Transcript Document

6th Annual Interdisciplinary
Prostate Cancer Congress
Meeting in a Box
Screening for Prostate Cancer –
The PSA Controversy
Leonard G. Gomella, MD
US Preventive Services Task Force
(USPSTF) Screening Recommendations
Task Force set
up by
congressional
mandate in
1984
Task Force:
– General physicians
– Nurses
– Health psychologists
– Epidemiologists
– Statisticians
Topic
assigned by
HHS Agency
for Healthcare
Research &
Quality
Grade the
quality of
evidencebased research
Defined prostate
screening as
grade D
recommendation
against the service.
They had moderate
or high certainty that
the service has no
net benefit or that
the harms outweigh
the benefits.
•
Per the 2012 USPSTF, no healthy man should undergo PSA screening unless
symptoms of prostate cancer present
•
Full implications have yet to be realized
HHS=US Health & Human Services Department; PSA=prostate-specific antigen.
Moyer VA, Ann Intern Med. 2012;157:120-34.
National Comprehensive Cancer
Network (NCCN) Screening Guidelines
•
NCCN panelists note the variability in prostate tumor behavior
– Key point is discussion between patient and provider about the risks and
benefits of early detection of and treatments for prostate cancer
– Goal is to evaluate aggressiveness of the cancer
•
Once a patient age 40 starts having risk and benefit discussion about baseline
digital rectal exam (DRE) and absolute PSA values
– May annually follow up with DRE and repeat PSA in patients with elevated
PSA (≥1.0 ng/mL), African Americans, men taking 5-alpha-reductase
inhibitors
– Testing and biopsy decisions should be individualized for men > age 75
years
•
Further timing of follow-ups and DRE and PSA testing dependent on age, and
life expectancy
– Trying to determine need for TRUS-guided biopsy, and may also use PSA
density, percent-free PSA, and PSA velocity to determine need for biopsy or
if cancer is present
PSA=prostate-specific antigen; DRE=digital rectal examination; TRUS=transrectal ultrasound.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer
Early Detection, V2.2012. Accessed Sep 9, 2013.
American Cancer Society (ACS)
Screening Guidelines
•
ACS supports informed discussion between healthcare provider and
asymptomatic men about screening for prostate cancer
– Average risk: annually beginning age 50 years with 10+ year life
expectancy
– Age 45 if high risk: High risk includes African-American men or
those with first-degree relative with prostate cancer <65 years of
age
– Age 40 if very high risk: Very high risk includes multiple family
members with prostate cancer at early age
– Include information about uncertainties, risks, and potential benefits
•
If testing performed, PSA with or without DRE
•
2009 guidelines reaffirmed in 2013
Wolf AM, et al. CA Cancer J Clin. 2010;118:244-50.
American Urological Association (AUA)
Screening Guidelines
•
•
Recommendations based on age and risk
– Average risk:
• < Age 40, not recommended
• Age 40-54: do not recommend routine screening
• Age 55-69: informed shared decision making about screening
risk and potential benefits
• Age 70+ or patients with <10-15 years life expectancy: do not
recommend routine screening
– Alternatively, can individualize based on baseline PSA
– High risk: <55 with positive family history or African-American race;
decisions should be individualized
If decision to screen, frequency should be 2+ years instead of annual
– Panel believes this will reduce overdiagnoses and false-positives
while maintaining the majority of the benefits
Carter HB et al. J Urol. 2013;190:419-26
PSA-Based Prostate Screening
Potential Benefits
•
Risks and Limitations
•
Earlier diagnosis:
– Allows finding cancer at earlier
stage, before it is symptomatic,
while it is likely localized
– 70% decrease in metastatic
disease at diagnosis1
•
Relative survival has increased to
close to 100% since PSA screening
became highly utilized1
– From 1975-1979, 10-year survival
was 55.7%
– Decrease in quality of life,
complications, and cost
•
Various physiological and pathological
factors can cause a rise in PSA, often
temporal
•
If PSA detectable, no matter how low,
prostate cancer still a possibility2
•
Can take time for effect of populationbased PSA screening to become
significant3
•
Though increase in survival of prostate
cancer patients, not able to directly link
it to PSA-based screening
– In 2000, 10-year survival was
98.4%
– US death rates have decreased
about 4% per year
Potential for overdiagnosis and
overtreatment in patients with clinically
insignificant cancer
1. Howlader N et al. SEER Cancer Statistics Review, 1975-2010, National Cancer Institute.
http://seer.cancer.gov/csr/1975_2010/. Accessed Sept 2, 2013.
