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Prostate 101
1. Dana Rathkopf, MD
Genitourinary Oncology Service
Memorial Sloan Kettering Cancer Center
Prostate Cancer 101
The following material is intended for MSKCC internal medicine housestaff teaching purposes only. The
slides are courtesy of Dr. Dana Rathkopf and were updated for the LibGuide in 2012-2013.
2. Jemal, A. et al. CA Cancer J Clin 2010
Estimated New Cancer Cases and Deaths, US, 2010
6. Iyer Cancer 1999
Simone Kaiser: Identification and Characterization of the Ion Channel TRPM8 in Prostate Cancer
7. Risk Factors for Prostate Cancer
• Age
– Less than 10% diagnosed in men <54 years
– 64% diagnosed between 55-74 years
• Ethnicity:
– BM 68% higher incidence, 158% higher mortality
• Dietary Fat:
– Increased relative risk by a factor of 1.6 to 1.9
• Family History:
• 5-10% of all patients have family history
• Relatives of patients younger than 55 years have greater risk
• 1 relative = 2x lifetime risk, >= 2 relatives = 4x lifetime risk
• At least 8 candidate susceptibility genes have been reported
8. Prostate Specific Antigen (PSA):
An Imperfect Tool
• Glycoprotein secreted by the prostate
• ORGAN specific (not cancer-specific)
• Sensitivity 70-80% and PPV 30% when PSA is
‘normal’ (< 4)
• Does not inform grade , and may lead to detection and
treatment of indolent disease
• Influenced by biologic variations, age, prostate volume,
inflammation, race/ethnicity
• NOT influenced by DRE or ejaculation
9. Improving the use of PSA for Detection
• PSA density: >0.15 suggestive of PC
CA causes a greater elevation in PSA /volume than BPH
• PSA velocity: >0.75 ng/ml/yr suggestive of PC
• Percent free PSA: <25% suggestive of PC
CA related PSA is bound to α-glycoprotein
• Age specific PSA: <2.5 ng/ml 40-49 yo
3.5 ng/ml 50-59 yo
4.5 ng/ml 60-69 yo
6.5 ng/ml 70-79 yo
10. Scardino and Kelman. Avery Press, 2005.
• Average age at diagnosis
is 68 years old
• PSA screening advances
lead time by 5-10 years
• Overdiagnosis?
Implications of Early Detection
in an Aging Population
11. ERSPC Bottom Line: YES
PSA-based screening reduced the rate of
death from prostate cancer by 20%; but was
associated with a high risk of overdiagnosis.
US PLCO Bottom Line: NO
The rate of death from prostate cancer was
very low and did not differ significantly
between the two study groups; but 40% of
usual care group had PSA testing.
Prostate Cancer Screening:
Results of 2 Randomized Controlled Studies
12. Prostate Cancer Screening Guidelines
PSA Screening
(life expectancy >10 yrs)
PSA Screening
(+risk factors)
American Cancer Society
www.cancer.org
Offer at age 50 Offer at age
40-45
American Urologic Association
www.auanet.org
Baseline 40 years old
National Comprehensive Cancer
Network
www.nccn.org
Baseline 40 years old:
>1 ng/mL annual follow-up
<1 ng/mL rescreen age 45
US Preventive Services Task Force
http://www.uspreventiveservicestaskforce.org
No screening for patients >75
(No screening ever??)
Baseline PSA at age 40 is a stronger independent predictor of PC risk
than ethnicity, family history, or DRE. (Loeb et al, AUA 2005)
13. Prostate Cancer Clinical States
FDA-approved Agents for Prostate Cancer
Rising
PSA
Clinical
Metastases:
Castrate
1st Line Chemo
Clinical
Metastases:
Castrate
Pre-Chemo
Clinically
Localized
Disease
Clinical
Metastases:
Non-Castrate
Clinical
Metastases:
Castrate
Post-Chemo
NON-CASTRATE
Diagnosis
241, 740
Androgen Deprivation
Therapy
CASTRATION -RESISTANT
Deaths From Disease
28, 170
Docetaxel
2004
Sipuleucel -T
2010
Cabazitaxel
2010
Abiraterone
2011
Enzalutamide
2012
Abiraterone
2012
14. Charles B. Huggins, MD
Nobel Prize in Physiology or Medicine, 1966
Huggins C, Hodges CV. Studies on prostatic cancer I. The effect of castration, estrogen,
and of androgen injection on serum phosphatases in metastatic carcinoma of the
prostate. Cancer Res. 1941;1:293–297.
