State of the Art: Treatment Options in
Advanced Genitourinary Cancers
David I. Quinn MBBS (Hons) PhD FRACP
Associate Professor of Medicine
Chief, Section of GU Medical Oncology
Division of Cancer Medicine & Blood Diseases
Medical Director, Norris Cancer Hospital & Clinics
Co-Leader, Developmental Therapuetics Program
Kenneth J. Norris Comprehensive Cancer Center
Keck School of Medicine, University of Southern California
David Quinn has received
honoraria and served on
advisory boards for
Genomic Health, Pfizer,
Novartis, Glaxo Smith
Kline and Genentech
Learning Objectives
After reading and reviewing this material, the
participant should be better able to:
• List the major potentially practice changing data
elements in the field of GU cancer to 2010
– Assess their merit
– As applicable apply their content to clinical
practice
• Understand the implications of how practice
changing and other material presented that may
impact clinical practice in GU oncology in the
coming years
Genitourinary Cancers - ASCO 2010:
Key prostate cancer abstracts
Intergroup randomized phase III study of androgen deprivation therapy
(ADT) plus radiation therapy (RT) in locally advanced prostate cancer
CRA4504
Impact of radiotherapy (RT) combined with androgen deprivation (ADT)
versus ADT alone for local control in clinically locally advanced prostate
cancer 4505
A randomized phase III trial of denosumab versus zoledronic acid in
patients with bone metastases from castration-resistant prostate cancer
LBA 4507
Cabazitaxel or mitoxantrone with prednisone in patients with metastatic
castration resistant prostate cancer (mCRPC) previously treated with
docetaxel: Final results of a multinational phase III trial (TROPIC).4508
A randomized, double-blind, placebo-controlled phase III trial comparing
docetaxel, prednisone, and placebo with docetaxel, prednisone, and
bevacizumab in men with metastatic castration-resistant prostate cancer
(mCRPC):Survival results of CALGB 90401. LBA4511
Genitourinary Cancers - ASCO 2010:
Key prostate cancer abstracts
Intergroup randomized phase III study of androgen deprivation therapy
(ADT) plus radiation therapy (RT) in locally advanced prostate cancer
CRA4504
Impact of radiotherapy (RT) combined with androgen deprivation (ADT)
versus ADT alone for local control in clinically locally advanced prostate
cancer 4505
A randomized phase III trial of denosumab versus zoledronic acid in
patients with bone metastases from castration-resistant prostate cancer
LBA 4507
Cabazitaxel or mitoxantrone with prednisone in patients with metastatic
castration resistant prostate cancer (mCRPC) previously treated with
docetaxel: Final results of a multinational phase III trial (TROPIC).4508
Locally advanced prostate cancer
Advanced prostate cancer: bone
metastases and osteoclast inhibition
Castrate
resistant
prostate
cancer
A randomized, double-blind, placebo-controlled phase III trial comparing
docetaxel, prednisone, and placebo with docetaxel, prednisone, and
bevacizumab in men with metastatic castration-resistant prostate cancer
(mCRPC):Survival results of CALGB 90401. LBA4511
ASCO 2010: Germ Cell, Renal Cell Cancer
and Urothelial Cancer Highlights
A randomized phase III study comparing standard dose BEP with
sequential high-dose cisplatin, etoposide, ifosfamide (VIP) plus stem
cell support in males with poor prognosis germ cell cancer: An
intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC
30974) 4512.
The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with
metastatic renal cell carcinoma.4514
Can the combination of temsirolimus and bevacizumab improve the
treatment of metastatic renal cell carcinoma (mRCC)? Results of the
randomized TORAVA phase II trial. 4516
Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/
cisplatin (PGC) to observation in patients with resected invasive bladder
cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG)
99/01 study. LBA4518
Randomized phase II/III trial comparing gemcitabine/carboplatin (GC)
and methotrexate/carboplatin/vinblastine (M-CAVI) in patients (pts)
with advanced urothelial cancer unfit for cisplatin-based chemotherapy
(CHT): Phase III results of EORTC study 30986. LBA4519
ASCO 2010: Germ Cell, Renal Cell Cancer
and Urothelial Cancer Highlights
A randomized phase III study comparing standard dose BEP with
sequential high-dose cisplatin, etoposide, ifosfamide (VIP) plus stem
cell support in males with poor prognosis germ cell cancer: An
intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC
30974) 4512.
The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with
metastatic renal cell carcinoma.4514
Can the combination of temsirolimus and bevacizumab improve the
treatment of metastatic renal cell carcinoma (mRCC)? Results of the
randomized TORAVA phase II trial. 4516
Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/
cisplatin (PGC) to observation in patients with resected invasive bladder
cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG)
99/01 study. LBA4518
Randomized phase II/III trial comparing gemcitabine/carboplatin (GC)
and methotrexate/carboplatin/vinblastine (M-CAVI) in patients (pts)
with advanced urothelial cancer unfit for cisplatin-based chemotherapy
(CHT): Phase III results of EORTC study 30986. LBA4519
High risk testis cancer
Renal cancer: immunotherapy
Locally advanced bladder cancer:
adjuvant therapy
“Unfit” patients with urothelial cancer
ASCO 2010: GU Summary Conclusions
Take home messages
Locally Advanced Prostate Cancer:
RT with ADT for 3 years is a standard of care
Monotherapy with ADT or RT are NOT
Castrate-Resistant Prostate Cancer:
Docetaxel needs a date or a mate: still looking!
BUT son of docetaxel, Cabazitaxel has a role in second line therapy
Options for Osteoclast inhibition broaden: Denosumab
Germ Cell Tumors: No role for first line HDCSCT
Optimal therapy at relapse: standard chemotherapy or SCT?
