state of the art: treatment options in advanced genitourinary cancers david i. quinn mbbs (hons) phd...
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State of the Art: Treatment Options in Advanced Genitourinary Cancers
David I. Quinn MBBS (Hons) PhD FRACPAssociate Professor of Medicine
Chief, Section of GU Medical OncologyDivision of Cancer Medicine & Blood Diseases
Medical Director, Norris Cancer Hospital & ClinicsCo-Leader, Developmental Therapuetics Program
Kenneth J. Norris Comprehensive Cancer CenterKeck 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
• 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
After reading and reviewing this material, the participant should be better able to:
Genitourinary Cancers - ASCO 2010: Key prostate cancer
abstractsIntergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced
prostate cancer CRA4504Impact 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 4507Cabazitaxel 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
abstractsIntergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced
prostate cancer CRA4504Impact 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 4507Cabazitaxel 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
Castrate resistant prostate cancer
Advanced prostate cancer: bone metastases and osteoclast inhibition
ASCO 2010: Germ Cell, Renal Cell Cancer and Urothelial Cancer
HighlightsA 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.
4516Randomized phase III trial comparing adjuvant
paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected
invasive bladdercancer: Results of the Spanish Oncology Genitourinary Group
(SOGUG) 99/01 study. LBA4518Randomized 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
HighlightsA 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.
4516Randomized phase III trial comparing adjuvant
paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected
invasive bladdercancer: Results of the Spanish Oncology Genitourinary Group
(SOGUG) 99/01 study. LBA4518Randomized 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 messagesLocally Advanced Prostate Cancer:
RT with ADT for 3 years is a standard of careMonotherapy 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 biomarkerSerial 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) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633)
Abstract CRA 4504P. 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)
Continuous ADT + RT(n = 603)
Continuous ADT(n = 602)Men with locally
advanced/high-risk prostate
cancer
(N = 1205)
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.
ADT ± EBRT in Locally Advanced/High-Risk
Prostate Cancer: Phase III Trial
• 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
Eligibility and Patient Characteristics at
Baseline
Warde PR, et al. ASCO 2010. Abstract CRA4504.
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, %
< 20 ng/mL 36 37
20-50 ng/mL 38 38
> 50 ng/mL 26 25
ADT ± EBRT: Overall Survival
Warde PR, et al. ASCO 2010. Abstract CRA4504.
100
80
60
40
20
00 3 6 9
Pati
ents
(%
)
Yrs
HR: 0.77 (95% CI: 0.61-0.98; p = .0331)
7-yr OS: 74%
7-yr OS: 66%ADTADT + RT
Patients at Risk, nADTADT + RT
602603
509512
213232
5160
Deaths
175
145
ADT ± EBRT: Disease-Specific Survival
Warde PR, et al. ASCO 2010. Abstract CRA4504. Reprinted with permission.
100
80
60
40
20
00 3 6 9
Yrs
HR: 0.57 (95% CI: 0.37-0.78; p = .001)
7-yr DSS: 90%
7-yr DSS: 79%
Patients at Risk, nADTADT + RT
602603
509512
213232
5160
ADTADT + RT
Prostate Cancer Deaths
89
51
Pati
ents
(%
)
ADT ± EBRT: Safety
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 4507K. 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, CAJ 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 multiple myeloma[2]
1. Stopeck A, et al. SABCS 2009. Abstract 22. 2. Henry D, et al. ECCO/ESMO 2009. Abstract 20LBA.
Denosumab 120 mg SC +Placebo IV q4w
(n = 950)
Zoledronic Acid 4 mg IV + Placebo SC q4w
(n = 951)
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 vs Zoledronic Acid in Patients With CRPC
and Bone Metastases Prospective, double-blind, placebo-controlled phase III trial
Denosumab vs Zoledronic Acid: Time to First On-Study
SRE
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
1.00
0.75
0.50
0.25
00 3 6 9 12 15 18 21 24 27
Pro
port
ion
of S
ubje
cts
With
out S
RE
Study Mo
DenosumabZoledronic acid
HR: 0.82 (95% CI: 0.71-0.95;P = .0002 noninferiority;P = .008 superiority)
KM Estimate ofMedian, Mos
20.717.1
Patients at Risk, nZoledronic acidDenosumab
951950
733758
544582
407472
299361
207259
140168
93115
6470
4739
Denosumab vs Zoledronic Acid: Safety
Fizazi K, et al. ASCO 2010. Abstract LBA4507.