2. Thompson IM et al. N Engl J Med. 2004;350:2239-46. 3. Loeb S et al. J Clin Oncol. 2011;29:464-7.
Implications for Patient Care
• PSA-based screening not appropriate for overall population
• Prostate cancer screening makes sense in certain populations
after informed discussion between patient and provider
– Patients at high risk for the disease
– Patients at high risk for death or morbidity from the disease
– Patients in good health with life expectancy > 10-15 years
• Can be difficult deciding treatment versus observation for an
individual patient
• Advise patients to seek a second opinion, especially with
clinician experienced with both active surveillance and active
treatment
Active Surveillance—
Current Status and Future Directions
E. David Crawford, MD
Watchful Waiting vs Active Surveillance /
Active Monitoring
Watchful Waiting
Active
Surveillance /
Active Monitoring
Avoid treatment
Individualize
management
Limited life
expectancy/
advanced disease
Fit for radical
treatment/
localized disease
Treatment timing
Delayed
Early
Treatment intent
Palliative
Curative
Primary aim
Patient / tumor characteristics
National Comprehensive Cancer Network
(NCCN) Guidelines on Active Surveillance
Recurrence Risk
Expected Survival
Initial Therapy
< 20 years
Active surveillance
preferred
≥ 20 years
1. Active surveillance
2. Radiotherapy
3. Radical prostatectomy
≥ 10 years
1. Active surveillance
2. Radiotherapy
3. Radical prostatectomy
Very low risk
Low risk
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer,
V4.2013. Accessed Sep 1, 2013.
Summary of Active Surveillance Studies
Author
N
Median
Follow-up
(mo)
pT3 in RP
Patients
OS
CSS
van As - Eur Urol.
326
22
8/18 44%
98
100
Carter - J Urol.
407
41
10/49 20%
98
100
533-1000
48
4/24 17%
90
99
Soloway
99
45
0/2
100
100
Roemeling
278
41
89
100
Khatami
270
63
Not stated
100
Klotz - J Clin
Oncol.
452
73
82
97 @ 10 yr
2130-3000
43
90
99.7
PRIAS
Total
14/24 58%
CSS=cancer-specific survival; mo=months; OS=overall survival; p=pathologic; RP=radical
prostatectomy.
Active Surveillance: Current Approach
• Offered to all men with Gleason 6, PSA ≤10 (accepted by most)
• PSA kinetics a guide only
• Confirmatory biopsy within 1 year, targeting
anterior/anterolateral horn
• Repeat biopsy every 3-5 years (age, risk tolerance, PSA) to age
80 years
• MP-MRI for PSA doubling time < 3 years or volume increase or
3+ minor element 4
• Treat if significant Gleason 4 or unequivocal lesion > 1 cm on
MRI
New Endocrine Options
for Advanced Prostate Cancer
Robert Dreicer, MD, MS, FACP, FASCO
Abiraterone Phase III Trials:
COU-AA-301 and COU-AA-302
Primary endpoint: OS
301 eligibility criteria:
• Progressive mCRPC pts
who failed a docetaxel
regimen ± another
chemotherapy
302 eligibility criteria:
• Progressive chemo-naïve
mCRPC, asymptomatic or
mildly symptomatic
Co-primary endpoints: OS +
rPFS by central review
(N=1195)
2:1 R
A
N
D
O
M
I
Z
E
Abiraterone 1000mg qd+ prednisone bid
Placebo qd+ prednisone bid
1:1
(N=1088)
Median OS
COU-AA-3011
Abiraterone
Placebo
14.8 mo
10.9 mo
Fluid retention and
edema, hypokalemia,
cardiac disorders
27.2 mo
Mineralocorticoidrelated + abnormalities
on liver-function testing
(P < 0.0001)
Not reached
COU-AA-3022
Adverse Events
(P = 0.01)
Abiraterone
1. de Bono et al. N Engl J Med. 2011;364:1995-2005. 2. Ryan CJ, et al. N Engl J Med. 2013;368:138-48.
