initial androgen treatment for progressive, metastatic or recurrent prostate cancer andrew loblaw...
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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
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