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
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
mCRPC
Pre-Chemo Tx 1st Line Chemotherapy
2nd Line Chemotherapy
Docetaxel + ZD4054
AstraZeneca 2012
Docetaxel + Lenalidomide
Celgene 2014-15
Docetaxel + Aflibercept (VEGF-TRAP)
Regeneron 2012
Docetaxel + DasatinibBMS 2012
Sipiluecel-TDendreon 2010
AbirateroneJ&J 2011
MDV3100Medivation
2014+
ZD4054AstraZeneca
2011
Docetaxel + AtrasentanSWOG 2013
CabazitaxelSanofi-Aventis
2010
AbirateroneJ&J 2012
IxabepiloneCALGB/SWOG
2014-15
SunitinibPfizer 2012
IpilimumabBMS 2013
Docetaxel + OGX-011Teva
• Leuprolide
• Goserelin
• Bicalutamide
• Flutamide
• Ketoconazole
• DES
• Docetaxel
• Mitoxantrone
• Bisphosphonates
• RT
Ap
pro
ved
A
gen
tsE
merg
ing
A
gen
ts
• Docetaxel
• Mitoxantrone
MDV3100Medivation 2013
Oral or IV+Oral
IV
IpilimumabBMS 2015
Docetaxel + OGX-011
Teva 2014-15
Ipilimumab + Docetaxel
BMS (2015)
TAK 700 & TOKai????
Docetaxel + BevazucimabCALGB 2010
Docetaxel + DN101
Novacea 2010
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 4511W. 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, CAJ Clin Oncol 28:18s, 2010 (suppl; abstr LBA4511)
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 withCRPC previously
untreated withchemotherapy
or biologic agents
(N = 1050)
Stratified by 24-mo survival probability (< 10%, 10% to 29.9%,
≥ 30%), age (< 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 +Placebo IV on Day 1 of 21-day cycle
(n = 526)
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
CALGB 90401: Phase III Trial of Chemotherapy ± Bevacizumab in
CRPC
Median DP = 21.5 (20.0-23.0)Median DPB=22.6 (21.1-24.5) HR= 0.91 (0.78-1.05)
0 6 12 18 24 30 36 42
Time(months)
0.0
0.2
0.4
0.6
0.8
1.0
Ove
rall
Su
rviv
al (
pro
bab
ility
)
Placebo+Docetaxel Bev+Docetaxel , log-rank p=0.181
526 480 390 305 199 100 44 22524 484 417 327 217 117 52 23
Placebo+DoceBev+Doce
Number of Patients at Risk
CALGB 90401: Kaplan-Meier Overall Survival Curves by Treatment Arm
CALGB 90401: Progression-Free Survival
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
1.0P
roba
bilit
y
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42
Mos
Placebo + CTBev + CT
526 303 134 75 34 8 4 0524 381 194 97 44 15 5 1
HR: 0.77 (95% CI: 0.68-0.88)Log rank P < .0001
Placebo + CT
Bevacizumab + CT
Median PFS, Mos (Range)
9.9 (9.1-10.6)
7.5 (6.7-8.0)
Patients at Risk, n
CALGB 90401: Endpoints
Kelly WK, et al. ASCO 2010. Abstract LBA4511.
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)< .0001Outcome, % (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
Longer-Term Use of Drug May Fight Ovarian CancerBy ANDREW POLLACKPublished: 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 won’t 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 man’s legs we would have Avastin approved for prostate cancer by now!”
