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

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

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

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

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 2004-2010: No New Drugs !

The Evolving Role of Chemotherapy in CRPC

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

Novel Hormonal Treatment

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

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

Abiraterone Acetate (CB7630) CYP17 is key to androgenic steroid synthesis Oral, selective inhibitor of CYP17 – one enzyme, dual function 17α –hydroxylase C17,20-lyase Inhibits testosterone production in testis, adrenal glands and prostate MW = 391.55 3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene

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

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

Abiraterone Acetate: Overview of post-docetaxel phase II program

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

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

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

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

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

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

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

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)

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

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

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

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)

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

Discussion

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

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?

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

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?

THANK YOU For your attention !