William Wallace Scott, Charles B. Huggins, and Clarence V. Hodges
19. Anti-Androgen Withdrawal
Kelly et al, 1997
Author
Scher
Dupont
Herrada
Sartor
Figg
Small
Small
Overall
50% PSA
Decline
16/57 (28%)
32/40 (80%)
11/39 (28%)
14/29 (48%)
7/21 (33%)
12/82 (15%)
4/8 (50%)
96/276 (35%)
Time to
Response
(weeks)
5.6
NS
<6
<4
<6
NS
<4
Duration of
Response
(months)
4
14.5
3.3
8
3.7
3.5
NS
20. Hormones: Limitations
• Hormones are NOT curative
• Significant side effect profile:
Diminished libido and potency
Osteoporosis
Weight gain
Diminished muscle mass
Breast enlargement and breast tenderness
Emotional changes
Fatigue
Anemia
21. Intermittent ADT Phase III Trials
Trial (Year) Patient
Population
No. of pts
randomized
Primary
Endpoint
NCIC PR7 (2011) PSA relapse after RT
Non-Metastatic
1386 OS
No difference
EC 507 (2007) PSA relapse after RP
Non-Metastatic
167 TTP
AP 17/95 (2007) Locally advanced/
Metastatic (~40%)
335 TTP
SEUG (2009) Locally advanced/
Metastatic (~30%)
766 TTP
FinnProstate (2012) Locally advanced/
Metastatic (~50%)
554 TTP
TULP (2011) Metastatic 193 TTP
SWOG 9346 (2012) Metastatic 1535 OS
MODIFIED FROM SLIDES by William Oh, M.D.
22. [TITLE]
Overall survival with Intermittent Hormonal Therapy is
NOT “NONINFERIOR” to Continuous Therapy
(Translation: it is POTENTIALLY inferior)
Modified Slide
23. Conclusions
Intermittent is NOT Non-Inferior to Continuous ADT
• Continuous ADT remains the standard of care for
hormone sensitive metastatic PC
• Neither this nor any randomized trial has EVER shown a
superior cancer outcome with intermittent ADT
• Will more potent reduction of intratumoral androgen
(abiraterone) or inhibition of AR signaling (enzalutamide)
lead to better outcomes with initial ADT?
24. Untreated
Primary
Metastatic Castration
Resistant
Scher et al.
Endocrine-Related
Cancer 11:2004;459
The Androgen Receptor is Often Overexpressed in
Castration Resistant Tumors and is a Target for Therapy
Increased AR protein
AR mRNA overexpression
Increased AR DNA
copy number
o
Post-Androgen
Depletion
25. AR
HSP90AR degraded
AR P
AR PARP
Transcription of
TMPRSS-ETS, etc
for growth and survival
SRC
Androgen
precursors
Androgens
Adrenal synthesis
Tumor synthesis
DHT
AR AR
Cell surface
ligand/receptor
AKT
ARP
mut
AR
AR
AR
ARAmp
AR
+
antiandrogens,
progestins
glucocorticoids
Modified from Chen et al.
