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Castrate resistance prostate cancer: Integrating novel agents into a therapeutic algorithm Charles J Ryan, MD Associate Professor of Medicine and Urology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco 1 U CSF Since 2010… • Four new drugs approved for advanced prostate cancer by the US FDA – Three based on improvements in survival (Cabazi, Abiraterone, Sipuleucel T) – (Initial phase I studies of abiraterone and Sip T done at UCSF in GU Medical Oncology Program) • Two Others- Alpharadin (Radium 223) and MDV3100 have shown OS Benefit in trials, FDA approval not yet granted. 1. How do we define Castration Resistant Prostate Cancer? 500 ng/mL 50 ng/ mL Testosterone Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL) PSA Castration Therapy Castration Resistance 5 2. What makes prostate cancer lethal and how do we assess prognosis in patients? 500 ng/mL 50 ng/ mL + Testosterone PSA Castration Therapy Castration Resistance 5 = Lethal Prostate cancer Prostate Cancer Standards and Novel Therapies: Clinically Localized Rising PSA post RP/RT ADT Resistant Pre-Chemotherapy Chemotherapy CRPC Docetaxel Resistant AR Targeted Therapy Chemotherapy Immunotherapy Targeted Therapy UCSF Prostate Cancer Standards and Novel Therapies: 2009 Clinically Localized Rising PSA post RP/RT ADT Resistant Pre-Chemotherapy Chemotherapy CRPC Docetaxel Resistant AR Targeted Therapy Docetaxel (Standard) Chemotherapy Immunotherapy Targeted Therapy Therapies showing a survival benefit UCSF New Treatments for Advanced Prostate Cancer Targeting the T Cell Androgen Synthesis Inhibitors Second line chemotherapy Alpha-emitting Radio-isotopes UCSF New Treatments for Advanced Prostate Cancer Targeting the T Cell UCSF Theoretical Kinetics of Treatment Response: Cytotoxic Therapy vs Immunotherapy Cytotoxic chemotherapy quickly debulks tumors Time on treatment – Resistance and tumor regrowth may occur Chemotherapy – Clinical effect may take time to develop – Responses may be sustained due to immunologic memory Tumor size Immunotherapy activates the immune system Progression Immunotherapy Time Webster et al. J Clin Oncol. 2005;23:8262. Sipuleucel-T: Background APC8015 Precursor APC Sip-T Antigen Processing Antigen-loaded precursor APC 20 Maturing antigenloaded APC PSA (ng/mL) Antigen Loading s Infuse patient 15 10 5 0 T cells attack tumor cells In vivo T cell activation -10 0 10 20 Week Small EJ et al., J Clin Oncol 18: 3894, 2000 30 Sipuleucel-T : (second) Pivotal Trial Results Phase 3 design allowed for crossover from placebo to vaccine Adverse Events PROVENGE (n=338) Adverse event † † Control (n=168) All Grades (%) Grades 3–5 (%) All Grades (%) Grades 3–5 (%) Chills 54.1 1.2 12.5 0 Fever (pyrexia) 29.3 0.3 13.7 1.8 Headache 16.0 0.3 4.8 0 Influenza-like illness 9.8 0 3.6 0 Myalgia 9.8 0.6 4.8 0 Hypertension 7.4 0.6 3.0 0 Hyperhidrosis 5.3 0 0.6 0 Groin pain 5.0 0 2.4 0 • Primary endpoint: Overall survival1,2 • Secondary endpoint: Objective disease progression2 †Control was nonactivated, autologous, peripheral blood mononuclear cells. Kantoff PW et al. N Engl J Med. 2010;363:411-422. UCSF Sipuleucel-T in CRPC: How do we use it? • Sipuleucel-T prolongs life in patients with asymptomatic met CRPC • Sipuleucel-T is extremely well tolerated • For use only in asymptomatic CRPC with no visceral mets • Not remission inducing • My bias – use it early before advancing to prednisone-containing regimens (abiraterone, docetaxel, cabazitaxel, mitoxantrone all require steroids) UCSF FDA Approves Sipuleucel-T on April 29, 2010 You +1‘d UCSF New Treatments for Advanced Prostate Cancer CYP-17 Inhibitors UCSF Keeping our eyes on the AR target…… “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.” Charles Huggins MD Nobel Lecture Dec 13, 1966 Journal of Clinical Oncology 1997 Small and Vogelzang define “secondary hormonal therapy” Matching Biology to Therapy along the Path to AR signaling Signaling Event Pre -Receptor Androgen Production Androgen Transport/Ci rculation/Up take Receptor Conversion to DHT AR Binding Aberration Intervention Drugs Intracrine Production