Enzalutamide Phase III AFFIRM Trial
(N=1199)
2:1
Eligibility criteria:
• CRPC pts who progressed
during or after treatment with a
docetaxel-based regimen
Primary endpoint: OS
•
•
R
A
N
D
O
M
I
Z
E
Enzalutamide 160 mg qd
Placebo qd
Median OS: 18.4 mo enzalutamide, 13.6 mo placebo (P < 0.0001)
Adverse events: Enzalutamide group reported 45% of patients with any
≥ grade 3 adverse event vs 53% with placebo
– 3% of enzalutamide group and 4% of placebo group had an adverse
event that led to death
– Highest reported ≥ grade 3 adverse event was fatigue, with 6% of the
enzalutamide group and 7% of placebo reporting
mOS=median overall survival.
Scher HI et al. N Engl J Med. 2012;367:1187-97.
Second-Line Hormonal Therapy:
Remaining Issues
• Optimal timing
• Role of combination therapy
• When to stop androgen biosynthesis inhibitors
– Major issue in the pre-chemotherapy setting
• Optimal dose of steroids for androgen biosynthesis
inhibitors
• Issues of divergent practice urology vs oncology
Endocrine Agents in Development
• Lyase inhibitors
–
–
–
–
–
Orteronel (TAK 700)
TOK-001 (galeterone)
CFG920
VT-464
EN3356
• Antiandrogens
–
–
–
–
–
ODM-201
ARN-509
AZD-3514
EZN-4176
TOK-001 (galeterone)
Evolving Approaches for Chemotherapy
for Advanced Prostate Cancer
Daniel P. Petrylak, MD
Docetaxel Hormone-Refractory
Prostate Cancer
TAX 3271,2
SWOG
99163
N
Randomized Arms
Docetaxel
Dosage
Outcome (mOS in mo)
1006
1. Mitoxantrone +
prednisone
2. Weekly docetaxel
+ prednisone
3. Docetaxel q3w +
prednisone
Arm 2: 30
mg/m2/wk 5 on; 1
off * 6 cycles
Arm 3: 75 mg/m2
q3wk up to 10
cycles
• Weekly docetaxel had
1.5 mo benefit*
HR Arm 1,2: 0.94, P = 0.14
• Docetaxel q3wk had 3
mo benefit*
HR Arm 1,3: 0.88, P =0.005
770
1. Mitoxantrone +
prednisone
2. Docetaxel +
Estramustine +
Dexamethasone
mg/m2
mOS: Arm 2 had 2 month
median survival benefit
HR: 0.80; P = 0.01
60
d2
• Docetaxel + prednisone remains the standard of care for firstline chemotherapy for metastatic disease
• Investigating markers for drug resistance
*Compared to mitoxantrone arm. d2=day 2 of cycle; HR=hazard ratio; mos=months;
mOS=median overall survival; pred=prednisone; q=every.
1. Tannock et al. N Engl J Med. 2004;351:1502-12. 2. Berthold DR, et al. ASCO Prostate Cancer Symposium 2007;
abstract 147. 3. Petrylak et al. New Engl J Med. 2004;351:1513-20.