Curr Opin Pharm, 2008
Therapeutic Targets of the AR Signaling Pathway
AGONIST CONVERSION
ALTERNATIVE LIGANDS
ADRENAL/INTRATUMORAL
ANDROGENS
LIGAND INDEPENDENT AR
PHOSPHORYLATION
26. FDA Approved Agents
with an Overall Survival Benefit in CRPC
Agent Year
Approved
Mechanism Median
Overall Survival
Hazard
Ratio
Docetaxel1
vs Mitoxantrone
2004 Anti-microtubule 2.5
18.9 vs 16.5
0.76
Sipuleucel-T2
vs Placebo
2010 Immunomodulatory 4.1
25.8 vs 21.7
0.78
Cabazitaxel3
vs Mitoxantrone
2010 Anti-microtubule 2.4
15.1 vs 12.7
0.70
Abiraterone4
vs Placebo
POST-DOCETAXEL*
2011 Androgen synthesis
inhibitor
3.7
14.8 vs 10.9
0.65
MDV31005
vs Placebo
POST-DOCETAXEL*
2012 AR antagonist 4.8
18.4 vs 13.6
0.63
1Tannock et al., NEJM 2004; 2Kantoff et al., NEJM 2010; 3DeBono et al., NEJM 2010; 4DeBono et al., NEJM 2011;
5Medivation Interim Analysis of the AFFIRM Trial in CRPC post-Docetaxel 11/3/11
*CTC biomarker analysis at MSKCC embedded in the phase 3 trials as a surrogate for survival
27. Adapted from J E Ang, et al, British Journal of Cancer, 2009
Secondary Mineralicorticoid Syndrome
*Low dose steroids minimizes toxicity*
Suppression of the Renin-
Angiotensin Pathway
4 fold increase due to elevated
ACTH partially reverses
17-hydroxylase activity
Abiraterone Acetate
Selective and Irreversible Inhibition of CYP17
30. Overall Study Design of COU-AA-302
CHEMONAIVE CRPC
• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151
sites in 12 countries
• Stratification by ECOG performance status 0 vs 1
• No prior novel anti-androgens (MDV3100), ketoconazole or chemotherapy
Co-Primary Endpoints:
• rPFS by central review
• OS
Secondary:
• Time to opiate use (cancer-
related pain)
• Time to initiation of
chemotherapy
• Time to ECOG-PS
deterioration
• TTPP
AA 1000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
Efficacy end points
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
R
A
N
D
O
M
I
Z
E
D
1:1
• Progressive chemo-
naïve mCRPC patients
(Planned N = 1088)
• Asymptomatic or
mildly symptomatic
Patients
31. Landmarks of Disease Progression in mCRPC
Planned Interim Analysis at 43% of Events
31
Baseline
PSA
Progression
Tumor/Bone
Progression
Pain
Death
Adapted from Halabi S. et al, J Clin Oncol. 2009;27:2766-2771.
Chemotherapy
ECOG PS Decline
Secondary Endpoints
ECOG PS= Eastern Cooperative Oncology Group
Performance Status
24-48 months
p < 0.0001 p < 0.0001 p = 0.001 p = 0.0053
rPFS
p < 0.0001
OS
p = 0.0097
32. Safety Profile Consistent Despite Longer
Duration of Exposure
Most Prevalent AE
AA + P
(n = 542)
%
Placebo + P
(n = 540)
%
All Grades Grades 3/4 All Grades Grades 3/4
Fatigue 39 2.2 34 1.7
Fluid retention 28 0.7 24 1.7
Hypokalemia 17 2 13 2
Hypertension 22 4 13 3
Cardiac disorders 19 6 16 3
ALT increased 12 5.4 5 0.8
AST increased 11 3.0 5 0.9
32
• Most of the ALT and AST increases occurred during the first 3 months of treatment
33. Statistically Significant Improvement in rPFS
Primary End Point
NR, not reached; PL, placebo.
100
80
60
40
20
0
0
ProgressionFree(%)
3 6 9 15 1812
AA + P (median, mos): NR
PL + P (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
P value: < 0.0001
546
542
489
400
340
204
164
90
12
3
0
0
AA
Placebo
46
30
Time to Progression or Death (Months)
AA
Placebo
34. Strong Trend in OS Primary End Point*†
*O’Brien-Fleming boundary used; †Data cut off 12/20/2011; ‡Nominal significance level 0.0008.
