State of the Art: Treatment Options in Advanced Genitourinary Cancers

1
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
2
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

3
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

4
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

Locally advanced prostate cancer
Advanced prostate cancer bone metastases and
osteoclast inhibition
Castrate resistant prostate cancer
5
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

6
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
7
ASCO 2010 GU Summary ConclusionsTake 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.

8
Intergroup randomized phase III study of androgen
deprivation therapy (ADT) plus radiation therapy
(RT) in locally advanced prostate cancer (CaP)
(NCIC-CTG, 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 2818s, 2010 (suppl abstr CRA4504)

9
ADT EBRT in Locally Advanced/High-Risk Prostate
Cancer Phase III Trial
Continuous ADT (n 602)
Men with locally advanced/ high-risk prostate
cancer (N 1205)
Continuous ADT RT (n 603)
Stratified by baseline PSA (lt 20 vs 20-50 vs gt 50
µg/L), hormonal therapy (orchiectomy vs LHRH
analogue antiandrogen therapy), lymph node
staging (clinical vs radiological vs surgical),
Gleason score (lt 8 vs 8-10), previous hormonal
therapy, and treatment center.
Warde PR, et al. ASCO 2010. Abstract CRA4504.
10
Eligibility and Patient Characteristics at
Baseline

• Main inclusion criteria
• T3/T4, N0/Nx prostate cancer or
• T2 prostate cancer with PSA gt 40 µg/L or
• T2 prostate cancer with PSA gt 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
PSA,
lt 20 ng/mL 36 37
20-50 ng/mL 38 38
gt 50 ng/mL 26 25
Warde PR, et al. ASCO 2010. Abstract CRA4504.
11
ADT EBRT Overall Survival
100
7-yr OS 74
80
Deaths 175 145
60
7-yr OS 66
Patients ()
ADT
ADT RT
40
HR 0.77 (95 CI 0.61-0.98 p .0331)
20
0
0
3
6
9
Yrs
Patients at Risk, nADTADT RT
602603
509512
213232
5160
Warde PR, et al. ASCO 2010. Abstract CRA4504.
12
ADT EBRT Disease-Specific Survival
100
7-yr DSS 90
80
7-yr DSS 79
Prostate Cancer Deaths 89 51
60
Patients ()
ADT
ADT RT
40
HR 0.57 (95 CI 0.37-0.78 p .001)
20
0
0
3
6
9
Yrs
Patients at Risk, nADTADT RT
602603
509512
213232
5160
Warde PR, et al. ASCO 2010. Abstract CRA4504.
Reprinted with permission.
13
ADT EBRT Safety
Late Adverse Event, ADT RT (n 595) ADT (n 596)
Diarrhea
Grade 1/2 14 8
Grade 3 1.3 0.7
Rectal bleeding
Grade 1/2 12 5
Grade 3 0.3 0.5
Genitourinary effects
Grade 1/2 44 42
Grade 3 2.3 2.3
Warde PR, et al. ASCO 2010. Abstract CRA4504.
14
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.
15
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 2815s, 2010 (suppl abstr 4505)

Median PFS 7.7 vs 1.7 years p lt 0.0001

• n273
• 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 Metastases PFS p lt 0.0183
16
(No Transcript)
17
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 2818s, 2010 (suppl abstr LBA4507)

18
Denosumab Properties and Pivotal Clinical
Investigation

• High affinity human monoclonal antibody that
  binds RANKL
• Administered via SC injection
• Specific does not bind to TNF-a, TNF-ß, TRAIL,
  or CD40L
• Inhibits formation and activation of osteoclasts
• Superior to zoledronic acid for
  preventing/delaying SREs in metastatic breast
  cancer1
• Non-inferior to zoledronic acid for
  preventing/delaying SREs in solid tumors and
  multiple myeloma2

1. Stopeck A, et al. SABCS 2009. Abstract 22. 2.
Henry D, et al. ECCO/ESMO 2009. Abstract 20LBA.
19
Denosumab vs Zoledronic Acid in Patients With
CRPC and Bone Metastases

