1. Abiraterone Changes in Landscape of Advanced Prostate Cancer
Professor Susanne Osanto, MD, PhD
Dept. of Clinical Oncology Leiden University Medical Center
The Netherlands

2. Current Paradigm
Prostate cancer is usually still androgen-driven at the castration-resistant stage.
Prostate cancer is as chemosensitive as other major epithelial cancers
The long interval before symptomatic progression and long period of symptomatic M+ period makes CaP an ideal candidate for various approaches period

3. AR signaling and CRPC High intratumoral androgens despite castration
Tumor progression despite castrate levels of androgens (serum testosterone <50 ng/mL).
Castration resistance associated with AR amplification
Mutations in AR increase AR transcriptional activity
Alternative hormonal treatments continue to have antitumor activity in CRPC patients

4. Changing Landscape More space in M+ phase for development of novel, less toxic, more effective drugs (phase III trials showing OS benefit)
Non-metastatic CRPC
Metastatic, hormone-naïve
Metastatic CRPC
Pre-Doc
Docetaxel
Post-Doc
Metastases

5. Historically Only Few Drugs Licensed
1981: Estramustine
1993: Strontium Reduction in new onset of painful bone lesions after radiotherapy (XRT) + isotope compared with XRT alone
1996: Mitoxantrone + prednisone Reduction in pain compared with prednisone, no OS benefit
1997: Samarium Reduction in bone pain compared with placebo
2002: Zoledronic acid Reduction in skeletal-related events compared with placebo
2004: Docetaxel + prednisone Prolonged OS compared with mitoxantrone + prednisone
: No New Drugs !

6. The Evolving Role of Chemotherapy in CRPC

7. Evolving Role of Chemotherapy in CRPC
Castrate-refractory prostate cancer
Second-line therapy
Castrate-sensitive prostate cancer
First-line therapy
Cabazitaxel
2010
OS benefit vs mitoxantrone
Study
TROPIC
LHRH analogues
Antiandrogens
LHRH antagonist
Mitoxantrone
Docetaxel
1996
Effective palliative treatment
2004
OS benefit vs mitoxantrone
Studies
TAX 327 SWOG 9916 7 7 7 7 7 7

8. Novel Hormonal Treatment

9. Emerging Targeted Hormonal Therapies for Advanced PCa
Androgens synthesized at 3 critical sites (testes, adrenals, prostate tumour cells) lead to tumor cell proliferation.
Arbiraterone inhibits synthesis of androgens that stimulate tumour cells.
Phase II studies showed PSA responses in chemo-naïve and post-chemo patients

10. Why develop another CRPC hormonal agent?
Prostate Cancer
Testosterone
Testis
Adrenal
Gland
ACTH LH
Brain
LHRH
Androgens
LHRH Analogue
Pituitary
LHRH analogues do not inhibit adrenal androgen synthesis
Responses observed with ketoconazole, but use is limited by poor tolerability, tachyphylaxis
Residual androgens persist in CRPC tissues despite LHRHa therapy
Intracrine or paracrine signaling
CRPC frequently remains driven by a ligand-activated androgen receptor (AR)
AR overexpression, TMPRSS2-ERG

11. Abiraterone Acetate (CB7630)
CYP17 is key to androgenic steroid synthesis
Oral, selective inhibitor of CYP – one enzyme, dual function
17α –hydroxylase
C17,20-lyase
Inhibits testosterone production in testis, adrenal glands and prostate
MW =
3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene

12. Hormonal Impact of Abiraterone Alone or with Low Dose Corticosteroids
Attard, et al, 2008 J. Clin. Oncol, Epub August

13. Abiraterone: Multiple inhibition of androgen synthesis
Prostate Cancer
Testosterone
Testis
Adrenal
Gland
ACTH LH
Brain
LHRH
Androgens
Pituitary
Inhibitor

14. Abiraterone Acetate: Overview of post-docetaxel phase II program

15. COU-AA-BMA: Phase II pre/post-docetaxel CRPC Study (Logothetis - MDACC)
100 50
-50
-100
PSA Change (%) 25
Prior Therapy
Ketoconazole or/and DES - 17/24 (71%)
Prior Chemotherapy – 19/24 (79%)
2≥ Chemotherapies – 13/24 (54%)
PSA Decline Rate
Durable ≥ 50% PSA declines in 11/23 (48%) median duration 6+ months
Durable ≥ 90% PSA declines in 4/23 (17%)
ECOG PS Improvement:
10 (43%) had at least a one point improvement in their functional status.
Abiraterone acetate 1000mg and
Prednisone 5 mg PO BID
Efstathiou et al, ASCO Annual Meeting 2008 Abstract #5017