Bevacizumab Associated With More Severe
ToxicitiesAdverse 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.
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, LAJ Clin Oncol 28:15s, 2010 (suppl; abstr 4508)
Cabazitaxel* 25 mg/m2 IV q3w + Prednisone 10 mg/day PO for 10 courses
(n = 378)
Mitoxantrone 12 mg/m2 IV q3w + Prednisone 10 mg/day PO for 10 courses
(n = 377)Patients with metastatic
CRPC progressingon docetaxel
(N = 755)
*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.
Stratified by ECOG performance score (0,1 vs 2), and measurable vs
nonmeasurable disease
De Bono JS, et al. ASCO 2010. Abstract 4508.
TROPIC: Randomized, Prospective, Open-Label, Multinational Phase III
Trial
De Bono JS, et al. ASCO 2010. Abstract 4508.
100
OS (
%)
80
60
40
20
00 6 12 18 24 30
Mos
MPCBZP
377 299 195 94 31 9378 321 241 137 60 19
TROPIC: Overall SurvivalUpdated ITT Analysis
Patients at Risk, n
MPCBZP
Censored
Combined medianfollow-up: 13.7 mos
28% reduction in risk of death
MP CBZP
Median OS, Mos 12.7 15.1
HR 0.72
95% CI 0.61-0.84
P value < .0001
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
mCRPC
Pre-Chemo Tx 1st Line Chemotherapy
2nd Line Chemotherapy
Docetaxel + ZD4054
AstraZeneca 2012
Docetaxel + Lenalidomide
Celgene 2014-15
Docetaxel + Aflibercept (VEGF-TRAP)
Regeneron 2012
Docetaxel + Aflibercept (VEGF-TRAP)
Regeneron 2012
Docetaxel + DasatinibBMS 2012
Sipiluecel-TDendreon 2010
Sipiluecel-TDendreon 2010
AbirateroneJ&J 2011
MDV3100Medivation
2014+
ZD4054AstraZeneca
2011
Docetaxel + AtrasentanSWOG 2012
CabazitaxelSanofi-Aventis
2010
CabazitaxelSanofi-Aventis
2010
AbirateroneJ&J 2012
IxabepiloneCALGB/SWOG
2014-15
IxabepiloneCALGB/SWOG
2014-15
SunitinibPfizer 2012
IpilimumabBMS 2013IpilimumabBMS 2013
Docetaxel + OGX-011Teva
Docetaxel + OGX-011Teva
• Leuprolide
• Goserelin
• Bicalutamide
• Flutamide
• Ketoconazole
• DES
• Docetaxel
• Mitoxantrone
• Bisphosphonates
• RT
Ap
pro
ved
A
gen
tsE
merg
ing
A
gen
ts
• Docetaxel
• Mitoxantrone
MDV3100Medivation 2013
Oral or IV+Oral
IV
IpilimumabBMS 2015IpilimumabBMS 2015
Docetaxel + OGX-011
Teva 2014-15
Docetaxel + OGX-011
Teva 2014-15
Ipilimumab + Docetaxel
BMS (2015)
Ipilimumab + Docetaxel
BMS (2015)
TAK 700 & TOKai????
TAK 700 & TOKai????
Docetaxel + BevazucimabCALGB 2010
Docetaxel + BevazucimabCALGB 2010
Docetaxel + DN101
Novacea 2010
1992-2005
Treatment options for RCC have been revolutionized in a short
period of time…
...but this rapid change has left many unanswered questions, including the optimal sequence of therapy
Sorafenib2
Sunitinib3
Temsirolimus4High dose
interleukin-21
1.Fyfe G et al. J Clin Oncol 13:688-696, 19952.Escudier B et al. N Engl J Med 356:125-134,20073.Motzer RJ et al. N Engl J Med 356:115-124,20074.Hudes G et al. N Engl J Med 356:2271-2281 20075. Escudier B et al. Lancet 370:2103-211, 20076. Rini BI et al. J Clin Oncol epud Oct, 20087. Motzer RJ et al. Lancet 372:449-456 20088. Sternberg C et al. ASCO 2009
2005 2006 2007 2008 2009
Bevazucimab + IFN5,6
Axitinib?