546
542
538
534
482
465
452
437
27
25
0
0
524
509
503
493
0
2
120
106
258
237
412
387
100
80
60
40
20
0
0
Survival(%)
3 12 15 27
Time to Death (Months)
33
AA
Placebo
6 9 30242118
AA
Placebo
AA + P (median, mos): NR
PL + P (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097‡
35. Summary: New Standard of Care?
AA and Prednisone for Pre-chemo mCRPC
• Delays disease progression
• Increases survival* (but not by pre-specified amount)
• Extends time with minimal or no symptoms
• No new important safety signals
* 55% Interim Analysis due at ASCO 2013
36. Compared to bicalutamide… 20-fold higher affinity for the AR
6/19/06
Rathkopf et al, Clin Cancer Res, 2011
-100%
-75%
-50%
-25%
0%
25%
50%
75%
100%
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55
Dose
decline post BMS Therapy BY DOSE
5 mg 10 mg 20 mg 40 mg 60 mg 100 mg
37. WISH LIST
Second Generation AR Antagonist
Bicalutamide BMS641988 2nd Gen AA
Effective in cells
with high AR
expression
X
Overcomes
agonist
activity
X X
Novel
mechanism
of action
X X
38. Ligand
1. AR Binding Affinity
• DHT ~ 5nM
• Bicalutamide ~160 nM
• MDV3100 ~35 nM
2. Nuclear Import
• DHT: ++++
• Bicalutamide: ++++
• MDV3100: ++
3. DNA Binding
• DHT: ++++
• Bicalutamide: ++
• MDV3100: -
4. Coactivator recruitment:
No agonist effects.
• DHT: ++++
• Bicalutamide: ++
• MDV3100: -
MDV3100: A Novel AR Antagonist
1
2
3
4
DNA
POL II
HSP90
LBD
HD
DBD
NTD
Chen et al. Lancet Oncol 10:981, 2009
Tran et al., Science 324:787, 2010.
39. MDV3100 is active in AR expressing tumor models and
inhibits AR nuclear translocation
Tran et al., Science 324:787, 2009
LnCAP-AR Cell Lines
RD162 is the precursor of the clinical candidate MDV3100
41. Pre- and Post-Treatment FDHT PET Imaging
On-Target Effect of AR inhibition with MDV3100
18-Fluorodihydrotestosterone (F-DHT) PET
Pre -Treatment
Post -Treatment
Scher HI et al., Lancet, 2010
Dosage
42. AFFIRM Trial Design
Enrollment between September 2009 and November 2010
156 centers from 15 countries and 5 continents.
R
A
N
D
O
M
I
Z
E
D
2:1
Primary
Endpoint:
Overall Survival
Enzalutamide
160 mg daily
n = 800
Placebo
n = 399
Patient Population:
1199 patients with
progressive CRPC
* Failed docetaxel
chemotherapy
43. Enzalutamide Prolonged Survival, Reducing
Risk of Death
HR = 0.631 (0.529, 0.752) P <0.0001
37% reduction in risk of death
Enzalutamide: 18.4 months
(95% CI: 17.3, NYR)
Placebo: 13.6 months
(95% CI: 11.3, 15.8)
Enzalutamide 800 775 701 627 400 211 72 7 0
Placebo 399 376 317 263 167 81 33 3 0
44. AFFIRM: Clinical Outcomes
Variable Enzalutamide
(800 pts.)
Placebo
(399 pts.)