Phase III Trials of
Docetaxel Combinations
Docetaxel+Prednisone vs
Docetaxel Combined With:
Status
Results
Bevacizumab
Completed
Negative
VEGF-Trap (aflibercept)
Completed
Negative
Atrasentan
Completed
Negative
ZD4054
Completed
Negative
Dasatinib
Completed
Negative
Lenalidomide
Completed
Negative
Ongoing
Pending,
completion
December 2013
Custirsen (OGX-011)
• To date, no combination improves on docetaxel and prednisone
Phase III TROPIC Registration Study of
Cabazitaxel vs Mitoxantrone in
Docetaxel-Resistant Patients
Eligibility criteria:
• mCRPC pts who
progressed during or after
treatment with a docetaxelbased regimen
Stratification:
• ECOG PS (0, 1 vs 2)
• Measurable vs nonmeasurable disease
Primary endpoint: OS
Secondary endpoints: PFS,
response rate, safety
•
•
(N=755)
R
A
N
D
O
M
I
Z
E
Cabazitaxel q3w +
prednisone/prednisolone qd * 10 cycles
Mitoxantrone q3w +
prednisone/prednisolone qd * 10 cycles
mOS: 12.7 mo mitoxantrone+prednisone, 15.1 mo cabazitaxel+prednisone
(P<0.0001)
Adverse events: Cabazitaxel group reported 8% patients with ≥ grade 3
febrile neutropenia vs 1% in mitoxantrone
– Diarrhea was reported in 6.2% of cabazitaxel group and 0.3% of
mitoxantrone group
– Leukopenia also higher in cabazitaxel group (68% to 42%)
de Bono et al. Lancet. 2010;376:1147-54.
Advances in Immunotherapy
Susan F. Slovin, MD, PhD
Rationale for Immunologic Approaches
in Prostate Cancer
1. Well-characterized cell surface molecules: PSA,
PSMA, PAP, STEAP, PSCA, Globo H, GM2,
MUC-1,2, Tn, TF, Lewisy
2. Biomarkers [PSA, CTCs] to study disease
progression/response
3. Widely applicable to all disease states:
–
Biochemical relapse thru castration-resistant disease
4. Likely potentiated via combinatorial approaches:
radiotherapy, chemotherapy, biologic agents (GMCSF, IL-2) or checkpoint inhibitors (anti-CTLA-4,
anti-PD-1), monoclonal antibody-chemo conjugates
Immunotherapies to Date…
•
•
•
•
Successes (limited)
Sipuleucel-T
Ipilimumab
PROSTVAC
Anti-PD-1
•
•
•
•
Failures (many)
G-Vax
Protein
Peptide
DNA
Brief Summary of Immunologic Trials
in Prostate Cancer
• Sipuleucel-T autologous immunotherapy: Median
overall survival benefit 4.1 mo in phase III IMPACT
trial (P = 0.03)1
• PROSTVAC-VF vaccine: Primary endpoint of PFS in
phase II trial similar with control, but at 3 years
median overall survival benefit 8.5 mo (P = 0.006)2
• Ipilimumab antibody to CTLA-4: 10 mg/kg with or
without radiotherapy had benefit for patients with
tumor-evaluable disease in phase II trial,3
– Ipilimumab is being further tested in 2 phase III trials:
one in chemotherapy-naïve, the other in docetaxelresistant cases
1. Kantoff PW et al. N Engl J Med. 2010;363:411-22.2. Kantoff PW et al. J Clin Oncol. 2010;28:1099-105. 3. Slovin
SF et al. Ann Oncol. 2013;24:1813-21.
Conclusions on Immunologic Approaches
in Prostate Cancer
• Not every immunotherapy fits a specific disease and
vice versa
• Appropriateness of immune therapy for all clinical
states of disease but clinical judgment prevails (ie,
potential delay in impact of immune therapy)
• Combinatorial approaches: checkpoint inhibitors
alone/together/chemo/RT/vaccines/cytokines
• Monoclonal antibody-chemo conjugates
Novel Therapies and Bone-Targeted
Therapy
Daniel P. Petrylak, MD
Skeletal-Related Events in Cancer
• The skeleton is the most common site of metastasis
• SRE: fracture, spinal cord compression, radiation or
surgery to bone, and hypercalcemia
Malignancy Site
Bone Lesions
SREs
65%-75%
68%
90%
49%
Lung
30%-40%
48%
Multiple Myeloma
95%-100%
51%
Breast
Prostate
SRE=skeletal-related event.
