non-metastatic crpc and asymptomatic metastatic crpc...
TRANSCRIPT
May 4, 2012 1
Non-metastatic CRPC and Asymptomatic Metastatic CRPC- Which treatment for which patient
Michael A. Carducci, M.D., FASCO AEGON Professor in Prostate Cancer Research Johns Hopkins Kimmel Cancer Center Baltimore, MD
Disclosures
• Consultant Amgen Bayer Sanofi Data Safety Monitoring Medivation/Astellas
Educational Objectives
• Discuss the clinical state “non-metastatic castration -resistant prostate cancer”
• Review treatment options and controversies for this patient population
• Examine differences between “non-metastatic” to “asymptomatic” CRPC and the treatment landscape
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Definition of Castration-resistant Prostate Cancer (CRPC) • CRPC defined as disease progression on androgen
deprivation therapy • Criteria defining CRPC vary
– Presence of progressive metastatic measurable disease (by RECIST)
– Progression of bone metastases (by bone scan) – Biochemical progression: 2 consecutive increases in PSA – Castrate testosterone levels (<50 ng/mL or <20ng/mL) – Progression despite anti-androgen withdrawal
(up to 4-6 weeks earlier)
Sternberg C, et al. BJU Intl. 2006;99:22-27. Bubley G, et al. J Clin Oncol. 1999;17:3461-3467. Winquist E, et al. BMC Cancer. 2006;6:112.
Scher HI. Et al. J Clin Oncol 2008; Mar 01.
What is meant by “Non-metastatic Castration-Resistant Prostate Cancer
• A state where the patient appears “radiographically-free” of metastatic disease
• Artificially created by early use of androgen deprivation therapy for rising PSA patients/ high risk patients after local therapy
• In general, it is assumed that these men have micro-metastatic disease
July 11, 2013 5
Clinical States of Prostate Cancer
Clinically localized
Biochemically Relapsed-
Rising PSA
Non-metastatic, hormone-
responsive
Metastatic, Hormone-responsive
Non-metastatic
CRPC
Metastatic
CRPC
10-15 years +
Death from co-morbidities
Death from disease
PSA=prostate-specific antigen; CRPC= castrate resistant prostate cancer Modified from: Scher HI, et al. Urology. 2000;55:323-327. Adapted from George D. ASCO Prostate 2007.
Issues with the Management of Men with “Non-metastatic” CRPC • Duration of ADT prior to CRPC and long term
effects of ADT – Estimates of time to metastatic disease vary – Bone health- osteopenia / fracture risk – Metabolic issues- ongoing cardiovascular risks
• Asymptomatic - so “concern” about side-effects of additional therapies – Again, estimates of time to metastatic disease
would help determine “aggressiveness” of treatment
July 11, 2013 7
Issues with the Management of Men with “Non-metastatic” CRPC • No standard approach to treatment but
“concern” is present for progression risk – What if we improve imaging to detect micro-mets? – Androgen pathway still active and inhibitors should
provide benefit – Immunotherapy may be more effective if provided
early • Clinical trials difficult to design and identify
clinically meaningful endpoint – Delay in time to metastasis- what is signficant?
July 11, 2013 8
Bone Health and Metabolic Issues
July 11, 2013 9
Negative Aspects of Androgen Deprivation • Hot flashes • Loss libido / erectile dysfunction • Bone mineral loss/ accelerated osteopenia • Weight gain • Changes in lipid/ glycemic metabolic profiles • Anemia • Neuro-cognitive changes
July 11, 2013 10
Osteoporosis From Hormonal Deprivation
• Normally seen in aging men • Fractures in spine most prevalent • Trabecular bone at highest risk • Deprivation accelerated by systemic
cancer therapy, especially problematic with use of antihormonal cancer agents
July 11, 2013 11
Fractures Affect Mortality and Life Expectancy • Hip fracture
– Affects life expectancy dramatically
• Aged 60-69 yrs: 11.5 yrs of decreased life expectancy • Aged 0-79 yrs: 5.0 yrs of decreased life expectancy
• Vertebral facture – Prevalence in men is high (20%)
– Clinical consequences: pain, kyphosis, loss of height, respiratory problems
• 4 x increased risk of subsequent fracture – Predict increased mortality in men with a 10-yr HR of 2.4
(95% CI: 1.6-3.9)
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Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy
Lumbar Spine
Total Hip
Smith MR, et al. J Urol. 2003;169:2008-2012.