Hazard Ratio P -value
OS
(months)
18.4 13.6 0.631 <0.0001
PSA progression
(months)
8.3 3.0 0.218 <0.0001
rPFS
(months)
8.3 2.9 0.404 <0.0001
1st SRE
(months)
16.7 13.3 0.621 <0.0001
CR + PR 28.9% 3.8% - <0.0001
FACT-P 43.3% 17.8% - <0.0001
Slide modified from presentation by Kevin Kelly, DO
45. Favorable Adverse Risk Profile
All Grades Grades >3*
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
AEs 98.1% 97.7% 45.3% 53.1%
Serious AEs 33.5% 38.6% 28.4% 33.6%
Discontinuations due
to AEs
7.6% 9.8% 4.6% 7.0%
AEs leading to death 2.9% 3.5% 2.9% 3.5%
All Grades Grade ≥ 3 Events
Enzalutamide
(n = 800)
Placebo
(n = 399)
Enzalutamide
(n = 800)
Placebo
(n = 399)
Seizure 0.6% 0.0% 0.6% 0.0%
Slide modified from presentation by Kevin Kelly, DO and Johann De Bono, MD
46. • AR antagonist drug class causes convulsions in laboratory animals at
high doses by an off-target mechanism
• AR antagonist seizure risk increases with brain drug concentrations
• AR antagonist drug class inhibits the GABA-A current1
• Seizures have been observed in clinical testing of the next generation
AR antagonists BMS-641988 and MDV3100
Seizure potential is an important consideration
in the development of AR antagonists*
*Slide adapted from discussion by Dr. WK Kelly at 2012 ASCO Annual Meeting
1Foster WR et al. Prostate . 2011
47. ARN-509 Produces Superior
Antitumor Responses than
Bicalutamide in Castration
Resistant LNCaP/AR-Luc Xenografts.
Clegg N et al., Cancer Res 2012
ARN-509: A Novel Anti-Androgen for Prostate Cancer Treatment
Exhibits Characteristics Predicting a Higher Therapeutic Index than Current AR Antagonists
48. Phase II Study of the Novel AR Antagonist ARN-509 in CRPC
Activity across the spectrum of CRPC including post-abiraterone
Non-Metastatic CRPC Metastatic CRPC Post-Abiraterone CRPC
Baseline PSA
(ng/mL, range)
9.7
(0.5, 201.7)
14.7
(1.1, 2552.1)
64.1
(12.0, 1315.2)
12-Week PSA
Response* 91% 88% 29%
%ChangeinPSAfrombaseline
Individual Patients
* Per PCWG2, the % of patients that reach ≥ 50% decline from baseline at week 12 (3 months) on study
n=45 n=25 n=14
Rathkopf et al. Poster Presentation, 2012 Prostate Cancer Foundation Annual Meeting
-100
-75
-50
-25
0
25
50
75
100
50. Chemotherapy for CRPC
Background
• 1985: No evidence for palliative benefit from chemotherapy.
Chemotherapy recommended only for clinical trials.
• 1996: Mitoxantrone + prednisone vs prednisone alone
establishes a palliative benefit for mitoxantrone in 30%
of symptomatic patients. Studies are too small to detect a survival
benefit. FDA approval.
• 2004: The larger TAX327 and SWOG 99-16 trials show a 3
month improvement in survival (1619 months) for Docetaxel
compared to Mitoxantrone. FDA approval.
52. TAX 327 Established Docetaxel as the First-Line Standard
of Care for Castration-Resistant Prostate Cancer:
Benefit Was Restricted to Every 3 Week Dosing
Months
Median
survival Hazard
(mos) ratio P-value
Docetaxel every 3 weeks: 18.9 0.76 0.009
Docetaxel weekly: 17.3 0.91 0.3
Mitoxantrone 16.4 – –
ProbabilityofSurviving
0 6 12 18 24 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Docetaxel 3 wkly
Docetaxel wkly
Mitoxantrone
Tannock et al., NEJM, 351:1502, 2004
53. 53
Cabazitaxel Primary Endpoint:
Overall Survival—Updated ITT Analysis*
28% reduction in risk of death
Time (months)
ProportionofOS(%)