• Prospective, double-blind, placebo-controlled
  phase III trial

Denosumab 120 mg SC Placebo IV q4w(n 950)
Patients with CRPC and bone metastases, no
current or previous IV treatment with
bisphosphonate (N 1901)
Zoledronic Acid 4 mg IV Placebo SC q4w(n
951)
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
20
Denosumab vs Zoledronic Acid Time to First
On-Study SRE
HR 0.82 (95 CI 0.71-0.95P .0002
noninferiorityP .008 superiority)
1.00
0.75
Proportion of Subjects Without SRE
0.50
KM Estimate ofMedian, Mos
0.25
DenosumabZoledronic acid
20.717.1
0
0
3
6
9
12
15
18
21
24
27
Study Mo
Patients at Risk, nZoledronic acidDenosumab
951950
733758
544582
407472
299361
207259
140168
93115
6470
4739
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
21
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
Most common adverse events
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
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
22
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.
23
CRPC Landscape In Transition
Pre-Chemo Tx
1st Line Chemotherapy
2nd Line Chemotherapy
Cabazitaxel Sanofi-Aventis 2010
Sipiluecel-T Dendreon 2010
Ipilimumab Docetaxel BMS (2015)
Docetaxel DN101 Novacea 2010
Abiraterone JJ 2011
Abiraterone JJ 2012
Docetaxel Bevazucimab CALGB 2010
Docetaxel Atrasentan SWOG 2013
MDV3100 Medivation 2014
MDV3100 Medivation 2013
Emerging Agents
Docetaxel ZD4054 AstraZeneca 2012
Sunitinib Pfizer 2012
Docetaxel Aflibercept (VEGF-TRAP) Regeneron
2012
Ipilimumab BMS 2015
Ipilimumab BMS 2013
Docetaxel Lenalidomide Celgene 2014-15
TAK 700 TOKai ????
Ixabepilone CALGB/SWOG 2014-15
Docetaxel OGX-011 Teva 2014-15
Docetaxel Dasatinib BMS 2012
ZD4054 AstraZeneca 2011
Docetaxel OGX-011 Teva
mCRPC

• Leuprolide
• Goserelin
• Bicalutamide
• Flutamide
• Ketoconazole
• DES

• Docetaxel
• Mitoxantrone
• Bisphosphonates
• RT

• Docetaxel
• Mitoxantrone

Approved Agents
Oral or IVOral
IV
24
Things change Stuff happens
25
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 90401Abstract 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 2818s, 2010 (suppl abstr LBA4511)

26
CALGB 90401 Phase III Trial of Chemotherapy
Bevacizumab in CRPC
Stratified by 24-mo survival probability (lt 10,
10 to 29.9, 30), age (lt 65 yrs 65 yrs),
previous history of arterial events
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)
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 Placebo IV on Day 1 of 21-day
cycle (n 526)
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
27
CALGB 90401 Kaplan-Meier Overall Survival
Curves by Treatment Arm
Median DP 21.5 (20.0-23.0) Median DPB22.6
(21.1-24.5) HR 0.91 (0.78-1.05)
28
CALGB 90401 Progression-Free Survival
Median PFS, Mos (Range)
1.0
9.9 (9.1-10.6) 7.5 (6.7-8.0)
Bevacizumab CT
0.8
Placebo CT
0.6
HR 0.77 (95 CI 0.68-0.88) Log rank P lt .0001
Probability
0.4
0.2
0
0
6
12
18
24
30
36
42
Mos
Patients at Risk, n
Placebo CT
526
303
134
75
34
8
4
0
Bev CT
524
381
194
97
44
15
5
1
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
29
CALGB 90401 Endpoints
Longer-Term Use of Drug May Fight Ovarian
CancerBy ANDREW POLLACK Published June 6,
2010 CHICAGO The widely used cancer drug
Avastin can help keep ovarian cancer in check,
but only if used for a long period of time,
researchers reported here on Sunday. A prostate
cancer study adding Avastin to chemotherapy
showed a benefit to the addition in every
parameter but overall survival, meaning it wont
be considered by the FDA . Dr. David I. Quinn, a
prostate oncologist at the University of Southern
California commented Improved progression-free
survival is good enough in other cancers if a
prostate were a nothing more than breast between
a mans legs we would have Avastin approved for
prostate cancer by now!
Outcome, Mos (Range) Bevacizumab (n 524) Placebo (n 526) HR (95 CI) P Value
Median OS 22.6 (21.1-24.5) 21.5 (20.0-23.0) 0.91 (0.78-1.05) .181
Median PFS 9.9 (9.1-10.6) 7.5 (6.7-8.0) 0.77 (0.68-0.88) lt .0001
Outcome, (95 CI) Bevacizumab (n 524) Placebo (n 526) P Value
50 decline in PSA 69.5 (65.2-73.5) 57.9 (53.3-62.3) .0002
Objective response 53.2 (46.8-59.6) 42.1 (36.2-48.2) .0113
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
30
Bevacizumab Associated With More Severe Toxicities
Adverse Event, Bevacizumab CT (n 524) Placebo CT (n 526)
Hematologic
Grade 3 11 12
Grade 4 24 17
Death 0 0
Nonhematologic
Grade 3 53 35
Grade 4 11 10
Death 3.8 1.1
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
31
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.
32
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 2815s, 2010 (suppl abstr 4508)