Coleman. Cancer. 1997;80:1588-94. Bubendorf, et al. Hum Pathol. 2000;31:578-83. Saad, et al. Cancer.
2007;110:1860. Coleman. Oncologist. 2004;9:14-27.
Phase III Trial of Denosumab vs Zoledronic
Acid in Castration-Resistant Prostate Cancer
(N=1901)
Eligibility criteria:
• Hormone-refractory
(castration-resistant)
• ≥1 bone metastasis
Stratification:
• Previous SRE
• PSA concentration
• Chemotherapy for prostate
cancer within 6 wks
R
A
N
D
O
M
I
Z
E
Zoledronic acid 4 mg IV + placebo sc
q4wk
Denosumab 120 mg sc + placebo IV
q4wk
• Supplemental calcium and vitamin D were strongly
recommended
• Primary endpoint: (noninferiority) time to first on-study SRE
• Secondary endpoint: superiority
IV=intravenous; SC=subcutaneous.
Fizazi et al. Lancet. 2011;377:813-22.
Phase III Trial of Denosumab vs
Zoledronic Acid Results
Denosumab
Zoledronic
Acid
HR (95% CI)
P Value
Median time to first
on-study SRE
20.7 mo
17.1 mo
HR=0.82 (0.71-0.95)
P =0.008*
Median TTP
8.4 mo
8.4 mo
HR=1.06 (0.95-1.18)
P =0.30
Median OS
19.4 mo
19.8 mo
HR=1.03 (0.91-1.17)
P =0.65
Endpoint
Adverse Event, n (%)
P Value
CTCAE grade 3/4
678 (72)
628 (66)
0.01
Hypocalcemia
121 (13)
55 (6)
<0.0001
22 (2)
12 (1)
0.09
Cumulative ONJ
*P=0.0002 non-inferiority.
CI=confidence interval; CTCAE=common terminology criteria for adverse events;
gr=grade; NR=not reported; TTP=time to progression.
Fizazi et al. Lancet. 2011;377:813-22.
FDA-Approved Bone-Targeting Radionuclides
for the Treatment of Bone Metastases
FDA Approval
March 20131
March
19972
June 19933
Bone Agent
Indication
Radium-223
Treatment of patients with
castration-resistant prostate
cancer, symptomatic bone
metastases, and no known
visceral metastatic disease
Samarium-153
lexidronam
Relief of pain in patients with
confirmed osteoblastic metastatic
bone lesions that enhance on
radionuclide bone scan
Strontium-89
Relief of bone pain in patients
with painful skeletal metastases
1. Xofigo [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013. 2. Quadramet [package
insert]. Princeton, NJ: EUSA Pharma (USA), Inc.; 2009. 3. Metastron [package insert]. Arlington Heights, IL: MediPhysics, Inc.; 1998.
Bone-Targeting Radionuclides for Patients
with Prostate Cancer Bone Metastases
Trial
Sartor, 2004
phase III
Porter, 1993
phase III
Parker, 2013
phase III
Bone Agent
N
Samarium-153lexidronam
101
Placebo
51
Stronium-89 +
EBR
126
Placebo + EBR
Radium-223
614
Placebo
307
Results (Improvement Over or vs
Placebo)
VAS: 2-4 wk (P≤0.05)
PDS: 1-4 wk (P≤0.05)
Analgesic use: 3-4 wk (P< 0.03)
New painful sites: 0.6 vs 1.2 (P< 0.0002)
Analgesic free at 3 mo: 17% vs 2%
(P<0.05)
Time to further RT: 35 vs 20 wk (P=0.006)
Median OS: 65 vs 49 wk (P <0.001)
Median time to first symptomatic skeletal
event: 68 vs 43 wk (P <0.001)
ALP=alkaline phosphatase; EBR=external beam irradiation; PDS=pain descriptor scale
(nonlinear); RT=radiotherapy; VAS=100-mm pain intensity visual analog scale (linear).
