A Forward Look at Options for Prostate Cancer Charles J Ryan, MD Associate Professor of Medicine Helen Diller Family Comprehensive Cancer Center University of California, San Francisco UC 1 SF UC SF Castration Resistant Prostate Cancer: Standards of Care 1. Androgen Deprivation Therapy: Should be Maintained. 2. Secondary hormonal therapy (e.g. Ketoconazole), may be considered, not FDA approved. 3. Zoledronic Acid: Prevention of Skeletal Related Events 4. Chemotherapy: Survival Benefit, FDA approved 5. Mitoxantrone, Estramustine: FDA Approved, secondary considerations. 6. Not approved, may be beneficial, no definitive data Carboplatin, etc 7. Palliative XRT, Radio-isotopes: Still useful in some. New Therapies in Advanced Prostate Cancer Non-cytotoxics leading the way Matching Drugs to Disease (and Androgen) Biology Building on Backbone Continued Promise of Immunotherapy The Development Landscape For Systemic Therapies In Prostate Cancer Diagnoses 186, 320 Clinically Localized Disease Non-Castrate Androgen depletion /blockade (bicalutamide) Rising PSA Clinical Metastases: Non-Castrate 1 Rising PSA: Castrate 2 Clinical Metastases: Castrate Pre- Castration resistant: Deaths From Disease 28,660 3 Clinical Metastases: Castrate 1st Line Standard 4 Clinical Metastases: Castrate Post- No Standard Deaths= 28,000 With detectable metastases: deaths from cancer exceed that from other causes 1
Castration Resistance- Understanding of Biology is Leading to New Therapies Genes Expressed at Higher Levels in AIPC BM Biopsies (Compared to primaries - among others) 500 ng/ml Testosterone Symbol Fold (AIPC:Primary) Gene Name Significance AR 5.84 Androgen Receptor AR AKR1C3 5.27 Aldo-keto reductase family 1, member C3 Converts androstenedione to testosterone 50 ng/ml PSA SRD5A1 2.1 5 alpha reductase type 1 Converts T to DHT Converts Androstenedione to Androstanedione HSD3B2 1.8 3 Beta -hydroxysteroid dehydrogenase type 2 Converts DHEA to Androstenedione AKR1C2 3.4 Aldo-keto reductase 2 Catabolizes DHT Can convert Androstanedione to Androstenedione Castration Therapy Castration Resistance 5 AKR1C1 3.1 Aldo-keto reductase 1 Catabolizes DHT Stanbrough et al Cancer Research March 1, 2006 U C S F The Biological Rationale for the Development of Secondary Hormonal Therapies ACTH Cholesterol Pituitary Adrenal Androgen Synthesis Ketoconazole Adrenal Cortex Abiraterone desmolase Pregnenolone 18OH- Progesterone DOC Corticosterone Aldosterone Corticosterone AR Amplification and Persistence CPRC Intratumor Androgen Production/conversion 3-BHSD-I 17α-hydroxylase 21-hydroxylase 11β-hydroxylase 18-hydroxylase 18-oxidase 17OH-pregnenolone 17OH-progesterone 11-DOC Cortisol MDV3100 Persistent Serum Androgens (e.g. adrenals) Abiraterone C17-20 lyase 3-BHSD-I Peripheral Tissues DHEA 3-BHSD-I Androstenedione Testosterone DHT 7 17-keto-reductase 5α-reductase 2
Both Ketoconazole and Abiraterone (CB760) Inhibit CYP17 Abiraterone 4 years on, what do we know? Haidar et al J. Steroid Biochemistry and Molecular Biol. 2003 Phase I Questions Tox and PSA effects Fasted vs Fed Capsule vs Tablet Adrenal Insufficiency? Corticosteroids necessary? Ryan et al JCO 2010 Danila et al JCO 2010 Reid et al JCO 2010 Phase II questions Efficacy/Durability Prechemotherapy with prednisone (02) Postchemotherapy without prednisone (03) Postchemotherapy with prednisone (04) Phase III questions Efficacy/Durability Survival vs Prednisone Pre vs Post. High Rate of Response to Abiraterone Even Post Ketoconazole Baseline Post Cycle 6 50% PSA decline 54.8% 50% PSA decline 45.2% Danila Et al JCO 2010 Ryan Et al JCO 2010 UC SF 3