AVEO-751?
Interferon-
Everolimus7
2010+
Pazopanib8
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
• 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
• 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
Primary EndpointPrimary EndpointPrimary EndpointPrimary Endpoint
Secondary EndpointsSecondary EndpointsSecondary EndpointsSecondary Endpoints
Tumor Shrinkage (n=118)
Max
imu
m %
Ch
ang
e in
Tar
get
Les
ion
s
PR
Response Comparison
Response* %Historical rate 14
IL-2 Select Trial (all pts n=120) 28p=0.016
95% CI=20.5-37.3%
IL-2 Select Trial (clear cell n=115)
30
p=0.0008
95% CI=21.4-38.8%
*Using WHO Criteria
Tumor type N (%) P-value*
Clear Cell (n=115) 32 (100) 0.32
Non-clear cell (n=5) 0 (0)
MSKCC Risk GroupFavorable 10 (32%, [17-
51%])0.08
Intermediate 20 (24%, [15-35%])
Poor 4 (67%, [22-96%])
UCLA Risk Group High (n=8) 0 (0%, [0%-37%]) 0.22
Intermediate (n=101) 30 (30%,[21%-40%])
Low (n=10) 3 (30%,[7%-65%])
Response by Baseline 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 ScoreHigh (>85%) 23% (14%-34%) 0.13
Low (<85%) 38% (23%-55%)
Combined ScoreGood (n=74) 24% (15%-36%) 0.67
Poor (n=72) 36% (22%-52%)
Response by Pathology Characteristics
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
0 0.5 1 1.5 2
Hazard Ratio
Hazard Ratio=1.02 p=0.945
Hazard Ratio=0.71 p=0.010
Hazard Ratio=0.75 p=0.019
Chemotherapy better Control better
Single agent cisplatinStuder
Sub-totalCisplatin-based combinations
SkinnerBonoFreihaStockleOtto
Sub-total
Total
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 DesignSOGUG 99/01 Study Design
R
A
N
D
O
M
I
Z
E
EligibilityEligibility::
• TCCTCC
• Post- Post- CystectomyCystectomy
• pT3-4 and/or pT3-4 and/or pN+pN+
• PS 0-1PS 0-1
• CrCl > 50 CrCl > 50 ml/minml/min
PGC x 4PGC x 4
ObservationObservation
PDPD
StratificationStratification::
• PS: 0 PS: 0 vv 1 1
• pN: N0 pN: N0 vv N+ N+
Multicenter Phase III Randomized Open Label TrialMulticenter Phase III Randomized Open Label Trial
OutcomeOutcome• Median follow-upfollow-up: - All patients: 29.8 months (1-95) - Alive patients: 51 months (2-95)• Deaths: 69 patients (49%)Deaths: 69 patients (49%) - PGC arm: 24 (36%) - Observation arm: 45 (61%)• Disease Progression: 76 patients Disease Progression: 76 patients
(54%)(54%) - PGC arm: 30 (44%) - Observation arm: 54 (73%)
Overall Survival - ITTOverall Survival - ITT
Adjusted - Cox MultivariateHR: 0.378 ( 95% CI: 0.649-0.221) P< 0.0004
ConclusionsConclusions
• 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 30986Abstract LBA 4519M. 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, BelgiumJ Clin Oncol 28:15s, 2010 (suppl; abstr 4519)
Phase III results of EORTC study 30986
M. De Santis phase III 30986 ASCO 2010
Treatment 1: Methotrexate / CArboplatin / VInblastine
Methotrexate 30 mg/m2 i.v. days 1, 15, 22Carboplatin dose in mg = 4.5 x (GFR+25) i.v. day 1Vinblastine 3 mg/m2 i.v. days 1, 15, 22
> Every 4 weeks for at least 2 cycles
Treatment 2: Gemcitabine / Carboplatin
Gemcitabine 1000 mg/m2 i.v. days 1 and 8Carboplatin dose in mg = 4.5 x (GFR+25) i.v. day 1
> Every 3 weeks for at least 2 cycles
Treatment plan
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 phase III 30986 ASCO 2010
* Therasse P et al, J Natl Cancer Instit 2000;92:205-216
Inclusion criteria (summary)
Phase III results of EORTC study 30986
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)
Phase III results of EORTC study 30986
M. De Santis phase III 30986 ASCO 2010
ªnot a SAT ; *patients with at least 1 SAT
Results: Toxicity