33
TROPIC Randomized, Prospective, Open-Label,
Multinational Phase III Trial
Stratified by ECOG performance score (0,1 vs 2),
and measurable vs nonmeasurable disease
Mitoxantrone 12 mg/m2 IV q3w Prednisone 10
mg/day PO for 10 courses (n 377)
Patients with metastatic CRPC progressing on
docetaxel (N 755)
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.
34
TROPIC Overall SurvivalUpdated ITT Analysis
MP CBZP
Median OS, Mos 12.7 15.1
HR 0.72 0.72
95 CI 0.61-0.84 0.61-0.84
P value lt .0001 lt .0001
100
80
60
OS ()
28 reduction in risk of death
40
Censored
MP
20
CBZP
Combined medianfollow-up 13.7 mos
0
0
6
12
18
24
30
Mos
Patients at Risk, n
MP
377
299
195
94
31
9
CBZP
378
321
241
137
60
19
De Bono JS, et al. ASCO 2010. Abstract 4508.
35
TROPIC Conclusions

• Cabazitaxel/prednisone significantly improved OS
  vs mitoxantrone/prednisone in metastatic CRPC
• Reduced risk of death 28 (HR 0.72 P lt .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.
36
CRPC Landscape In Transition
Pre-Chemo Tx
1st Line Chemotherapy
2nd Line Chemotherapy
Ipilimumab Docetaxel BMS (2015)
Docetaxel DN101 Novacea 2010
Abiraterone JJ 2011
Abiraterone JJ 2012
Docetaxel Atrasentan SWOG 2012
Docetaxel Bevazucimab CALGB 2010
MDV3100 Medivation 2014
MDV3100 Medivation 2013
Emerging Agents
Docetaxel ZD4054 AstraZeneca 2012
Sunitinib Pfizer 2012
Docetaxel Aflibercept (VEGF-TRAP) Regeneron
2012
Ipilimumab BMS 2015
Ipilimumab BMS 2013
Docetaxel Lenalidomide Celgene 2014-15
TAK 700 TOKai ????
Ixabepilone CALGB/SWOG 2014-15
Docetaxel OGX-011 Teva 2014-15
Docetaxel Dasatinib BMS 2012
ZD4054 AstraZeneca 2011
Docetaxel OGX-011 Teva
mCRPC

• Leuprolide
• Goserelin
• Bicalutamide
• Flutamide
• Ketoconazole
• DES

• Docetaxel
• Mitoxantrone
• Bisphosphonates
• RT

• Docetaxel
• Mitoxantrone

Approved Agents
Cabazitaxel Sanofi-Aventis 2010
Oral or IVOral
Sipiluecel-T Dendreon 2010
IV
37
(No Transcript)
38
Treatment options for RCC have been
revolutionized in a short period of time
Bevazucimab IFN5,6
Everolimus7
Pazopanib8
High dose interleukin-21
Temsirolimus4
Axitinib? AVEO-751?
Sorafenib2
Sunitinib3
1992-2005
2005
2006
2007
2008
2009
2010
...but this rapid change has left many unanswered
questions, including the optimal sequence of
therapy
Interferon-?