Sartor et al. Urology. 2004;63:940-5. Nilsson et al. Lancet Oncol. 2007;8:587-94. Porter et al. Int J Radiat Oncol
Biol Phys. 1993;25:805-13.
Cabozantinib in Bone Metastatic
Prostate Cancer
• Phase II Trial1
– Cabozantinib administered 100 mg daily
– 67% of patients (total N=171) showed bone scan response after
retrospective review
– Reduction in bone markers
– Other benefits:
• Pain improvement and narcotics reduction
• PFS benefit seen regardless of docetaxel pretreatment or naïve
• PSA changes discordant with other measures of antitumor activity
• 2nd trial to attempt lower starting doses to limit adverse events2
– Primary outcome was week 6 bone scan response
– For N=24 at 40 mg, 1 complete response, 15 partial responses,
8 stable disease with tolerable adverse event profile
• Phase IIIs ongoing
1. Smith DC et al. J Clin Oncol. 2013;31:412-19. 2. Lee RJ et al. Clin Cancer Res. 2013;19:3088-94.
Conclusions on Novel Therapies and
Bone-Targeted Therapies
• Alpha-emitting isotope therapy improves survival in
men with CRPC
• Minimal toxicity
• Combination studies with
hormonal/chemotherapeutic agents are underway
• New agents are targeting bone and have promising
activity
Can We Combine Novel Agents
in the Management of
Advanced Prostate Cancer?
Robert Dreicer, MD, MS, FACP, FASCO
Combination Therapy in Metastatic CastrationResistant Prostate Cancer: Current Status
• Testosterone suppression
– + second-line hormonal therapy
– + sipuleucel-T
– + docetaxel, + bone-targeted agents
– + radiotherapy
Brief Summary of Abiraterone +
Enzalutamide Trials in Prostate Cancer
• Phase II MDV3100 in bone metastatic CRPC
(NCT01650194)
– N=60, prior chemotherapy allowed
• Proposed Intergroup 3-arm phase III metastatic
CRPC
– Enzalutamide + abiraterone + prednisone
– Enzalutamide monotherapy
– Abiraterone + prednisone
CRPC=castration-resistant prostate cancer; Ph=phase.
Combination and/or Sequential Therapy
in CRPC: Challenges
• Current reimbursement paradigm is slowly but
inexorably coming to an end.
• Compendium listing of drugs will be nice, but will
increasingly miss the point.
• In a world of Accountable Care Organizations,
medical homes, and contracts for populations, we
need to think about VALUE in addition to
science/clinical results.
Radium-223 Combination Therapy
• Excellent toxicity profile
• Unique mechanism of action
• Combination studies with androgen receptor-targeted
agents
– Issues of other bone-targeted therapy when combined
with two potent agents that decrease SREs/impact
survival
• Combination with immunomodulatory agents
Near-Term Questions for
Combination Therapy
• Can more-potent androgen receptor-targeted therapy
cure patients with minimal disease?
– The adjuvant breast paradigm
– Lyase inhibitor + next-generation androgen receptor
antagonist
• Locally-advanced prostate cancer status post
combined modality therapy
• Cost effective/value-based care questions
Emerging Biomarkers:
Ready for Prime Time?