GC(n=119)n (%)
M-CAVI(n=119)n (%)
CR+PR 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)
Phase III results of EORTC study 30986
M. De Santis phase III 30986 ASCO 2010
Results: Best Overall Response
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)
Phase III results of EORTC study 30986
Results: Overall Survival
(years)0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment108 119 37 13 7 3 1 1 1110 119 44 15 5 2 2 1 1
M-CAVIGC
%
HR=0.94 (95%CI: 0.72, 1.22)p=0.64
M. De Santis phase III 30986 ASCO 2010
8.1 months (95%CI: 6.1, 10.3)9.3 months (95%CI: 7.6, 11.3)
What have we learnt?
ASCO 2010: GU Summary Conclusions
Take home messagesLocally Advanced Prostate Cancer:
RT with ADT for 3 years is a standard of careMonotherapy 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 biomarkerSerial 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 StudyPost ASCO 2010
64 year old Attorney, controlled HTNPSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE
normalPSA 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 metastasesCT: right iliac and RP LNs
How would treat this patient?
Prostate Cancer Case StudyPost ASCO 2010
64 year old Attorney, controlled HTNPSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE
normalPSA 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 metastasesCT: right iliac and RP LNs
How would treat this patient?
Androgen deprivation therapy: Continuous or Intermittent?
Bone therapy: he starts calcium and vitamin DWould you start bone directed therapy now? Yes or No
If you would what is your therapeutic aim?
Prostate Cancer Case StudyPost ASCO 2010
64 year old Attorney, controlled HTNPSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE
normalPSA 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 metastasesCT: 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 DWould 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 StudyPost ASCO 2010
64 year old Attorney, controlled HTNPSA screening annually for more than 10 years: PSA 2.3 – 3.0, DRE
normalPSA 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 metastasesCT: 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 DWould 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 StudyPost ASCO 2010
64 year old Attorney, controlled HTNPSA screening annually for more than 10 years: PSA 2.3 – 3.0,
DRE normalPSA 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 LNsHe 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 StudyPost ASCO 2010
64 year old Attorney, controlled HTNPSA screening annually for more than 10 years: PSA 2.3 – 3.0,
DRE normalPSA 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 LNsHe 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 bicalutamideC.Clinical trial with abiraterone or TAK-700 or MDV 3100
D.Sipuleucel T (Provenge)E.Docetaxel chemotherapy
Prostate Cancer Case StudyPost ASCO 2010
64 year old Attorney, controlled HTNMetastatic 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 bicalutamideC.Clinical trial with abiraterone or TAK-700 or MDV 3100
D.Sipuleucel T (Provenge)E.Docetaxel chemotherapy
Prostate Cancer Case StudyPost ASCO 2010
64 year old Attorney, controlled HTNMetastatic 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.MitoxantroneC.Cabazitaxel
D.Oral cyclophosphamideE.Best supportive care
Thank YouJaoquim Belmunt, Bernard Escudier, Cora
Sternberg, Kevin Kelly, Howard Scher, Primo Lara, Nicholas Vogelzang, Mria
DeSantes, Karim Fizazi, Nicholas Nottet
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