377
378
299
321
195
241
94
137
31
60
9
19
100
80
60
40
20
0
0 6 12 18 24 30
MP CBZP
Median OS (months) 12.7 15.1
Hazard ratio 0.72
95% CI 0.61–0.84
P-value <.0001
Number
at Risk
MP
CBZP
Censored
MP
CBZP
Combined median
follow-up: 13.7 months
* Data cut-off 3/10/2010
54. Why do we need clinical trials?
• Hormones and chemotherapy are not curative
• Durability of effects is limited
• Despite the proven benefits, both have significant side
effects
• There are patients who will not respond to standard
treatments
55. RADIUM-223
T1/2 Range in tissue
Average
particle
energy
per decay
Bone surface
to red bone
marrow dose
ratio
Strontium 89 50.5 d 2.4 mm 0.58 MeV 1.6
Samarium
153-EDTMP
1.9 d 0.55 mm 0.22 MeV 4.4
Radium 223 11.4 d < 0.1 mm 27.4 MeV 10.3
Adapted from Bruland et al, Clin Cancer Res, 2006
56. Radium-223 Targets Bone Metastases
• Radium-223 acts
as a calcium mimic
• Naturally targets
new bone growth
in and around
bone metastases
• Radium-223 is
excreted by the
small intestine
Ra
Ca
57. ALSYMPCA (ALpharadin in SYMptomatic Prostate
CAncer) Phase III Study Design
TREATMENT
6 injections at
4-week intervals
Radium-223 (50 kBq/kg) +
Best standard of care
(IV q 4 weeks up to 6 treatments)
Placebo (saline)
+ Best standard of care
R
A
N
D
OM
I
S
E
D
2:1
N = 921
PATIENTS
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Post-docetaxel
or unfit for
docetaxel
Primary Endpoint: Overall Survival
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
STRATIFICATION
Clinicaltrials.gov identifier: NCT00699751
60. ALYSMPCA Updated Analysis Conclusions
• Significantly improved OS (3.6m), SRE (5.5m)
• Favorable safety profile
• Has activity and safety profile compatible for use with
patients who are not good candidates for docetaxel
Radium-223, a novel alpha-pharmaceutical, may provide a new
standard of care for the treatment of CRPC patients with bone
metastases
61. Cabozantinib (XL184)
in Chemotherapy-pretreated Metastatic Castration
Resistant Prostate Cancer (mCRPC): Results from a Phase
2 Nonrandomized Expansion Cohort
(abstract #4513)
M.R. Smith, C. Sweeney, D. Rathkopf, H.I. Scher, C. Logothetis, D.J.
George, C.S. Higano, E.Y. Yu, A.L. Harzstark, E.J. Small, O.A. Sartor, M.S.
Gordon, N.J. Vogelzang, D.C. Smith, M. Hussain,
J.S. de Bono, N.B. Haas, C. Scheffold, Y. Lee, P.G. Corn
Massachusetts General Hospital Cancer Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Sidney Kimmel Center for Prostate and
Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX;
Duke University Medical Center, Durham, NC; Fred Hutchinson Cancer Research Center, Seattle, WA; University of California, San Francisco,
San Francisco, CA; Tulane Cancer Center, New Orleans, LA; Pinnacle Oncology Hematology, Scottsdale, AZ; US Oncology Research/
Comprehensive Cancer Centers NV, Las Vegas, NV; University of Michigan, Ann Arbor, MI; Royal Marsden Hospital & Institute of Cancer
Research, Sutton, United Kingdom; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Exelixis, South San Francisco, CA;
University of Texas M. D. Anderson Cancer Center, Houston, TX
62. Cabozantinib (XL-184)
Oral TKI that Inhibits MET and VEGFR
• Randomized discontinuation trial in CRPC
– High rates of bone scan improvement
– Reduction in bone markers
– Regression of soft tissue disease
– PFS improvement
– Pain improvement and narcotics reduction
– PSA changes discordant with other
measures of antitumor activity
M. Hussain et al. ASCO 2011 (Abstract #4516)
Bone scan
Baseline Follow-up
64. Most Frequently Reported Adverse Events (N = 93)
Adverse Event All Grades, n (%) Grade 3, n (%) Grade 4, n (%)
Fatigue 77 (83) 24 (26) 2 ( 2)
Decreased appetite 68 (73) 6 ( 6) -
Diarrhea 65 (70) 10 (11) -
Nausea 62 (67) 9 (10) -
Vomiting 35 (38) 4 (4) -
Dysgeusia 35 (38) - -
Weight decreased 34 (37) 3 (3) -
Dysphonia 33 (35) - -
Back pain 32 (34) 5 (5) 2 (2)
Dyspnea 30 (32) 4 (4) 1 (1)
Hypothyroidism 29 (31) - -
Adverse Events of Interest
Hand-foot syndrome 23 (25) 5 (5) -
Hypertension 22 (24) 8 (9) -
Thrombosis venous 12 (13) 1(1) 5 (5)
One patient with extensive liver disease experienced a related Grade 3 portal vein thrombosis with Grade 5 liver failure
84% of patients experienced at least one dose reduction due to AE
65. SUMMARY
Exciting Time in Treatment for CRPC
• The Androgen Receptor remains a relevant target.