• Fyfe G et al. J Clin Oncol 13688-696, 1995
• Escudier B et al. N Engl J Med 356125-134,2007
• Motzer RJ et al. N Engl J Med 356115-124,2007
• Hudes G et al. N Engl J Med 3562271-2281 2007
• 5. Escudier B et al. Lancet 3702103-211, 2007
• 6. Rini BI et al. J Clin Oncol epud Oct, 2008
• 7. Motzer RJ et al. Lancet 372449-456 2008
• 8. Sternberg C et al. ASCO 2009

39
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 2815s, 2010 (suppl abstr 4514)

40
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
• 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

Secondary Endpoints
41
Tumor Shrinkage (n118)
Maximum Change in Target Lesions
PR
42
Response Comparison
Response
Historical rate 14
IL-2 Select Trial (all pts n120) 28
p0.016
95 CI20.5-37.3
IL-2 Select Trial (clear cell n115) 30 p0.0008 95 CI21.4-38.8

Using WHO Criteria
43
Response by Baseline Characteristics
Tumor type N () P-value
Clear Cell (n115) 32 (100) 0.32
Non-clear cell (n5) 0 (0)

MSKCC Risk Group
Favorable 10 (32, 17-51) 0.08
Intermediate 20 (24, 15-35)
Poor 4 (67, 22-96)

UCLA Risk Group
High (n8) 0 (0, 0-37) 0.22
Intermediate (n101) 30 (30,21-40)
Low (n10) 3 (30,7-65)
44
Response by Pathology Characteristics
Histology risk group RR (95 CI) P-value
Good (n11) 36 (14-34) 0.61
Intermediate (n 84) 26 (17-37)
Poor (n24) 33 (16-55)

CA-9 Score
High (gt85) 23 (14-34) 0.13
Low (lt85) 38 (23-55)

Combined Score
Good (n74) 24 (15-36) 0.67
Poor (n72) 36 (22-52)
45
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

46
(No Transcript)
47
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 2815s, 2010 (suppl abstr 4518)

48
Introduction and Background

• Standard treatment for locally invasive bladder
  cancer is radical cystectomy.
• Systemic relapse is the most frequent cause of
  failure, suggesting the presence of
  micro-metastatic disease at the time of the
  initial surgery
• Cisplatin-based chemotherapy is effective in
  metastatic disease and as neo-adjuvant treatment
• The role of adjuvant chemotherapy in this setting
  has been studied over the last three decades

49
Adjuvant Post-Operative Chemotherapy in
Invasive Bladder Cancer Meta-analysis Survival
Hazard Ratio
Single agent cisplatin
Studer
Sub-total
Hazard Ratio1.02 p0.945
Cisplatin-based combinations
Skinner
Bono
Freiha
Stockle
Otto
Hazard Ratio0.71 p0.010
Sub-total
Total
Hazard Ratio0.75 p0.019
0
0.5
1
1.5
2
Chemotherapy better
Control better
Test for interaction ?21.20, p0.237
Only 283 events in 491 patients 6 small trials!
Very wide confidence intervals!
Eur Urol. 2005 Aug48(2)189-199
50
SOGUG 99/01 Study Design
Multicenter Phase III Randomized Open Label Trial
R A N D O M I Z E

• Eligibility
• TCC
• Post- Cystectomy
• pT3-4 and/or pN
• PS 0-1
• CrCl gt 50 ml/min

PGC x 4
PD
Observation

• Stratification
• PS 0 v 1
• pN N0 v N

51
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)

52
Overall Survival - ITT
Adjusted - Cox Multivariate HR 0.378 ( 95 CI
0.649-0.221) Plt 0.0004
53
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.