16. COU-AA-003: Ph II post-docetaxel CRPC Study (DeBono – UK)
Patient characteristics
Median baseline PSA: 536
Presence of bone mets: 27/34 pts
Prior docetaxel – 100%
55% (18/34) due to progression
45% (16/34) stopped for toxicity
Antitumor Response
20 pts with measurable disease at baseline by RECIST
5/20 (25%) confirmed radiological PR
10/20 stable disease at 3 months
4/20 progressive disease
1/20 < 3 mths on study
PSA Response:
47% (16/34) pts ≥50% decline
65% (22/34) pts ≥30% decline
71% (24/34) pts had a PSA decline
De Bono et al, ASCO Annual Meeting Abstract 5005, 2008

17. COU-AA-004: Phase II post-docetaxel CRPC Study (Danila - MSKCC)
Prior Hormonal Therapy
LHRH analogues – 100%
1 Line – 2/38 (5%)
2 Lines – 6/38 (16%)
3 Lines – 8/38 (21%)
4 Lines – 8/38 (21%)
> 4 Lines – 14/38 (37%)
Ketoconazole – 14/38 (37%)
Prior Chemotherapy
68% (26/38) received 1 prior line of therapy (docetaxel)
32% (12/38) received a second line cytotoxic chemotherapy
PSA Rate Declines
40% (14/35) with PSA 50% decline)
(3 pts too early to evaluate)
= No prior Ketoconazole = Prior Ketoconazole
Danila et al, ASCO Annual Meeting Abstract 5019, 2008

18. Phase I & II Experience: Adverse Events
The adverse event profile, consisting primarily of hypertension, fluid retention and hypokalemia, has been acceptable for this group of pretreated patients
The incidence of hypertension, fluid retention and hypokalemia appears to be decreased with the combination of abiraterone acetate and prednisone
Only Grade 1 hypokalemia was observed in COU-AA-004

19. COU-AA-301
COU-AA-301: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy 19

20. COU-AA-301
COU-AA-301: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy 20

21. 301 Study Rationale Investigational Arm Control Arm
Abiraterone acetate has unique mechanism of action
Well tolerated when administered with concurrent prednisone
Encouraging phase II data in post-docetaxel CRPC patients
Control Arm
Prednisone is often given as post-chemo CRPC 2nd-line therapy
No treatment options currently approved by regulatory agencies in post-docetaxel CRPC setting

22. Study Objectives Primary:
To compare the clinical benefit of abiraterone acetate plus prednisone with placebo plus prednisone in patients with metastatic CRPC who have failed one or two chemotherapy regimens, one of which contains docetaxel
Secondary:
Evaluate the safety profile of abiraterone plus prednisone
Pharmacokinetics (PK) of abiraterone plus prednisone
Circulating tumor cells (CTCs) as a surrogate for clinical benefit
To evaluate the impact on health-related quality of life (QOL)

23. Efficacy Endpoints Primary Endpoint Overall survival
Secondary endpoints
Proportion of patients achieving a PSA decline ≥ 50% according to Prostate Specific Antigen Working Group (PSAWG) criteria
Time-to-PSA progression based on PSAWG criteria
Progression-free survival (PFS) based on imaging studies

24. Inclusion Criteria
Histologically or cytologically confirmed adenocarcinoma of the prostate
Ongoing androgen deprivation with serum testosterone < 2.0nM (< 50 ng/dL)
1-2 cytotoxic chemo regimens for metastatic CRPC.
At least one regimen must have contained docetaxel
ECOG Performance Status of ≤ 2
* Partial list of 301 study inclusion criteria 24

29. 29 29

31. 2nd line Arbiraterone vs Prednisone
Median survival
2nd line Arbiraterone vs Prednisone
14.8 vs 10.9 months

37. Three new active cancer drugs improving OS in CRPC FDA approved in 2010/2011
Sipuleucel-T (pre – 1st line CT)
Cabazitaxel (2nd line CT after Doc)
Arbiraterone (2nd line after Doc)

38. Novel Androgen receptor inhibitors.. New kids around the block….

39. Discussion

40. Question: will you be able to incorporate Abiraterone into your routine clinical practice ?
Yes No
Maybe
Yes, if it were approved in my country

41. Q. What treatment would you advice the postdocetaxel patient?
Cabazitaxel (medonc? Too toxic? better? costs?)
Abiraterone (medonc or urologist? better toxicity profile? better OS?, costs?)
Again Docetaxel in case of good prior response (less expensive, as good?)
Mitoxantrone?

42. Discussion Abiraterone
Positioning of the various novel drugs in the changing landscape?
Abiraterone, selective inhibition of CYP17, safe and has an easily manageable side effect profile
But, only a few months OS benefit for subset of patients….
High costs related to use of oral drug

43. Discussion
Abiraterone (Zytiga) registered post-docetaxel, but maybe soon pre-docetaxel space…...
Four lines of hormonal treatment (LHRH, bicalutamide, Cyp17A blockers, AR inhibitors) pre-docetaxel. New sequence? Will 1st line LHRH analogues be replaced?
Urologists will administer pre-docetaxel
Healthcare costs unsustainable?

44. THANK YOU For your attention !