RCC: Selection can improve HDIL2 outcome but still no biomarker
Serial monotherapy: ruling therapeutic paradigm for targeted therapy
Urothelial cancer: adjuvant chemotherapy may have a place …
In medical unfit patients Gemcitabine/Carboplatin remains a default
standard
Concurrent mitomycin C and 5FU adds to disease control with RT.
Intergroup randomized phase III study of androgen
deprivation therapy (ADT) plus radiation therapy (RT)
in locally advanced prostate cancer (CaP) (NCICCTG, SWOG, MRC-UK, INT: T94-0110;
NCT00002633)
Abstract CRA 4504
P. R. Warde, M. D. Mason, M. R. Sydes, M. K. Gospodarowicz, G. P.
Swanson, P. Kirkbride, E. Kostashuk, J. Hetherington, K. Ding, W.
Parulekar, NCIC CTG PR.3/ MRC PRO7/ SWOG JPR3 investigators;
Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto,
Toronto, ON, Canada; Velindre Hospital, Cardiff, United Kingdom; Clinical Trials Unit,
Medical Research Council, London, United Kingdom; University of Texas Health Science
Center at San Antonio, San Antonio, TX; Weston Park Hospital, Sheffield, United Kingdom;
British Columbia Cancer Agency, Surrey, BC, Canada; Castle Hill Hospital, Hull, United
Kingdom; NCIC Clinical Trials Group, Kingston, ON, Canada
J Clin Oncol 28:18s, 2010 (suppl; abstr CRA4504)
ADT ± EBRT in Locally
Advanced/High-Risk Prostate
Cancer: Phase III Trial
Men with locally
advanced/
high-risk prostate
cancer
(N = 1205)
Continuous ADT
(n = 602)
Continuous ADT + RT
(n = 603)
Stratified by baseline PSA (< 20 vs 20-50 vs > 50 µg/L), hormonal therapy
(orchiectomy vs LHRH analogue + antiandrogen therapy), lymph node staging
(clinical vs radiological vs surgical), Gleason score (< 8 vs 8-10), previous hormonal
therapy, and treatment center.
Warde PR, et al. ASCO 2010. Abstract CRA4504.
Eligibility and Patient
Characteristics at Baseline
• Main inclusion criteria
– T3/T4, N0/Nx prostate cancer or
– T2 prostate cancer with PSA > 40 µg/L or
– T2 prostate cancer with PSA > 20 µg/L and Gleason stage 8-10
Characteristic
ADT + RT (n = 603)
ADT (n = 5)
Median age, yrs
69.7
69.7
T3/T4 prostate cancer, %
88
89
Gleason score ≤ 7, %
81
81
 < 20 ng/mL
36
37
 20-50 ng/mL
38
38
 > 50 ng/mL
26
25
PSA, %
Warde PR, et al. ASCO 2010. Abstract CRA4504.
ADT ± EBRT: Overall
Survival
100
7-yr OS: 74%
Patients (%)
80
60
40
Deaths
7-yr OS: 66%
175
ADT
ADT + RT 145
HR: 0.77 (95% CI: 0.61-0.98; p = .0331)
20
0
0
Patients at Risk, n
ADT
602
ADT + RT
603
3
509
512
Yrs
6
9
213
232
51
60
Warde PR, et al. ASCO 2010. Abstract CRA4504.
ADT ± EBRT: DiseaseSpecific Survival
100
7-yr DSS: 90%
Patients (%)
80
60
40
Prostate
Cancer Deaths
89
ADT
ADT + RT 51
7-yr DSS: 79%
HR: 0.57 (95% CI: 0.37-0.78; p = .001)
20
0
0
Patients at Risk, n
ADT
602
ADT + RT
603
3
509
512
Yrs
6
9
213
232
51
60
Warde PR, et al. ASCO 2010. Abstract CRA4504. Reprinted with permission.
ADT ± EBRT: Safety
Late Adverse Event, %
ADT + RT (n = 595)
ADT (n = 596)
 Grade 1/2
14
8
 Grade ≥ 3
1.3
0.7
 Grade 1/2
12
5
 Grade ≥ 3
0.3
0.5
 Grade 1/2
44
42
 Grade ≥ 3
2.3
2.3
Diarrhea
Rectal bleeding
Genitourinary effects
Warde PR, et al. ASCO 2010. Abstract CRA4504.
ADT ± EBRT: Conclusions
• In men with locally advanced or high-risk prostate
cancer, addition of EBRT to ADT associated with
significant efficacy improvements vs ADT alone
– 23% improvement in OS
– 43% improvement in disease-specific survival
• Late toxicity similarly low with ADT vs ADT plus
EBRT
• These data suggest combined modality therapy
should be standard of care for patients with locally
advanced/high-risk prostate cancer
Warde PR, et al. ASCO 2010. Abstract CRA4504.
Impact of radiotherapy (RT) combined with androgen
deprivation (ADT) versus ADT alone for local control
in clinically locally advanced prostate cancer.