54
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).Abstra
ct 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 2815s, 2010 (suppl abstr 4517)

• n360
• RT /- concurrent mitomycin and 5FU weeks 1 and 4
• Locoregional DFS improved with combined therapy
• HR0.61, 95 CI 0.42 - 0.90 p 0.01
• Overall survival data awaited
• Potential concurrent regimen in CDDP unfit
  patients

55
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
30986Abstract 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 2815s, 2010 (suppl abstr 4519)

56
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 (GFR25)
i.v. day 1 Vinblastine 3 mg/m2 i.v. days 1, 15,
22 gt Every 4 weeks for at least 2 cycles
Treatment 2 Gemcitabine / Carboplatin Gemcitabi
ne 1000 mg/m2 i.v. days 1 and
8 Carboplatin dose in mg 4.5 x (GFR25) i.v.
day 1 gt Every 3 weeks for at least 2 cycles
57
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 lt GFR lt 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

Therasse P et al, J Natl Cancer Instit
200092205-216
58
Phase III results of EORTC study 30986
Results Toxicity
GC (n118) n () M-CAVI (n118) 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
59
Phase III results of EORTC study 30986
Results Best Overall Response
GC (n119) n () M-CAVI (n119) n ()
CRPR Confirmed response 49 (41.2) 43 36 (30.3) 25
No change 39 (32.8) 41 (34.5)
Progression 18 (15.1) 17 (14.3)
Early death 4 (3.4) 10 (8.4)
Not assessable 9 (7.6) 15 (12.6)

• The difference in response rate between the two
  treatment arms is not significant (p0.08)
• The difference in confirmed response rate between
  the two treatment arms is significant (p0.01)

60
Phase III results of EORTC study 30986
Results Overall Survival
100
HR0.94 (95CI 0.72, 1.22) p0.64
90
80
70
60
8.1 months (95CI 6.1, 10.3) 9.3 months (95CI
7.6, 11.3)

50
40
30
20
10
(years)
0
0
1
2
3
4
5
6
7
8
N
O
Number of patients at risk
Treatment
108
119
37
13
7
3
1
1
1
M-CAVI
110
119
44
15
5
2
2
1
1
GC
61
What have we learnt?
62
ASCO 2010 GU Summary ConclusionsTake 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.

63
Prostate Cancer Case StudyPost 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 336, right Gleason 448, PNI
• Bone scan multiple bone metastases
• CT right iliac and RP LNs
• How would treat this patient?

64
Prostate Cancer Case StudyPost 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 336, right Gleason 448, 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?

65
Prostate Cancer Case StudyPost 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 336, right Gleason 448, 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

66
Prostate Cancer Case StudyPost 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 336, right Gleason 448, 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

67
Prostate Cancer Case StudyPost 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 336, right Gleason 448, 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)

68
Prostate Cancer Case StudyPost 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 336, right Gleason 448, 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?
• Ketoconazole and Corticosteroid
• Triple dose bicalutamide
• Clinical trial with abiraterone or TAK-700 or MDV
  3100
• Sipuleucel T (Provenge)
• Docetaxel chemotherapy

69
Prostate Cancer Case StudyPost 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?
• Ketoconazole and Corticosteroid
• Triple dose bicalutamide
• Clinical trial with abiraterone or TAK-700 or MDV
  3100
• Sipuleucel T (Provenge)
• Docetaxel chemotherapy

70
Prostate Cancer Case StudyPost 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?
• Restart docetaxel
• Mitoxantrone
• Cabazitaxel
• Oral cyclophosphamide
• Best supportive care

71
Thank You Jaoquim Belmunt, Bernard Escudier, Cora
Sternberg, Kevin Kelly, Howard Scher, Primo Lara,
Nicholas Vogelzang, Mria DeSantes, Karim Fizazi,
Nicholas Nottet