SCC Inhibitors CYP 17 Inihibitors Ketoconazole Abiraterone Tak-700 Tok-001 Polymorphisms Block Transport None Amplified 5 Alpha Reductase Amplified AR Splice Variant AR 5-Alpha Reductase inhibitors Novel AR Inhibitors Dutasteride MDV-3100 ARN-509 Tok-001 From Ryan and Tindall JCO 2011 Higher AR levels in CRPC tumors CRPC samples have robust AR expression Mohler et al AR expression in Bone Marrow Mets Stanbrough et al Cancer Research 2006 Holzberlein et al Am J Pathology At autopsy – 73% of 15 samples exhibit AR amplification. Friedlander/Paris et al 17 UC SF Prostate Cancer can make its own androgens 0 -5 P<0.0001 P=0.0091 -10 -15 -20 -25 BP CP METS 3BHSD1 0 -5 BP CP METS 3BHSD2 P=0.0005 -10 -15 -20 -25 BP CP METS CYP17A 5 0 -5 P<0.0001 P=0.0026 -10 -15 -20 BP CP METS AKR1C3 5 0 BP CP METS 17BHSD3 P=0.0050 P=0.0004 -5 -10 -15 -20 BP CP METS SRD5A1 BP CP METS SRD5A2 P=0.0013 0 -5 -10 P=0.0031 -15 -20 -25 BP CP METS UGT2B15 Montgomery RB et alCancer Res. 2008 Jun 1;68(11):4447-54 BP CP METS UGT2B17 1. Transcripts encoding steroidogenic enzymes are detected within tumor 2. Tumor androgens in CRPC metastases from anorchid patients exceed levels in prostate cancer tissues from eugonadal subjects 3. These may be particularly relevant for tumors with overexpressed AR Abiraterone: Provides durable androgen suppression Abiraterone - no rise in Androgens at PD. Ketoconazole – Androgens Rise at PD Androgens during Rx with Ketoconazole (CALGB 9583) 1.2 Change from Baseline 1 DHEAS 0.8 DHEAS 0.6 Androstenedione 0.4 0.2 0 Baseline Month 1 Progresion TEST Small et al JCO 2004 Ryan et al JCO 2010 UCSF COU-AA-301: Abiraterone Acetate Improves Overall Survival in post chemotherapy mCRPC Abiraterone acetate: 14.8 months 100 80 HR = 0.646 (0.54-0.77) P < 0.0001 Survival (%) 60 40 Placebo: 10.9 months 20 AA Placebo 0 0 100 200 300 400 500 600 700 Days From Randomization AA 797 728 631 475 204 25 0 Placebo 398 352 296 180 69 8 1 UC20SF Survival Benefit Consistently Observed Across Patient Subgroups Variable Subgroup N HR 95% CI All subjects All 1195 0.66 0.56–0.79 Baseline ECOG 0–1 1068 0.64 0.53–0.78 2 127 0.81 0.53–1.24 <4 659 0.64 0.50–0.82 4 536 0.68 0.53–0.85 1 833 0.63 0.51–0.78 2 362 0.74 0.55–0.99 PSA only 363 0.59 0.42–0.82 Radiographic 832 0.69 0.56–0.84 Baseline PSA above median YES 591 0.65 0.52–0.81 Visceral disease at entry YES 709 0.60 0.48–0.74 Baseline LDH above median YES 581 0.71 0.58–0.88 Baseline ALK-P above median YES 587 0.60 0.48–0.74 North America 652 0.64 0.51–0.80 Other 543 0.69 0.54–0.90 Baseline BPI No. of prior chemo regimens Type of progression Region Favors AA ALK-P, alkaline phosphatase 0.5 0.75 1 1.5 Favors placebo de Bono et al. N Engl J Med. 2011;364:21. UCSF Study: Abiraterone Provides Durable and Complete Responses in the chemotherapy naïve setting Baseline Ryan et al CCR 2011 Post Cycle 6 Response n (%) PSA Decline ≥30% 27/31 (87.1) PSA Decline ≥50% 26/31 (83.9) PSA Decline ≥90% 13/31 (41.9) Undetectable PSA (≤0.1) 2/31 (6.0%) UCSF COU-AA-302: Does Abiraterone Improve Survival in its physiologic space (pre-chemotherapy mCRPC)? Progressive Prostate Cancer WITHOUT prior Docetaxel based chemotherapy RANDOMIZE • Arm A •Abiraterone plus Prednisone Arm B Placebo plus Prednisone Endpoints – PFS, Overall Survival UCSF Abiraterone in CRPC: How do we use it? • Abiraterone prolongs life in patients with met CRPC post chemotherapy • Does benefit translate into the pre-chemotherapy setting? • Can it be combined with other therapies? Should it be continued after disease progression? • What are the mechanisms of resistance? – – – – Pharmaco-kinetic? Pharmaco-genomic? Alternate signaling paths? AR mediated progression? UCSF MDV3100 • Second-generation AR antagonist • Binds AR more potently than does bicalutamide • Not a partial agonist of AR • Inhibits translocation of AR into nucleus and decreases AR binding to DNA • Oral agent; 160 mg daily (seizures at higher doses) • Compared with placebo in ongoing randomized phase 3 trial (post-chemotherapy, ketoconazole-naïve) Tran et al. Science. 2009;324(5928):787-790. Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010. Scher et al. Lancet. 