Abstract 4505
N. Mottet, M. Peneau, J. Mazeron, V. Molinie, P. Richaud;
Clinique Mutualiste, St. Etienne, France; CHU Fort de France, Fort de France, France;
Pitie-Salpetriere Hospital, Paris, France; Hospital Saint Joseph, Paris, France; Radiation
Therapy and Oncology Department, Institut Bergonié, Bordeaux, France
J Clin Oncol 28:15s, 2010 (suppl; abstr 4505)
•
•
•
•
•
•
n=273
French based trial, shorter follow-up than
Intergroup trial
Locally advanced patients
3 years of LHRH agonist +/- RT
Major advantage for combination relative to
biochemical, local and distant-metastatic
progression-free survival
• Data on testosterone recovery not
available
No difference in overall survival at this time
Median PFS: 7.7 vs 1.7 years p < 0.0001
Median Metastases PFS: p < 0.0183
A randomized phase III trial of denosumab versus
zoledronic acid in patients with bone metastases from
castration-resistant prostate cancer
Abstract LBA 4507
K. Fizazi, M. A. Carducci, M. R. Smith, R. Damião, J. E. Brown, L. Karsh,
P. Milecki, H. Wang, R. D. Dansey, C. D. Goessl
Institut Gustave Roussy, Villejuif, France; Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins University, Baltimore, MD; Massachusetts General Hospital, Boston, MA;
Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; Cancer Research UK Clinical
Centre, Leeds, United Kingdom; The Urology Center of Colorado, Denver, CO; Wielkopolskie
Centrum Onkologii, Poznan, Poland; Amgen, Thousand Oaks, CA
J Clin Oncol 28:18s, 2010 (suppl; abstr LBA4507)
Denosumab: Properties and
Pivotal Clinical Investigation
• High affinity human monoclonal antibody that
binds RANKL
• Administered via SC injection
• Specific: does not bind to TNF-α, TNF-β,
TRAIL, or CD40L
• Inhibits formation and activation of osteoclasts
• Superior to zoledronic acid for
preventing/delaying SREs in metastatic breast
cancer[1]
• Non-inferior to zoledronic acid for
preventing/delaying SREs in solid tumors and
[2]
multiple
myeloma
1. Stopeck A, et al.
SABCS 2009.
Abstract 22.
2. Henry D, et al. ECCO/ESMO 2009. Abstract 20LBA.
Denosumab vs Zoledronic Acid
in Patients With CRPC and
Bone Metastases
 Prospective, double-blind, placebo-controlled phase III trial
Patients with CRPC
and bone metastases,
no current or previous
IV treatment with
bisphosphonate
(N = 1901)
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
Denosumab 120 mg SC +
Placebo IV q4w
(n = 950)
Zoledronic Acid 4 mg IV +
Placebo SC q4w
(n = 951)
Denosumab vs Zoledronic Acid:
Time to First On-Study SRE
HR: 0.82 (95% CI: 0.71-0.95;
P = .0002 noninferiority;
P = .008 superiority)
Proportion of Subjects
Without SRE
1.00
0.75
0.50
KM Estimate of
Median, Mos
0.25
Denosumab
Zoledronic acid
20.7
17.1
0
0
3
Patients at Risk, n
Zoledronic acid
951 733
Denosumab
950 758
6
9
12 15
Study Mo
18
21
24
27
544 407 299 207 140 93
582 472 361 259 168 115
64
70
47
39
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
Denosumab vs Zoledronic
Acid: Safety
Adverse Event, %
Zoledronic Acid
(n = 945)
Denosumab
(n = 943)
Serious adverse events
60
63
Adverse events causing treatment discontinuation
15
17
 Anemia
36
36
 Back pain
30
32
 Decreased appetite
29
28
 Nausea
26
29
 Fatigue
24
27
Acute-phase reactions (first 3 days)
17.8
8.4
Renal adverse events
16.2
14.7
ONJ
1.3
2.3
Hypocalcemia
5.8
12.8
Most common adverse events
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
Denosumab vs Zoledronic
Acid: Conclusions
• Denosumab superior to zoledronic acid in delaying or
preventing SREs in patients with CRPC and bone
metastases
• No significant difference between treatments in survival
or disease progression
• High incidence of adverse events in both arms
– More patients who received zoledronic acid experienced
acute phase reaction
– More patients who received denosumab experienced
hypocalcemia
– ONJ rare but occurred in approximately twice as many
patients with denosumab vs zoledronic acid
• Denosumab potential treatment option for patients with
CRPC and bone metastases
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
CRPC Landscape In Transition
Pre-Chemo Tx
Emerging Agents
Sipiluecel-T
Dendreon 2010
1st Line Chemotherapy
2nd Line Chemotherapy
Cabazitaxel
Sanofi-Aventis
2010
Docetaxel + DN101
Novacea 2010
Ipilimumab +
Docetaxel
BMS (2015)
Docetaxel +
Atrasentan
SWOG 2013
Docetaxel +
Bevazucimab
CALGB 2010
Ipilimumab
BMS 2015
Docetaxel +
ZD4054
AstraZeneca 2012
Docetaxel +
Aflibercept
Sunitinib
Pfizer 2012
TAK 700 &
TOKai
????
Docetaxel +
Lenalidomide
Celgene 2014-15
Regeneron 2012
Ipilimumab
BMS 2013
ZD4054
AstraZeneca
2011
Docetaxel +
Dasatinib
BMS 2012
Docetaxel + OGX011
Teva 2014-15
Abiraterone
J&J 2011
MDV3100
Medivation
2014+
Abiraterone
J&J 2012
MDV3100
Medivation 2013
(VEGF-TRAP)