• New technology to evaluate response and progression:
circulating tumor cells, FDHT PET.
• Collaborative efforts to increase accrual and share concepts
and ideas.
• 4 new drugs approved …More to come!!!
Editor's Notes
Dr. Gleason: Pathologist from Minnesota who pulblished a morphometric scale of PC grading
T1a incidental TURPT1c indicental PSAT2 palpableT3 ECE/SVIT4 Adjacent organs*Not everyone does LND*T score imperfect measure of dz: ie T1C Gleason 9 6 cores versus Gl 6 1 core
Enzyme liquifies semenInitially described in the forensic literatureMay have a role in local activation of GF at metastatic sitesPre and post DRE bx: change in value 0.04
• PSA density is used to help differentiate between cancer and BPH in men with moderately high PSA levels (4 to 10 ng/mL) and normal DRE results. Cancer causes a greater elevation in PSA per prostate volume than BPH -- which means PSA density should be higher in men with cancer. To find PSA density, doctors divide the PSA results by prostate volume (as estimated by transrectal ultrasound). This method is imperfect, but studies showing that PSA density levels over 0.15 indicate a high risk of cancer have led doctors to use PSA density tests for men with PSA levels between 4 and 10 ng/mL.• PSA velocity monitors changes in PSA over time. PSA levels rise more rapidly in men with prostate cancer than in other men. To be most effective, PSA should be measured at least three times over a two-year period to calculate PSA velocity. Research has found that about 70% of men with a PSA velocity of 0.75 ng/mL or greater have cancer when PSA is 4 to 10 ng/mL. But only about 50% of men with a PSA velocity below 0.75 ng/mL per year have cancer. The test is used primarily to determine the need for a repeat biopsy in those with PSA levels between 4 to 10 ng/mL and a prior negative biopsy.• Age-specific PSA levels have been suggested for younger men, because PSA levels usually rise with age. Thus, while 2 ng/mL may be normal in a 60-year old, this level is more likely to signify cancer in men between ages 40 and 49. Since research has yet to show that using age-specific PSA values will increase the detection of curable cancers, for now the standard cut-off of 4 ng/mL is still considered preferable for men between age 50 and 70.• Percent free PSA is the ratio of free (unbound) PSA to bound (attached to proteins) PSA in the blood. Men with prostate cancer have a lower percent free PSA than men without cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.
60-70% of all PC diagnosed >70 yoIn an aging population, the implications of detecting and diagnosing all prostate cancers is clear68 life expectancy 14.5-16.3 yrs; may die of other causes
The use of HT in PC was pioneered by Huggins et al in 1941 when they:he proved that administration of the female hormone estrogen slowed the growth of prostate cancer in males."the Huggins operation" -- castration -- for particularly advanced cases. Dr. Huggins, in collaboration with his students Clarence V. Hodges and William Wallace Scott, published three papers in 1941 that demonstrated the relationship between the endocrine system and the normal functioning of the prostate gland. The regression and the consequent relief of pain was often spectacular and occurred within days or sometimes even hours after treatment. Four of Dr. Huggins' original 21 hormone-therapy patients lived for more than 12 years after treatmentPalliation, relief of urinary symptoms, concomitant decline in acid phosphatase.
