State of the Art: Treatment Options in Advanced Genitourinary Cancers David I. Quinn MBBS (Hons) PhD...

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


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


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


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


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


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


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


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


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


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


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


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


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


CRPC Landscape In Transition

mCRPC

Pre-Chemo Tx 1st Line Chemotherapy

2nd Line Chemotherapy

Docetaxel + ZD4054

AstraZeneca 2012

Docetaxel + Lenalidomide

Celgene 2014-15


Regeneron 2012


Regeneron 2012

Docetaxel + DasatinibBMS 2012



AbirateroneJ&J 2011

MDV3100Medivation

2014+

ZD4054AstraZeneca

2011

Docetaxel + AtrasentanSWOG 2012


2010


2010

AbirateroneJ&J 2012


2014-15


2014-15

SunitinibPfizer 2012

IpilimumabBMS 2013IpilimumabBMS 2013



• 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


BMS (2015)


BMS (2015)

TAK 700 & TOKai????

TAK 700 & TOKai????



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


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


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



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


• 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


* Therasse P et al, J Natl Cancer Instit 2000;92:205-216

Inclusion criteria (summary)


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

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)



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)


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


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?







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?







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






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


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


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)


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


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


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


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

State of the Art: Treatment Options in Advanced Genitourinary Cancers David I. Quinn MBBS (Hons) PhD...

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Transcript of State of the Art: Treatment Options in Advanced Genitourinary Cancers David I. Quinn MBBS (Hons) PhD...