PSA <6 ng/mL within 30 days of randomization

ELAAT Inclusion Criteria

1. Patients who have had a primary or salvage radical prostatectomy, salvage cryotherapy, thermal ablation, photodynamic therapy or high intensity focus ultrasound

2. Patients who are within 4 years of their brachytherapy implantation date

3. Patients with medical conditions in which goserelin or bicalutamide is contraindicated in the opinion of the supervising oncologist or urologist

4. Patients with another active malignancy or malignancy treatment within 5 years (except for basal or squamous cell skin cancers)

5. Patients who are geographically inaccessible for follow-up

6. Patients who fail to provide written informed consent

ELAAT Exclusion Criteria

1.Bicalutamide 50 mg po OD days 1-30 (may

be given continuously at the discretion of supervising oncologist)

2.Goserelin 10.8 mg SC day 10-17 + q3months until patient discontinuation

ELAAT Treatment

ELAAT Outcomes

•Time to androgen independent disease (AID)

•Cause specific survival•Overall survival•Quality of Life•Complications of advanced malignancy

(CAM)•Bone Fractures

ELAAT Follow-Up

Physical exam + digital rectal examination

CBC, Testosterone, PSA (within 30days of randomization)

Quality of Life

Goserelin compliance

√

√

√

During the last 6 months:Fractures

Need for palliative radiotherapy, palliative surgery, TURP, spinal cord compression or ureteric obstruction

Chemotherapy, antiandrogens, bisphosphonates, calcium, vitamin D or erythropoietinDual x-ray absorption (DEXA) scan √*

Baseline q 6months

√

√

√

√

√

√

√

√**

* within 1 month of 1st injection, ** every 2 years after 1st injection of goserelin

ELAAT Statistical Considerations

Sample size determination – A non-inferiority time to event analysis based on

two exponential survival curves

Assumptions on sample size calculation – Androgen independent disease at 10 years =

30% for immediate LHRH group– True difference 7.5% (i.e. Hazard Ratio = 1.318)– (Deferred LHRH - Immediate LHRH) < 7.5%– Alpha 2.5% – Power 80%

Total 1064 patients (n=532/per arm)– Total recruitment will be 1100 patients

(n=550/per arm) to account for 3.2% lost to follow-up

Canadian survey: 1500 eligible patients per year

Accrual estimate: 225 patients for 1st year 450 patients for subsequent

years

Complete accrual: 3-4 years

First analysis: at 7 years median follow-up

ELAAT Study Timelines

Contract Signed Jun 2006

Health Canada CTA NOL Aug 2006

Ontario Cancer REB Approval Nov 2006

Study Activation Aug 2007

Clinical Practice

• “After RT failure, I don’t think there is a compelling survival advantage with early ADT and I recommend not starting ADT until symptoms arise”

• or• “I don’t know when ADT should be

started after RT failure and I would support a clinical trial designed to address the issue”

Summary

• Recurrent prostate cancer after radical treatment a common problem

• Well characterized toxicity profile but…– Conflicting evidence for WW and CSS

benefit– No evidence for N0 post rP or RT– Benefit in OS, CSS for N+ after rP?

• Further study in development

Intermittent Androgen Blockade

• N = 766 (626 enrolled), locally advanced / M1

• 3 mo IAB (CPA + LH) vs CAB• Trigger: PSA < 4 ng/ml (or 80% reduction)• mFU 51 mo• Progression: HR 0.81 (0.63 – 1.05, p=0.11)• OS: 0.99 (0.80 – 1.23)• Improved QOL• 52 wk median off-treatment IAB

Calais da Silva FEC Eur Urol 55:1269-77;2009

IAB Cont’d

• NCIC PR7 press release May 2010 – failed to reach primary endpoint

• IAB practiced commonly• ? Sufficient evidence to change

guidelines