Approved
Agents
mCRPC
• Leuprolide
• Docetaxel
• Docetaxel
• Goserelin
• Mitoxantrone
• Mitoxantrone
• Bicalutamide
• Bisphosphonates
• Flutamide
• RT
• Ketoconazole
• DES
Ixabepilone
CALGB/SWOG
2014-15
Docetaxel + OGX011
Teva
Oral or IV+Oral
IV
Things
change
Stuff happens
A randomized, double-blind, placebo-controlled phase
III trial comparing docetaxel, prednisone, and
placebo with docetaxel, prednisone, and bevacizumab
in men with metastatic castration-resistant prostate
cancer (mCRPC): Survival results of CALGB 90401
Abstract LBA 4511
W. K. Kelly, S. Halabi, M. A. Carducci, D. J. George, J. F. Mahoney, W.
M. Stadler, M. J. Morris, P. Kantoff, J. P. Monk III, E. J. Small,
Cancer and Leukemia Group B; Yale University School of Medicine, New Haven, CT; Duke
University Medical Center, Durham, NC; Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins University, Baltimore, MD; Carolinas Hematology-Oncology Associates,
Charlotte, NC; University of Chicago, Chicago, IL; Memorial Sloan-Kettering Cancer Center,
New York, NY; Dana-Farber Cancer Institute, Boston, MA; The Ohio State University,
Columbus, OH; University of California, San Francisco, San Francisco, CA
J Clin Oncol 28:18s, 2010 (suppl; abstr LBA4511)
CALGB 90401: Phase III Trial of
Chemotherapy ± Bevacizumab in
CRPC
Stratified by 24-mo survival probability
(< 10%, 10% to 29.9%,
≥ 30%), age (< 65 yrs ≥ 65 yrs),
previous history of arterial events
Patients with
CRPC previously
untreated with
chemotherapy
or biologic agents
(N = 1050)
Dexamethasone 8 mg PO x 3 doses +
Docetaxel 75 mg/m2 on Day 1 of 21-day cycle +
Prednisone 10 mg/day PO +
Bevacizumab 15 mg/kg IV on Day 1 of 21-day cycle
(n = 524)
Dexamethasone 8 mg PO x 3 doses +
Docetaxel 75 mg/m2 on Day 1 of 21-day cycle +
Prednisone 10 mg/day PO +
Placebo IV on Day 1 of 21-day cycle
(n = 526)
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
0.2
0.4
0.6
0.8
Median DP = 21.5 (20.0-23.0)
Median DPB=22.6 (21.1-24.5)
HR= 0.91 (0.78-1.05)
Placebo+Docetaxel
Bev+Docetaxel , log-rank p=0.181
0.0
Overall Survival (probability)
1.0
CALGB 90401: Kaplan-Meier Overall Survival
Curves by Treatment Arm
0
6
Number of Patients at Risk
Placebo+Doce
526
480
Bev+Doce
524
484
12
18
24
30
Time(months)
36
42
390
417
305
327
44
52
22
23
199
217
100
117
CALGB 90401: ProgressionFree Survival
Median PFS,
Mos (Range)
1.0
Bevacizumab + CT
Placebo + CT
Probability
0.8
0.6
9.9 (9.1-10.6)
7.5 (6.7-8.0)
HR: 0.77 (95% CI: 0.68-0.88)
Log rank P < .0001
0.4
0.2
0
0
6
12
18
Patients at Risk, n
Placebo + CT
526 303 134
Bev + CT
524 381 194
75
97
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
24 30
Mos
34
44
8
15
36
42
4
5
0
1
CALGB 90401: Endpoints
Longer-Term Use of Drug May Fight Ovarian Cancer
Bevacizumab
Outcome,
By ANDREW POLLACK
Mos
(Range)
(n = 524)
Published:
June 6, 2010
Placebo
(n = 526)
HR
(95% CI)
P Value
Median
OS— The widely22.6
21.5 can help keep
0.91
CHICAGO
used cancer drug Avastin
ovarian cancer
in
.181
(21.1-24.5)
(0.78-1.05)
check, but only if used
for a long period(20.0-23.0)
of time, researchers
reported here on
Sunday.
Median
PFS
9.9
7.5
0.77
< .0001
(9.1-10.6)
(6.7-8.0)
(0.68-0.88)
A prostate cancer study adding Avastin to chemotherapy showed a benefit to the
addition in every parameter but overall survival, meaning it won’t be considered by the
FDA …. Dr. David I. Quinn, a prostate oncologist at the University of Southern
Outcome,
% (95% CI)
Bevacizumab
Placebo
P Value
California commented:
(n = 524)
(n = 526)
“Improved
survival is good
in other
≥ 50%
decline inprogression-free
PSA
69.5 (65.2-73.5)
57.9enough
(53.3-62.3)
.0002
cancers;response
if a prostate 53.2
were(46.8-59.6)
a nothing more
breast between
Objective
42.1than
(36.2-48.2)
.0113
a man’s legs we would have Avastin approved for prostate cancer
by now!”
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
Bevacizumab Associated
With More Severe
Toxicities
Adverse Event, %
Bevacizumab + CT
(n = 524)
Placebo + CT
(n = 526)
 Grade 3
11
12
 Grade 4
24
17
0
0
 Grade 3
53
35
 Grade 4
11
10
3.8
1.1
Hematologic
 Death
Nonhematologic
 Death
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
CALGB 90401: Conclusions
• Addition of bevacizumab to
docetaxel/prednisone/ dexamethasone
did not significantly increase OS of
patients with CRPC
• Bevacizumab did significantly improve
other clinical outcomes
– PFS, PSA decline, incidence of measurable
disease
• Bevacizumab treatment associated with
more severe toxicities
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
Cabazitaxel or mitoxantrone with prednisone in
patients with metastatic castration resistant
prostate cancer (mCRPC) previously treated with
docetaxel: Final results of a multinational phase III
trial (TROPIC)
Abstract 4508
J. S. De Bono, S. Oudard, M. Ozguroglu, S. Hansen, J. H. Machiels, L.
Shen, P. Matthews, A. O. Sartor, for the TROPIC Investigators; Drug
Development Unit, Royal Marsden NHS Foundation Trust and The
Institute of Cancer Research, Sutton, United Kingdom; Hôpital
Européen Georges Pompidou, Paris, France; Istanbul University,
Istanbul, Turkey; Odense University Hospital, Odense, Denmark;
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain,
Brussels, Belgium; sanofi-aventis, Malvern, PA; Tulane University, New
Orleans, LA
J Clin Oncol 28:15s, 2010 (suppl; abstr 4508)
TROPIC: Randomized, Prospective,
Open-Label, Multinational Phase III
Trial
Stratified by ECOG performance score
(0,1 vs 2), and measurable vs
nonmeasurable disease
Patients with
metastatic
CRPC progressing
on docetaxel
(N = 755)
Mitoxantrone 12 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 377)
Cabazitaxel* 25 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 378)
*Cabazitaxel group premedicated with antihistamine, steroid, and H2 antagonist IV at
least 30 min prior to each cabazitaxel dose. Antiemetic prophylaxis administered as
necessary in either arm.