Cougar Biotechnology: Schematic of Phase III Trial Design (Trial 301) Progressive Prostate Cancer after based chemotherapy RANDOMIZE Arm A Abiraterone plus Prednisone Arm B Placebo plus Prednisone Cougar Biotechnology: Schematic of Phase III Trial Design (Trial 302) Progressive Prostate Cancer WITHOUT prior based chemotherapy RANDOMIZE Arm A Abiraterone plus Prednisone Arm B Placebo plus Prednisone 2:1 Randomization Primary Endpoint - Overall Survival Endpoints PFS, Overall Survival Higher AR levels in HRPC tumors The Amplified AR As A Drug Target Stanbrough et al Cancer Research 2006 Holzberlein et al MDV-3100 and ARN- 509 Figure 2. Range of AR expression and analyses of CKS2 and LRRC15 by quantitative real-time RT-PCR. A, range of AR expression in primary (Pr) and androgen-independent tumors (AIPCa) from Affymetrix data. B, CKS2 and LRRC15 expression assessed by quantitative real-time RT-PCR using unamplified RNA from 5 primary tumors and 10 androgen-independent prostate cancer bone marrow metastases. Expression levels are in arbitrary units based on the lowest level expression being set at 10. Bars, mean expression. (CKS2 associates with cyclin-dependent kinases and enhances their interaction with CDC25 phosphatases, which dephosphorylate them at the G2- M transition LRRC15 is a cell surface glycoprotein major transcriptional target of the Wilms tumor 1 (WT1; +KTS) isoform and is overexpressed due to a WT1 fusion protein in a rare, highly aggressive tumor type, desmoplastic small round cell tumor ) Figure 3. AR expression in human prostate cancers. A: Bar graph representing AR transcript levels based on hybridization of cdna target to oligonucleotide arrays. Two different probe sets for AR are presented. B and C: Immunohistochemical detection of the AR in representative primary untreated prostate cancer with low level of AR transcripts (B) and metastatic AARPC with high levels (C). D and E: Fluorescent in situ hybridization for AR (red) and chromosome X centromere (green) in metastatic AARPC with high levels of AR transcripts and no amplification of the AR gene (D) and metastatic AARPC with high level of AR expression and AR amplification (E). 15 UC SF Both developed in model of AR amplification MDV-3100 Phase III ARN-509 phase I pending 4
MDV3100 A Second-Generation Antiandrogen AR Antagonism with MDV-3100 Possibly Related Grade 2/3 Adverse Events in >2 Patients 1. Engineered for activity in prostate cancer cells that overexpress the androgen receptor (AR). 2. Binds the AR more potently than bicalutamide. Adverse Event Fatigue Nausea Anorexia Seizure All Doses (N = 140) <240 mg/day (N = 60) G2 G3 G2 G3 29 (21%) 11 ( 8%) 4 ( 3%) 12 (9%) 3 (2%) 8 (13%) 2 ( 3%) 3 (5%) 3. Unlike bicalutamide, MDV3100 inhibits nuclear translocation of the AR and its binding to DNA. 4. Induces apoptosis in prostate cancer cells. 1. Only one subject discontinued treatment due to fatigue which coincided with disease progression 2. There were 2 witnessed seizures (1 each at 600 and 360 mg/day) and a possible unwitnessed seizure (at 480 mg/day). Both patients with witnessed seizures were taking concomitant medications that can cause seizure 3. MTD determined to be 240 mg/day; patients at higher doses were lowered to 240 mg/day Scher et al Proc ASCO 2009Abstract # 5011 Waterfall Plot of Best Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) 62% (40/65) >50% Decline Post-Chemotherapy (N=75) Scher et al Proc ASCOAbstract # 5011 51% (38/75) >50% Decline Medivation: Schematic of Phase III Trial Design Progressive Prostate Cancer after based chemotherapy No prior Abiraterone or Ketoconazole 2:1 Randomization Primary Endpoint - Overall Survival Secondary aims PFS and Pain control RANDOMIZE Arm A MDV3100 Arm B Placebo 5
Chemotherapy for CRPC HRPC Trials 1. Survival Improvement shown ( over Mitoxantrone) in 2004 2. To date, no proven benefit to additional therapy to docetaxel 3. Issues of Timing remain 4. Second line chemotherapy under development UC SF TAX 327 1 N=1006 SWOG 9916 2 N=770 *Warfarin and aspirin Randomize Randomize Mitoxantrone 12 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles 30 mg/m 2 /wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles 75 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles Mitoxantrone 12 mg/m 2 Prednisone 5 mg bid Q 21 days 60 mg/m 2 d 2 Estramustine 280 mg d1-5* Dexamethasone 20 mg, tid d 1 & 2 1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520. Overall Survival TAX 327 Can the Efficacy of Chemotherapy be enhanced? Probability of Surviving 1.0 0.9 3 wkly 0.8 wkly Mitoxantrone 0.7 0.6 0.5 Median 0.4 survival Hazard (mos) ratio P-value 0.3 Combined: 18.2 0.83 0.03 0.2 D 3 wkly: 18.9 0.76 0.009 0.1 D wkly: 17.3 0.91 0.3 Mitoxantrone 0.0 16.4 0 6 12 18 24 30 Months Tannock et al. N Engl J Med 2004:351;1502-1512. Addition of non-cytotoxic drugs Bevacizumab FAILED Calcitriol FAILED Immunotherapy GVAX - FAILED 25 6
