Placebo - The Prostate Net

MANAGEMENT PROTOCOLS FOR ADVANCED PROSTATE CANCER:

Walter Stadler, MD, FACP University of Chicago

Disclosures •

(All Non-University &/or Financial Dealings with Potential, Real, or Perceived Conflicts of Interest) Consultant: – Novartis, Pfizer/Wyeth, GSK, Roche/Genentech, Takeda, Caremark/CVS, Aveo, Ligand Pharmaceuticals, NCI/SAIC-Frederick

• Speakers Bureau:

– CME providers (sponsorship unknown): Imedex, CME Innovations, Researchto-Practice, NOCR, Clinical Care Options, Medical Communications Media, – Pfizer, Bayer

• Grant/Research Support:

– Active Biotech, Bayer, Bristol-Myers-Squibb, Boerhinger-Ingelheim, Novartis, Genentech (Roche), Glaxo-Smith-Kline, Medivation, Solvay (Abbott), Pfizer, ImClone (Lilly), Amgen, Takeda (Millenium), NIH, CALGB

• Stockholder:

– Abbott (Spouse)

• Expert Witness – None

• Miscellaneous: – Kidney Cancer Assoc, Bladder Cancer Advocacy Network, Up-To-Date, NexCura, Demos Medical Publishing

Castrate Resistant Disease • Not really “hormone refractory” • AR still a relevant target • Other potential targets – Immune system – DNA and DNA repair

• Mechanisms of castrate resistance – – – – –

AR amplification AR mutation AR modification Ligand availability AR interactions

AR Activation in Castrate Patients

Scher and Sawyers, JCO, 2005

What we know… •

Prostate cancer requires AR signaling for development and sustenance.

•

AR activation is required throughout the natural history of prostate cancer.

•

AR activation in CRPC occurs via many mechanisms.

•

Successful blockade of the receptor pathways will confer greater therapeutic control on metastatic prostate cancer.

Abiraterone/TAK-700

Abiraterone Phase II Attard JCO 2009

Pre-Chemo Ryan ASCO 2009

Danila ASCO 2009

Post-Chemo Reid ASCO 2009

COU-AA-301 Study Design Patients • 1195 patients with progressive mCRPC • Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel

R A N D O M I Z E D 2:1

• •

Abiraterone 1000 mg daily Prednisone 5 mg BID n=797

Efficacy endpoints (ITT) Primary end point • OS (25% improvement; HR 0.8) Secondary endpoints (ITT)

Placebo daily Prednisone 5 mg BID n=398

• TTPP • PFS • PSA response

Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) Stratification according to – – – –

ECOG performance status (0-1 vs 2) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present]) Prior chemotherapy (1 vs 2) Type of progression (PSA only vs radiographic progression with or without PSA progression)

Abbreviations: BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastatic castrate-resistant prostate cancer. Source: Clinicaltrials.gov identifier: NCT00638690.

COU-AA-301 Patient Disposition Abiraterone (n=797)

Placebo (n=398)

791

394

8 (1-21)

4 (1-21)

Treatment ongoing, n (%)

222 (28.1)

54 (13.7)

Treatment discontinued, n (%)

569 (71.9)

340 (86.3)

Subjects treated Median number of cycles of therapy (range)

COU-AA-301 Baseline Demographics Abiraterone (n=797) 69.0 (42-95)

Placebo (n=398) 69.0 (39-90)

Total (n=1195) 69.0 (39-95)

White

93.3

92.7

93.1

Black

3.5

3.8

3.6

Asian

1.4

2.3

1.7

ECOG PS 2, %

10.7

11.1

10.8

Significant pain present, %

44.3

44.0

44.2

2 Prior chemotherapies, %

28.2

28.4

28.3

Median age, years (range) Race, %

COU-AA-301 Baseline Disease Characteristics Abiraterone (n=797)

Placebo (n=398)

Bone

89.2

90.4

Node

45.4

41.5

Liver

11.3

7.6

Lung

13.0

11.4

Primary site of disease, %

COU-AA-301: Abiraterone Acetate Improves OS in mCRPC 100 HR=0.646 (0.54-0.77) P