De Bono JS, et al. ASCO 2010. Abstract 4508.
TROPIC: Overall Survival
Updated ITT Analysis
100
Median OS, Mos
OS (%)
80
HR
60
CBZP
12.7
15.1
0.72
95% CI
0.61-0.84
P value
< .0001
28% reduction in risk of death
40
Censored
MP
CBZP
20
0
MP
Combined median
follow-up: 13.7 mos
0
6
Patients at Risk, n
MP
377
299
CBZP 378
321
12
Mos
195
241
De Bono JS, et al. ASCO 2010. Abstract 4508.
18
24
30
94
137
31
60
9
19
TROPIC: Conclusions
• Cabazitaxel/prednisone significantly improved OS vs
mitoxantrone/prednisone in metastatic CRPC
– Reduced risk of death: 28% (HR: 0.72; P < .0001)
• Cabazitaxel/prednisone also significantly improved
PFS, response rates, and TTP vs
mitoxantrone/prednisone
• Associated with acceptable safety profile
– Febrile neutropenia and diarrhea more common with
cabazitaxel/prednisone vs mitoxantrone/prednisone
• Cabazitaxel/prednisone first treatment to
demonstrate survival benefit in patients with
metastatic CRPC who failed docetaxel-based therapy
De Bono JS, et al. ASCO 2010. Abstract 4508.
CRPC Landscape In Transition
Emerging Agents
Pre-Chemo Tx
1st Line Chemotherapy
2nd Line Chemotherapy
Docetaxel + DN101
Novacea 2010
Ipilimumab +
Docetaxel
BMS (2015)
Docetaxel +
Atrasentan
SWOG 2012
Docetaxel +
Bevazucimab
CALGB 2010
Ipilimumab
BMS 2015
Docetaxel +
ZD4054
AstraZeneca 2012
Docetaxel +
Aflibercept
Sunitinib
Pfizer 2012
TAK 700 &
TOKai
????
Docetaxel +
Lenalidomide
Celgene 2014-15
Regeneron 2012
Ipilimumab
BMS 2013
ZD4054
AstraZeneca
2011
Docetaxel +
Dasatinib
BMS 2012
Docetaxel + OGX011
Teva 2014-15
Abiraterone
J&J 2011
MDV3100
Medivation
2014+
Abiraterone
J&J 2012
MDV3100
Medivation 2013
(VEGF-TRAP)
Approved
Agents
mCRPC
• Leuprolide
• Docetaxel
• Docetaxel
• Goserelin
• Mitoxantrone
• Mitoxantrone
• Bicalutamide
• Bisphosphonates
• Flutamide
• RT
• Ketoconazole
• DES
Sipiluecel-T
Dendreon 2010
Ixabepilone
CALGB/SWOG
2014-15
Docetaxel + OGX011
Teva
Cabazitaxel
Sanofi-Aventis
2010
Oral or IV+Oral
IV
Treatment options for RCC have been
revolutionized in a short period of time…
Bevazucimab + IFN5,6
Everolimus7
High dose
interleukin-21
Temsirolimus4
Axitinib?
Sorafenib2 Sunitinib3
1992-2005
Interferon-
2005
2006
Pazopanib8
AVEO-751?
2007
2008
2009
2010+
...but this rapid change has left many
unanswered questions, including the optimal
sequence of therapy
1. Fyfe G et al. J Clin Oncol 13:688-696, 1995
2. Escudier B et al. N Engl J Med 356:125-134,2007
3. Motzer RJ et al. N Engl J Med 356:115-124,2007
4. Hudes G et al. N Engl J Med 356:2271-2281 2007
5. Escudier B et al. Lancet 370:2103-211, 2007
6. Rini BI et al. J Clin Oncol epud Oct, 2008
7. Motzer RJ et al. Lancet 372:449-456 2008
8. Sternberg C et al. ASCO 2009
The high-dose aldesleukin (HD IL-2) "SELECT" trial
in patients with metastatic renal cell carcinoma
(mRCC).
Abstract 4514
D. F. McDermott, M. S. Ghebremichael, S. Signoretti, K. A. Margolin, J.
Clark, J. A. Sosman, J. P. Dutcher, T. Logan, R. A. Figlin, M. B. Atkins,
Cytokine Working Group; Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber
Cancer Institute, Boston, MA; University of Washington, Seattle, WA; Loyola University
Medical Center, Maywood, IL; Vanderbilt University Medical Center, Nashville, TN;
Montefiore Medical Center North Division, New York, NY; Indiana University Cancer
Center, Indianapolis, IN; City of Hope, Duarte, CA
J Clin Oncol 28:15s, 2010 (suppl; abstr 4514)
Study Endpoints
Primary Endpoint
•
Response Rate
To prospectively determine if the RR to HD IL-2 in mRCC pts
with “good” pathologic predictive features was significantly
higher that a historical, unselected population
Secondary Endpoints
The response rate for patients with “poor” pathologic
features.
If components of other predictive and prognostic models
(MSKCC1, UCLA SANI Score2) can help to further define
the optimal population to receive HD IL2.