-4
-2
0
2
4
6
8 P < .001 for each comparison
Final 12-Mo Data
BM
D P
erce
nt C
hang
e
Zoledronic acid Placebo
Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy
Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.
-6
-4
-2
0
2
4
6 P < .005 for each comparison
Final 12-Mo Data
BM
D P
erce
nt C
hang
e
Zoledronic acid 4 mg/yr IV Placebo
Lumbar Spine
Total Hip
Denosumab Increased BMD at All Skeletal Sites
10 8 6 4 2 0
-2 -4 -6
0 1 3 6 12 24 36 Mos
Cha
nge
in B
MD
Fr
om B
asel
ine
(%)
Femoral Neck
Denosumab
Placebo
Difference at 24 mos, 3.9 percentage points
10 8 6 4 2 0
-2 -4 -6
0 1 3 6 12 24 36 Mos
Cha
nge
in B
MD
Fr
om B
asel
ine
(%) 8
6 4 2 0
-2 -4 -6
0 1 3 6 12 24 36 Mos
Cha
nge
in B
MD
Fr
om B
asel
ine
(%)
Lumbar Spine
Denosumab
Placebo
Difference at 24 mos, 6.7 percentage points
Denosumab
Placebo
Difference at 24 mos, 4.8 percentage points
Total Hip
8 6 4 2 0
-2 -4 -6
0 1 3 6 12 24 36 Mos
Cha
nge
in B
MD
Fr
om B
asel
ine
(%)
Placebo
Difference at 24 mos, 5.5 percentage points
Distal Third of Radius
Smith MR, et al. N Engl J Med. 2009;361:745-755.
Denosumab
10
10
Denosumab for Fracture Prevention
12 Mos
24 36
P = .004 P = .004 P = .006
1.9
0.3
3.3
1.0
3.9
1.5
0
2
4
6
8
10
New
Ver
tebr
al F
ract
ure
(%) Placebo
Denosumab
13 2 22 7 26 10 Pts at Risk, n
Smith MR, et al. N Engl J Med. 2009;361:745-755.
Metabolic Complications of ADT
Metabolic Syndrome
Insulin Resistance Hyperglycemia
Dyslipidemia
Long Term Effect of ADT
Met
abol
ic S
yndr
ome
in M
en o
n L
ong-
term
AD
T Br
aga-
Bas
aria
M e
t al J
CO
200
6
Metabolic Syndrome
• Metabolic syndrome present in more than 50% of men undergoing long-term ADT – Abdominal obesity, hyperglycemia,
hypertriglyceridemia, hypertension, and low HDL • Abdominal obesity and hyperglycemia were
responsible for this higher prevalence • Maybe one factor for accelerated
cardiovascular mortality in men with PCA
• Patients and physicians require education about increased incidence of metabolic issue in men on long term ADT July 11, 2013 19
Predicting Progression
July 11, 2013 20
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.
PSA > 24.0 ng/mL PSA 7.7-24.0 ng/mL PSA < 7.7 ng/mL
Prop
ortio
n of
Pat
ient
s W
ith B
one
Met
asta
ses
or D
eath
Yrs Since Random Assignment
0.8
0.6
0.4
0.2
0
1.0
Rising PSA in Nonmetastatic CRPC: PSA Levels
0 0.5 1.0 1.5 2.0 2.5 3.0
Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.
