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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.
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Abiraterone Changes in Landscape of Advanced Prostate Cancer Professor Susanne Osanto, MD, PhD Dept. of Clinical OncologyLeiden University Medical Center The Netherlands
Current Paradigm • Prostate cancer isusuallystillandrogen-drivenat the castration-resistant stage. • Prostate cancer isas chemosensitiveas other major epithelial cancers • The long intervalbeforesymptomatic progression and long period of symptomatic M+ periodmakesCaP an ideal candidate for variousapproachesperiod
AR signaling and CRPC • High intratumoral androgens despite castration • Tumor progression despite castrate levels of androgens (serum testosterone <50 ng/mL). • Castration resistance associated withAR amplification • Mutations in AR increase AR transcriptional activity • Alternative hormonal treatments continue to have antitumor activity in CRPC patients
Changing LandscapeMore 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 !
Evolving Role of Chemotherapy in CRPC Castrate-refractoryprostate cancer Second-line therapy Castrate-refractory prostate cancer First-line therapy Castrate-sensitiveprostate cancer Cabazitaxel 2010 OS benefitvs mitoxantrone Study TROPIC LHRH analogues Antiandrogens LHRH antagonist Mitoxantrone Docetaxel 1996 Effective palliativetreatment 2004 OS benefitvs mitoxantrone Studies TAX 327SWOG 9916 7
Emerging Targeted Hormonal Therapies for Advanced PCa • Androgenssynthesizedat 3 critical sites (testes, adrenals, prostate tumourcells) lead to tumorcellproliferation. • Arbirateroneinhibitssynthesis of androgensthatstimulatetumourcells. • Phase II studiesshowed PSA responses in chemo-naïve and post-chemo patients
LHRH Analogue LHRH Brain Pituitary LH ACTH Adrenal Gland Testis Testosterone Androgens Prostate Cancer Why develop another CRPC hormonal agent? • 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 LHRH Brain Pituitary Inhibitor LH ACTH Inhibitor Adrenal Gland Testis Testosterone Androgens Inhibitor Prostate Cancer
Abiraterone Acetate: Overview of post-docetaxel phase II program
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. -100 -50 PSA Change (%) 0 25 50 100 COU-AA-BMA: Phase II pre/post-docetaxel CRPC Study (Logothetis - MDACC) Abiraterone acetate 1000mg and Prednisone 5 mg PO BID Efstathiou et al, ASCO Annual Meeting 2008 Abstract #5017
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 COU-AA-003: Ph II post-docetaxel CRPC Study (DeBono – UK) 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 hypokalemiaappears 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
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
Investigational 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 301 Study Rationale
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
2nd line Arbirateronevs Prednisone Median survival 2nd line Arbirateronevs 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)
NovelAndrogen receptor inhibitors..New kids around the block….
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 variousnoveldrugsin the changinglandscape? • 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 costsrelated to use of oral drug
Discussion • Abiraterone (Zytiga) registeredpost-docetaxel, but maybesoonpre-docetaxelspace…... • Four lines of hormonal treatment(LHRH, bicalutamide, Cyp17A blockers, AR inhibitors) pre-docetaxel. New sequence? Will 1st line LHRH analogues bereplaced? • Urologistswilladministerpre-docetaxel • Healthcarecostsunsustainable?