New factors that might be associated with response
Maximum % Change in Target Lesions
Tumor Shrinkage (n=118)
PR
Response Comparison
Response*
%
Historical rate
14
IL-2 Select Trial (all pts n=120)
28
p=0.016
95% CI=20.537.3%
IL-2 Select Trial (clear cell n=115)
30
p=0.0008
95% CI=21.438.8%
*Using WHO Criteria
Response by Baseline Characteristics
Tumor type
N (%)
P-value*
Clear Cell (n=115)
Non-clear cell (n=5)
32 (100)
0.32
0 (0)
MSKCC Risk Group
Favorable
Intermediate
Poor
10 (32%, [17-51%])
0.08
20 (24%, [15-35%])
4 (67%, [22-96%])
UCLA Risk Group
High (n=8)
Intermediate (n=101)
Low (n=10)
0 (0%, [0%-37%])
30 (30%,[21%40%])
3 (30%,[7%-65%])
0.22
Response by Pathology Characteristics
Histology risk group
RR (95% CI)
P-value*
Good (n=11)
36% (14%-34%)
0.61
Intermediate (n= 84)
26% (17%-37%)
Poor (n=24)
33% (16%-55%)
CA-9 Score
High (>85%)
23% (14%-34%)
Low (<85%)
38% (23%-55%)
0.13
Combined Score
Good (n=74)
24% (15%-36%)
Poor (n=72)
36% (22%-52%)
0.67
Conclusions
• The RR for HD IL-2 in this trial was significantly better
than the historical experience
• Clinical and pathologic features (e.g. SANI score and
histology) may identify patients who are unlikely to
respond to HD IL-2
• In this trial, analysis of tumor based predictive markers
through central pathology review and staining for CAIX
was unable to improve the selection criteria for HD IL-2
• Efforts to understand these results are ongoing ..
– CAIX SNPs
– B7H1, B7H3
– Immune SNPs
– etc
Randomized phase III trial comparing adjuvant
paclitaxel/gemcitabine/cisplatin (PGC) to observation
in patients with resected invasive bladder cancer:
Results of the Spanish Oncology Genitourinary Group
(SOGUG) 99/01 study.
Abstract LBA 4518
L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A.
Anton, M. Hevia, F. de la Rosa, V. Guillem, J. Bellmunt;
Hospital Universitario Virgen del Rocío, Seville, Spain; IVO, Valencia, Spain; Hospital
Universitario Central de Asturias, Oviedo, Spain; HCULB, Zaragoza, Spain; Hospital Clinico
San Carlos, Madrid, Spain; Hospital Miguel Servet, Zaragoza, Spain; Hospital Central de
Asturias, Oviedo, Spain; Hospital Doce de Octubre, Madrid, Spain; Hospital Vall d'Hebron,
Barcelona, Spain
J Clin Oncol 28:15s, 2010 (suppl; abstr 4518)
Adjuvant [Post-Operative] Chemotherapy
in Invasive Bladder Cancer Meta-analysis
Survival
Hazard Ratio
Single agent cisplatin
Studer
Sub-total
Hazard Ratio=1.02 p=0.945
Skinner
Bono
Freiha
Stockle
Otto
Sub-total
Hazard Ratio=0.71 p=0.010
Total
Hazard Ratio=0.75 p=0.019
Cisplatin-based combinations
0
0.5
Chemotherapy better
1
1.5
2
Control better
Test for interaction χ2=1.20, p=0.237
Only 283 events in 491 patients
6 small trials!
Very wide confidence intervals!
Eur Urol. 2005 Aug;48(2):189-199
SOGUG 99/01 Study Design
Multicenter Phase III Randomized Open Label Trial
Eligibility:
• TCC
• PostCystectomy
• pT3-4 and/or
pN+
• PS 0-1
• CrCl > 50 ml/min
R
A
N
D
O
M
I
Z
E
Stratification:
• PS: 0 v 1
• pN: N0 v N+
PGC x 4
PD
Observation
Outcome
• Median follow-up:
- All patients: 29.8 months (1-95)
- Alive patients: 51 months (2-95)
• Deaths: 69 patients (49%)
- PGC arm: 24 (36%)
- Observation arm: 45 (61%)
• Disease Progression: 76 patients (54%)
- PGC arm: 30 (44%)
- Observation arm: 54 (73%)
Overall Survival - ITT
Adjusted - Cox Multivariate
HR: 0.378 ( 95% CI: 0.649-0.221)
P< 0.0004
Conclusions
• Adjuvant Chemotherapy with the PGC
regimen resulted in improved outcomes,
including overall survival in the current
study.
• Treatment compliance was high and toxicity
was acceptable.
• The final sample size of the study limits the
robustness of these conclusions.
• Meta-analysis of the available trials and
further molecularly-tailored studies are
warranted.
Results of a phase III randomized trial of
synchronous chemoradiotherapy (CRT) compared to
radiotherapy (RT) alone in muscle-invasive bladder
cancer (MIBC) (BC2001 CRUK/01/004).
Abstract LBA 4517
N. D. James, S. A. Hussain, E. Hall, P. Jenkins, J. Tremlett, C. Rawlings,
C. Hendron, R. Lewis, S. Rogers, R. A. Huddart, on behalf of the
BC2001 Investigators;
CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom; Cancer
Research UK Institute for Cancer Studies, Birmingham, United Kingdom; Institute of Cancer Research
Clinical Trials and Statistics Unit, Sutton, United Kingdom; Cheltenham General Hospital, Cheltenham,
United Kingdom; Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom; South
Devon Healthcare NHS Foundation, Torbay, United Kingdom; CRUK Institute for Cancer Studies,
Birmingham, United Kingdom; Institute of Cancer Research, Sutton, United Kingdom
J Clin Oncol 28:15s, 2010 (suppl; abstr 4517)
•
•
•
•
•
n=360
RT +/- concurrent mitomycin and 5FU weeks 1 and 4
Locoregional DFS improved with combined therapy
• HR=0.61, 95% CI: 0.42 - 0.90; p = 0.01
Overall survival data awaited
Potential concurrent regimen in CDDP unfit patients
Randomized phase II/III trial comparing
gemcitabine/carboplatin (GC) and
methotrexate/carboplatin/vinblastine (M-CAVI) in
patients (pts) with advanced urothelial cancer (UC)