Daniel P. Petrylak, MD
Potential DNA Biomarkers
• APC = adenomatosis polyposis coli
– Inactivated in various malignancies including prostate cancer by
genetic and epigenetic mechanisms
• GSTP1 = glutathione-S-transferase-P1/π
– Believed to play a role in the protection of DNA from oxidative
damage
• RASSF1A = Ras association domain family 1 isoform A
– Tumor suppressor
• RARβ2 = retinoic acid receptor β2
– Tumor suppressor
• MDR1 = multidrug resistance 1
– May play a role in anticancer drug resistance
• CCND2 = cyclin D2
– Cell-cycle regulator
PSA Response to CRPC
• While a ≥50% decrease from baseline has been
accepted as clinically relevant response,1 a ≥30%
decrease has also been demonstrated as a surrogate
threshold for predicting survival.2,3
• Record the percentage change from baseline (rise or
fall) at 12 weeks, and separately, the maximal
change (rise or fall) at any time using a waterfall
plot.4
1. Scher HI, et al. J Clin Oncol. 2011;29:3695-704. 2. Petrylak DP, et al. JNCI. 2006;98:516-21. 3. Armstrong AJ, et
al. J Clin Oncol. 2007;25:3965-70. 4. Scher HI, et al. J Clin Oncol. 2008;26:1148-59.
PSA Does Not Always Accurately Reflect
Response to CRPC Therapy
• Newer therapies, such as sipuleucel-T will improve
survival without decreasing PSA levels.
• For cytotoxic or hormonal therapies, early PSA
responses, rises or declines, should not be used for
clinical decision making.1
– Discordance between PSA change and clinical
responses, such as pain response2 or
progression/regression of bone metastases,
have been reported.3
1. Scher HI, et al. J Clin Oncol. 2008;26:1148-59. 2. Berthold DR, et al. Clin Cancer Res. 2008;14:2763-7. 3. Ryan
CJ, et al. Clin Cancer Res. 2011;17:4854-61.
Other Biomarkers With Correlation
to Outcomes in Prostate Cancer
Biomarker
Testosterone (T)1,2
Circulating tumor cells
(CTCs)
Population
Correlation
Retrospective newly
diagnosed bone-only
metastatic treated with
LHRH agonist
Correlation of serum T and
intraprostatic DHT:
• None seen at beginning
• Could be observed after 6 mo
neoadjuvant ADT
CRPC patients receiving
chemotherapy3
OR
Metastatic CRPC pts on
abiraterone after failing on
docetaxel4
• CTCs are useful for predicting
treatment response/survival
with cytotoxic and hormonal
therapies
• However, ~50% of patients do
not have detectable CTC
levels by current detection
methods
• More-ensitive CTC detection
techniques needed
ADT=androgen-deprivation therapy; DHT=dihydroxytestosterone; LHRH=luteinizing
hormone-releasing hormone
1. Perachino M, et al. BJUI. 2010;105:648-51. 2. Nishiyama T, et al. Cancer Res. 2004;10:7121-6. 3. de Bono JS, et
al. Clin Cancer Res. 2008;14:6302-9.
Other Biomarkers With Correlation to
Outcomes in Prostate Cancer (cont.)
Biomarker
Population
TMPRSS2-ERG fusion1-4
– Rearrangements present
~50% of newly diagnosed
patients
– Creates androgen
receptor-driven expression
of ERG
AR35
– In vitro studies suggest
AR3 promotes androgenindependent growth
Correlation
•
TMPRSS2-ERG no
rearragement, Edel (1 or
2+), and Esplit patient
samples
Patient samples from
benign, hormone-naïve,
and hormone-resistant
tumors
•
AR3 appears to be upregulated
during prostate cancer
progression during hormone
therapy, and is associated with
androgen-resistant growth
•
CRPC6
Interleukin (IL)-6
Metastatic
and
metastatic CRPC receiving
first-line docetaxel7
Exact rearrangement may
indicate lethality of tumor2,3
Association between ERG
fusion and PSA decline
seen in patients treated with
abiraterone4
•
Higher baseline IL-6
associated with worse
prognosis6,7
Correlation with response to
docetaxel7
1. Danila DC, et al. Eur Urol. 2011;60:897-904. 2. Mehra R, et al. Cancer Res. 2008;68:3584-90. 3. Attard G, et al.
Oncogene. 2008;27:253-63. 4. Attard G, et al. Cancer Res. 2009;69:2912-8. 5. Guo Z, et al. Cancer Res.
2009;69:2305. 6. George DJ, et al. Clin Cancer Res. 2005;11:1815-20.