TAX3501 in earlier stage prostate cancer? RP Randomize Observation ADT ADT + P R O G R E S S I O N ADT ADT + P R O G R E S S I O N 27 Early? ADT vs ADT + Chemotherapy in Non-met rising PSA Rising PSA following definitive local therapy PSA doubling time of <9 months Minimum PSA of 2 Testosterone >180 RANDOMIZE Arm A 75 mg/m 2 q 3 weeks x 6 months Leuprolide x 24 months Arm B Leuprolide x 24 months CALGB 90203: Neoadjuvant Preoperative Estimate (Kattan Nomogram)of Biochemical RFS 60% 6 Cycles Chemotherapy 70 mg/m2 q 21 days. Prednisone 5 mg po bid LHRH Agonists x4 months Surgical Intervention Staging Pelvic Lymphadenopathy Radical Prostatectomy* Surgical Intervention Staging Pelvic Lymphadenopathy Radical Prostatectomy* Open The study is designed to detect a hazard ratio of 1.5 with the median time to progression of 36 months vs. 54 months, as defined by a detectable PSA. Patient 28 must have a testosterone >50 to be evaluable. QOL will assessed in both arms. *Patients with positive surgical margins will be allowed to receive immediate adjuvatn external beam radiation to the prostatic fossa at the discretion of the treating physician. Adjuvant radiation must be initiated within 6 months of the date of surgery. 29 7
What about Taxane refractory disease?? Unmet medical need Cabazetaxel Microtubule Stabilizer Poor prognosis. Chemotherapy vs other approaches? Developed in resistant prostate cancer cell lines. 30 31 TROPIC Cabazetaxel vs MP Tropic Phase III Trial - Results Cabazetaxel 25 mg/m2 q 21 days Prednisone 10 mg daily Pt Characteristics CBZ MP PSA 128 144 OVERALL SURVIVAL Results CBZ MP P value 15.1 12.7 <0.001 CRPC PD During or after 146 Sites/ 26 Countries RANDOMIZE N=755 Mitoxantrone Prednisone 10 mg daily Age 67 68 Prior docetaxel (cumulative dose) Last Visceral Disease (%) 576 mg 529 0.8 years 0.7 years 25 25 PFS 2.8 1.4 <0.001 PSA Response Rate (%) 39.2 18 TTP 6.4 3.1 # Cycles (median) 6 4 32 33 8
Primary Endpoint: Overall Survival (ITT Analysis) Proportion of OS (%) 100 80 60 Median OS (months) Hazard Ratio 95% CI P-value MP CBZP 12.7 15.1 0.70 0.59 0.83 <.0001 Proportion of PFS (%) Progression-Free Survival (PFS) 100 Results MP 80 60 Median PFS (months) Hazard Ratio 95% CI P-value CBZP 1.4 2.8 0.74 0.64 0.86 <.0001 PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death. 40 40 20 20 Number at risk 0 0 months 6 months 12 months 18 months 24 months 30 months MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4 34 0 0 months 3 months 6 months 9 months 12 months 15 months 18 months 21 months Number MP 377 115 52 27 9 6 4 2 at risk CBZP 378 168 90 52 15 4 0 0 35 Total Deaths During Study Safety Population MP (n=371) CBZP (n=371) Total deaths during study 275 (74.1%) 227 (61.2%) Due to progression 253 (68.2%) 197 (53.1%) Due to AEs 7 (1.9%) 18 (4.9%) Due to other reasons 15 (4.0%) 12 (3.2%) 38 Immunotherapy in CRPC FDA Approval of Provenge 4-29- 10 9
Theoretical Kinetics of Treatment Response: Cytotoxic Therapy vs Immunotherapy APC8015 (Provenge ) Ex -Vivo Dendritic Cell Priming APC8015 Cytotoxic chemotherapy quickly debulks tumors Resistance and tumor regrowth may occur Immunotherapy activates the immune system Clinical effect may take time to develop Responses may be sustained due to immunologic memory Tumor size Time on treatment Time Chemotherapy Progression Immunotherapy Antigen Precursor APC Antigen Loading Antigen-loaded precursor APC T cells attack tumor cells Antigen Processing Maturing antigenloaded APC In vivo T cell activation Infuse patient Webster et al. J Clin Oncol. 2005;23:8262. Results: Overall Survival (ITT population) Percent Survival 100 75 50 25 APC8015 (n=82) Placebo (n=45) P = 0.01 (log-rank) HR = 1.7 (95% CI: 1.126, 2.563) Phase 3 Trial #D9901 0 0 10 20 30 40 Survival (months) Small JCO 2006 43 10
Summary In advanced CRPC remains the standard of care Many new agents in development three in late stage and may gain approval in next 2-3 years. Non-cytotoxic approaches leading the charge 44 45 11