unfit for cisplatin-based chemotherapy (CHT): Phase
III results of EORTC study 30986
Abstract LBA 4519
M. De Santis, J. Bellmunt, G. Mead, J. M. Kerst, M. G. Leahy, G.
Daugaard, T. Gil, J. P. Maroto, S. Marreaud, R. Sylvester;
ACR-ITR VIEnna/CEADDP, LBI-ACR VIEnna, and KFJ-Spital, Vienna, Austria; Hospital del
Mar, IMIM, Barcelona, Spain; Royal South Hants Hospital, Southhampton, United Kingdom;
The Netherlands Cancer Institute, Amsterdam, Netherlands; St. James Hospital, Leeds,
United Kingdom; Rigshospitalet, Copenhagen, Denmark; Institut Jules Bordet, Brussels,
Belgium; Hospital Santa Creu, Barcelona, Spain; EORTC Headquarters, Brussels, Belgium
J Clin Oncol 28:15s, 2010 (suppl; abstr 4519)
Phase III results of EORTC study 30986
Treatment plan
Treatment 1: Methotrexate / CArboplatin / VInblastine
Methotrexate
30 mg/m2 i.v. days 1, 15, 22
Carboplatin
dose in mg = 4.5 x (GFR+25) i.v. day 1
Vinblastine
3 mg/m2 i.v. days 1, 15, 22
> Every 4 weeks for at least 2 cycles
Treatment 2: Gemcitabine / Carboplatin
Gemcitabine
Carboplatin
1000 mg/m2 i.v. days 1 and 8
dose in mg = 4.5 x (GFR+25) i.v. day 1
> Every 3 weeks for at least 2 cycles
M. De Santis
phase III 30986
ASCO 2010
Phase III results of EORTC study 30986
Inclusion criteria (summary)

Patients ineligible (unfit) for cisplatin-based
chemotherapy:
PS (WHO) 2 and /or
impaired renal function (30 ml/min < GFR < 60 ml/min)

Histologically proven TCC of the urinary tract

Unresected lymph nodes (N+), distant metastases (M1,
stage IV) or unresectable primary bladder cancer (T3-4)

Measurable disease (RECIST criteria V1.0 *)

No previous systemic treatment, neither cytotoxic nor
biologic
*
M. De Santis
Therasse P et al, J Natl Cancer Instit 2000;92:205-216
phase III 30986
ASCO 2010
Phase III results of EORTC study 30986
Results: Toxicity
GC
(n=118)
n (%)
M-CAVI
(n=118)
n (%)
Leukopenia G 3/4 ª
53 (44.9)
55 (46.6)
Neutropenia G 3/4 ª
62 (52.5)
75 (63.5)
Thrombocytopenia G 3/4 ª
57 (48.3)
23 (19.4)
Febrile Neutropenia G 3/4
5 (4.2)
17 (14.4)
Infection G 3/4 ª
14 (11.8)
15 (12.7)
Severe Acute Toxicity (SAT)*
11 (9.3)
25 (21.2)
ªnot a SAT ; *patients with at least 1 SAT
M. De Santis
phase III 30986
ASCO 2010
Phase III results of EORTC study 30986
Results: Best Overall Response
CR+PR
GC
(n=119)
n (%)
49 (41.2)
M-CAVI
(n=119)
n (%)
36 (30.3)
43
25
39 (32.8)
18 (15.1)
4 (3.4)
9 (7.6)
41 (34.5)
17 (14.3)
10 (8.4)
15 (12.6)
Confirmed response
No change
Progression
Early death
Not assessable
The difference in response rate between the two treatment arms is not significant (p=0.08)
The difference in confirmed response rate between the two treatment arms is significant (p=0.01)
M. De Santis
phase III 30986
ASCO 2010
Phase III results of EORTC study 30986
Results: Overall Survival
100
90
80
70
60
%
50
40
30
20
10
0
0
O N
108 119
110 119
M. De Santis
HR=0.94 (95%CI: 0.72, 1.22)
p=0.64
8.1 months (95%CI: 6.1, 10.3)
9.3 months (95%CI: 7.6, 11.3)
(years)
1
2
3
4
5
Number of patients at risk :
37
13
7
3
1
44
15
5
2
2
phase III 30986
6
1
1
7
8
Treatment
1
M-CAVI
1
GC
ASCO 2010
What have we learnt?
ASCO 2010: GU Summary Conclusions
Take home messages
Locally Advanced Prostate Cancer:
RT with ADT for 3 years is a standard of care
Monotherapy with ADT or RT are NOT
Castrate-Resistant Prostate Cancer:
Docetaxel needs a date or a mate: still looking!
BUT son of docetaxel, Cabazitaxel has a role in second line therapy
Options for Osteoclast inhibition broaden: Denosumab
Germ Cell Tumors: No role for first line HDCSCT
Optimal therapy at relapse: standard chemotherapy or SCT?
RCC: Selection can improve HDIL2 outcome but still no biomarker
Serial monotherapy: ruling therapeutic paradigm for targeted therapy
Urothelial cancer: adjuvant chemotherapy may have a place …
In medical unfit patients Gemcitabine/Carboplatin remains a default
standard
Concurrent mitomycin C and 5FU adds to disease control with RT.
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
PSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE normal
PSA 4.2, falls on ciprofloxacin
Follow up 4 months later: PSA 7.8, DRE firmness of left.