Rising PSA in Nonmetastatic CRPC: PSA Doubling Time
PSADT < 6.3 mos PSADT 6.3-18.8 mos PSADT > 18.8 mos
Prop
ortio
n of
Pat
ient
s W
ith B
one
Met
asta
ses
or D
eath
Yrs Since Random Assignment
0.8
0.6
0.4
0.2
0
1.0
0 0.5 1.0 1.5 2.0 2.5 3.0
Denosumab to Prevent Metastases
Primary endpoint: bone metastasis–free survival
Denosumab 120 mg monthly Patients with CRPC and no bone metastases;
PSA > 8 or PSADT < 10 mos
(N = 1435)
Placebo monthly
Smith MR, et al. Lancet. 2012.
Primary Endpoint: Bone Metastasis-Free Survival
716 716
691 695
569 605
500 521
421 456
375 400
345 368
300 324
259 279
215 228
0 3 6 9 12 15 18 21 24 27 Study Mo
Pro
porti
on o
f Pat
ient
s W
ith
Bon
e M
etas
tasi
s–Fr
ee S
urvi
val
Placebo Denosumab
30 33 36 39 42
Median Mos 25.2 29.5
HR: 0.85 (95% CI: 0.73-0.98; P = .028)
Placebo Denosumab
168 185
137 153
99 111
60 59
36 35
Patients at Risk, n
Smith MR, et al. Lancet. 2012.
1.0
0.8
0.6
0.4
0
0.2
Metastasis-Free Survival What is meaningful? • ODAC meeting to discuss 11/2011
– Meaningful > 1 year, and based on toxicity profile
• ARN-509 / Enzalutamide / Orteronel- each will launch Phase III studies to delay metastasis
• Can immunotherapy be moved to this setting, when no improved PFS noted in more advanced disease
July 11, 2013 25
Androgen Pathways Still Active
• Maintenance of castrate level of testosterone life long
• Second line hormonal therapy most commonly used – Anti-androgens- bicalutamide, nilutamide,
flutamide – Androgen synthesis inhibitors- ketoconazole – Estrogens – Newer agents (not yet approved but available)
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M0 M1 Death
Low-volume metastases, no/minimal symptoms
Progressive metastases,
symptomatic
High-volume or symptomatic
metastases
1st line
Docetaxel Curtisen
Cabazitaxel Mitoxantrone
1st line Cytotoxic
Sipuleucel-T Ketoconazole
Estrogens Abiraterone
Orteronel Enzalutamide Tasquinimod Ipilumimab Radium-223
1st line
Mitoxantrone Abiraterone Cabazitaxel
Enzaluatmide Radium 223
Cabozantinib
2nd line
M0 M1 Death
Low-volume metastases, no/minimal symptoms
Progressive metastases,
symptomatic
High-volume or symptomatic
metastases
1st line
Docetaxel Curtisen
Cabazitaxel Mitoxantrone
1st line Chemotherapy
Based
Sipuleucel-T Ketoconazole
Estrogens Abiraterone
Orteronel Enzalutamide Tasquinimod Ipilumimab
1st line
Extend time Delay symptoms
Defer chemotherapy
Improve survival QoL
FDA-Approved Agents for Prevention of SREs in Metastatic Prostate Cancer
NCCN recommends either zoledronic acid or denosumab for prevention/delay of SREs in men with metastatic CRPC[1]
Choice between agents may be guided by
– Underlying comorbidities
– Adverse events: renal insufficiency, ONJ, hypocalcemia
– Logistics - Differences in administration (SQ vs IV)
– Cost considerations
Agent Drug Class Recommended Dose and Schedule Zoledronic acid Bisphosphonate 4 mg IV q3-4w Denosumab RANKL-targeted MAb 120 mg SQ q4w
1. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.4.2011.
Summary
• In 2013, “Non-metastatic” CRPC remains a clinical state
• Management remains conservative – Reliance on traditional agents – Bone health – Attention to metabolic issues
• Asymptomatic metastatic CRPC in the midst of changing treatment landscape, with limited data on sequence /timing
July 11, 2013 30