9 % relative risk of death with intermittent therapyHowever upper limit of 95% CI was > 1.24 (more than the prespecified threshold of 1.2). SO OS with IT was NOT NON-INFERIOR to CONTINUOUSSurvival much better than 3 yrs expected so it took longer to observe the number of deaths required for the final analysis hence the longer duration
(1) AR is bound to the molecular chaparone HSP90 which prevents its degradation. HSP90 inhibitors, such as 17-AAG, cause AR degradation and decrease AR levels. (Dave Solit)(2) In men treated with GnRH agonists to shut down testicular androgen synthesis, residual serum androgens are synthesized by the adrenal glands. In additional, evidence suggests intratumoral androgen synthesis. Both can be inhibited by the nonspecific p450 inhibitor ketoconazole and the 17-lyase inhibitor abiraterone.(3) Testosterone is converted to the more potent dihydrotestosterone (DHT) by 5α-reductase, which is inhibited by finasteride and dutasteride. (Morris)(4) Ligands, such as DHT bind to AR and this is inhibited by antiandrogens such as bicalutamide and novel agents MDV-3100 and BMS641988. Mutation of AR as well as AR overexpression can convert endogenous steroids (e.g. progestins, estrogens, and corticosteroids) and some antiandrogens into agonists. MDV-3100 was designed to suppress AR function even when AR is overexpressed. (5) Activation of receptor tyrosine kinases, can lead to downstream AR activation. Two downstream kinases that directly phosphorylate AR on tyrosine are Ack1 and SRC. Other downstream pathways of receptor tyrosine kinases, including the AKT and MAP kinase pathways, are also implicated. Antibodies such as trastuzamab and pertuzumab and small molecular TKI inhibitors such as erlotinib and lapatinib target HER2. Dasatinib targets SRC. (6) Proper transcription mediated by AR requires the proper chromatin state. HDAC inhibitors inhibit transcription of AR target genes by the disruption of chromatin structure and inhibition of recruitment of coactivators and RNA polymerase II.
First time a hormone used post-chemo with a survival benefit. AR STILL RELEVANT.
The Kaplan Meier curve for the co-Primary endpoint of rPFS is shown here. The radiographic Progression Free Survival (rPFS), as assessed by independent radiologic review in the AA/Prednisone arm had not yet been reached and was 8.3 months in the Placebo/Prednisone arm, associated with a Hazard ratio of 0.43 (95% Confidence Interval 0.35-0.52) P<0.0001.
The Kaplan Meier plot for the Co-Primary endpoint of Overall Survival is shown here.the Median survival in the Prednisone control arm is 27.2 months while the median survival has not yet been reached in the Abiraterone arm., This conforms to a Hazard ratio of 0.75 and a p value of 0.0097 -A strong statistical trend in favor of AAThe prespecified p value for significance of OS at 43% of events is 0.0008 by the O’Brien-Fleming boundary (as implemented in the LanDemets alpha-spending method).
Taken in aggregate,AA proved favorable across a broad spectrum of clinical outcomes including: delay progression, improve survival, maintain QOLAs clinical oncologists charged with providing safe and effective treatment to our patients, these findings merit consideration of providing a new approach to a population in need of treatment with less toxicity.
Confocal microscopy
KETO: PRE 55/77 (71%) VS POST 23/63 (37%) This set the stage not just for using MDV3100 in CRPC post-chemo pts previously assumed tobe refractory, but also abiraterone.
>90% bone metsCurrently approved radiopharmaceuticalsdealy SRE but do not effect survivalAlkaline earth metals- taken up in bone
Sx= any analgesic or palliative RT within 12 weeks (even if rendered pain free)
Consistent across all subgroups: Doc, Bisphos,
Heme: Modest increase grade ¾ thrombocytopeniaExcretion: GI
Potent oral TKIInhibits MET and VEGFR2Randomized discontinuation trial of cabo inmCRPC