Biospy: left Gl 3+3=6, right Gleason 4+4=8, PNI
Bone scan: multiple bone metastases
CT: right iliac and RP LNs
How would treat this patient?
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
PSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE normal
PSA 4.2, falls on ciprofloxacin
Follow up 4 months later: PSA 7.8, DRE firmness of left.
Biospy: left Gl 3+3=6, right Gleason 4+4=8, PNI
Bone scan: multiple bone metastases
CT: right iliac and RP LNs
How would treat this patient?
Androgen deprivation therapy: Continuous or Intermittent?
Bone therapy: he starts calcium and vitamin D
Would you start bone directed therapy now? Yes or No
If you would what is your therapeutic aim?
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
PSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE normal
PSA 4.2, falls on ciprofloxacin
Follow up 4 months later: PSA 7.8, DRE firmness of left.
Biospy: left Gl 3+3=6, right Gleason 4+4=8, PNI
Bone scan: multiple bone metastases
CT: right iliac and RP LNs
How would treat this patient?
Androgen deprivation therapy: A. Continuous or B. Intermittent?
Bone therapy: he starts calcium and vitamin D
Would you start bone directed therapy now? A. Yes or B. No
If you would what is your PRIMARY therapeutic aim?
A. Prevent bone loss or
B. Prevent further skeletal related events
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
PSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE normal
PSA 4.2, falls on ciprofloxacin
Follow up 4 months later: PSA 7.8, DRE firmness of left.
Biospy: left Gl 3+3=6, right Gleason 4+4=8, PNI
Bone scan: multiple bone metastases
CT: right iliac and RP LNs
How would treat this patient?
Androgen deprivation therapy: A. Continuous or B. Intermittent?
Bone therapy: he starts calcium and vitamin D
Would you start bone directed therapy now? A. Yes or B. No
If you would what is your PRIMARY therapeutic aim?
A. Prevent bone loss or
B. Prevent further skeletal related events
Which agent would you use?
A. Zelodronic acid B. Pamidronate C. oral bisphosphonate D. Denosumab
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
PSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE
normal
PSA 4.2, falls on ciprofloxacin
Follow up 4 months later: PSA 7.8, DRE firmness of left.
Biospy: left Gl 3+3=6, right Gleason 4+4=8, PNI
Bone scan: multiple bone metastases; CT: right iliac and RP LNs
He commences Goserelin and Bicalutamide, PSA falls to 0.1. He also
commences zelodronic acid yearly.
2 years later his PSA rises to 1.0 and bicalutamide is stopped.
Following month PSA is 2.1.
Bone scan shows new lesions compared to prior scan.
CT scan is stable.
Does the patient have disease progression?
Yes (A) or No (B)
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
PSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE
normal
PSA 4.2, falls on ciprofloxacin
Follow up 4 months later: PSA 7.8, DRE firmness of left.
Biospy: left Gl 3+3=6, right Gleason 4+4=8, PNI
Bone scan: multiple bone metastases; CT: right iliac and RP LNs
He commences Goserelin and Bicalutamide, PSA falls to 0.1. He also
commences zelodronic acid yearly.
2 years later his PSA rises to 1.0 and bicalutamide is stopped.
Following month PSA is 2.1. Bone scan shows new lesions compared to prior
scan. CT scan is stable. He has no symptoms.
What therapy would your recommend?
A.Ketoconazole and Corticosteroid
B.Triple dose bicalutamide
C.Clinical trial with abiraterone or TAK-700 or MDV 3100
D.Sipuleucel T (Provenge)
E.Docetaxel chemotherapy
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
Metastatic prostate cancer. He commences Goserelin and Bicalutamide,
PSA falls to 0.1. He also commences zelodronic acid yearly.
2 years later his PSA rises to 1.0 and bicalutamide is stopped.
Following month PSA is 2.1. Bone scan shows new lesions compared to prior
scan. CT scan is stable. He has no symptoms.
He opts for Sipuleucel T. Some chills after infusions. 8 weeks after
treatment his PSA is 3.7, further new bone lesions on bone scan. CT shows
stable disease but he has a left DVT and pulmonary emboli. Starts LMWH.
He develops back pain, starts monthly bisphosphonates.
What therapy would your recommend?
A.Ketoconazole and Corticosteroid
B.Triple dose bicalutamide
C.Clinical trial with abiraterone or TAK-700 or MDV 3100
D.Sipuleucel T (Provenge)
E.Docetaxel chemotherapy
Prostate Cancer Case Study
Post ASCO 2010
64 year old Attorney, controlled HTN
Metastatic prostate cancer. He commences Goserelin and Bicalutamide,
PSA falls to 0.1. He also commences zelodronic acid yearly.
2 years later his PSA rises to 1.0 and bicalutamide is stopped.
He opts for Sipuleucel T. 8 weeks after treatment his PSA is 3.7, further
new bone lesions on bone scan. Left DVT and pulmonary emboli. Starts
LMWH. He develops back pain, starts monthly bisphosphonates.
He starts docetaxel q3weekly with prednisone.
After 10 cycles he is pain free, PSA 0.3, CT and bone scan improved.
Therapy is stopped electively. 4 weeks later he has severe back and risb
pain. PSA is 26, bone scan shows PD, MRI no spinal cord compression. CT:
lung and liver metastases.
What therapy would your recommend?
A.Restart docetaxel
B.Mitoxantrone
C.Cabazitaxel
D.Oral cyclophosphamide
E.Best supportive care
Thank You
Jaoquim Belmunt, Bernard Escudier, Cora
Sternberg, Kevin Kelly, Howard Scher, Primo Lara,
Nicholas Vogelzang, Mria DeSantes, Karim Fizazi,
Nicholas Nottet