2010;375(9724):1437-1446. MDV3100: Phase 1/2 Study Radiographic Responses No prior chemotherapy Total Prior chemotherapy 59 25 34 Partial response 13 (22%; 13%-35%) 9 (36%; 19%-57%) 4 (12%; 4%-28%) Stable disease 29 (49%; 36%-62%) 11 (44%; 25%-65%) 18 (53%; 30%-70%) 109 41 68 61 (56%; 46%-65%) 26 (63%; 47%-77%) 35 (51%; 39%-64%) 22 12 10 ≥25% ↓ from baseline 10 (45%; 25%-67%) 4 (33%; 11%-65%) 6 (60%; 27%-86%) <25% ↓ from baseline 12 (55%; 33%-75%) 8 (67%; 35%-89%) 4 (40%;14%-73%) Soft tissue Bone scan (week 12) Stable disease FDG-PET (week 12) MDV3100 induced >50% PSA declines in 56% of mCRPC patients, including those were prechemotherapy (n = 65) and postchemotherapy (n = 75). .FDG-PET, 2-¹⁸F-fl uoro-2-deoxy-D-glucose positron emission tomography. Scher et al. Lancet. 2010;375(9724):1437-1446. MDV-3100 Time to PSA Progression Scher HI et al. Lancet. 2010;375:1437. MDV3100: Phase 3 Trial (AFFIRM) POSITIVE N = 1170 Men with docetaxelpretreated mCRPC (ketonaïve) R A N D O M I Z E 2 MDV3100 160 mg once daily + prednisone 5 mg twice daily 1 Placebo once daily + prednisone 5 mg twice daily Primary objective: OS Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010. MDV-3100 And Abiraterone both extend survival post-docetaxel Placebo MDV-3100 P value Overall Survival 13.6 mo 18.4 mo <0.001 Rx Duration 3.0 mo 8.3 mo <0.001 Soft Tissue resp 8.3% 2.9% <0.001 Subsequent therapy -Abiraterone -Cabazitaxel 24.3% 12% 21% 14% *Seizures 0.6% (5cases) 0 Scher-Proc ASCO GU 2012 San Francisco 2/2/2012 New Treatments for Advanced Prostate Cancer Second Line Chemotherapy UCSF SeSecond Line Chemotherapy •CRPC patients inevitably progress following Docetaxel treatment1-5 •Despite Many studies (6,7,8): – There has been no data showing that we can improve survival with second line chemotherapy – UCSF led early studies of second line chemotherapy (Rosenberg, Harzstark) and helped establish this the estimates for survival and response in this setting. 1. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520. 2. Tannock IF, et al. N Engl J Med. 2004;351(15):1502-1512. 3. Oudard S, et al. J Clin Oncol. 2005;23(15):3343-3351. 4. Nelius T, et al. BJU Int. 2006;98(3):580-585. 5. Nelius T, et al. Onkologie. 2005;28(11):573-578. 6. Garmey EG, et al. Clin Adv Hematol Oncol. 2008;6(2):118-132. 7. Rosenberg JE, et al. Cancer. 2007;110(3):556-563. 8. Sternberg CN, et al. J Clin Oncol. 2009;27(32):5431-5438. Two Different Chemical Entities Docetaxel (C43H53NO14) Docetaxel is an esterified product of 10-deacetyl baccatin III Cabazitaxel (XRP6258) (C45H57NO14) Cabazitaxel is a 7,10 dimethoxy analogue of docetaxel Mita AC, et al. Clin Cancer Res 2009;15:723-730; Ojima I, et al. J Med Chem 1996;39:3889-3896; Greenberger LM, Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug Resistance. Totowa, New Jersey: Humana Press; 2006:329-358; Raub TJ. Mol Pharm 2005;3:3-25; www.Taxotere.com. The TROPIC study: cabazitaxel or mitoxantrone with prednisone in patients with metastatic CRPC previously treated with docetaxel (De Bono et al) Men with metastatic CRPC progressing during and after docetaxel (N=755) R A N D O M I Z E Cabazitaxel 25 mg/m² q 3 wk + prednisone for 10 courses (CBZP, n=378) Mitoxantrone 12 mg/m² q 3 wk + prednisone for 10 courses (MP, n=377) Primary objective: Overall survival Secondary objectives: PFS (tumor progression, pain progression, PSA progression, or death from any cause), response rate, safety UCSF Primary Endpoint (Overall Survival) Met 100 Median OS (months) Hazard ratio Proportion of OS (%) 80 MP CBZP 12.7 15.1 0.72 95% CI 0.61–0.84 P-value <.0001 60 40 Censored MP CBZP 20 Combined median follow-up: 13.7 months 0 0 6 12 18 24 30 Time (months) UCSF 3 7 Summary of Hematologic AEs Hematologic AEsa Neutropeniab Febrile neutropenia a In JEVTANA® 25 mg/m² q 3 wk + prednisone 10 mg qd (n=371) mitoxantrone 12 mg/m² q 3 wk + prednisone 10 mg qd (n=371) Grade 1–4, n (%) Grade 3–4, n (%) Grade 1–4, n (%) Grade 3–4, n (%) 347 (94%) 303 (82%) 325 (87%) 215 (58%) 27 (7%) 27 (7%) 5 (1%) 5 (1%) Anemiab Leukopeniab 361 (98%) 355 (96%) 39 (11%) 253 (69%) 302 (82%) 343 (93%) 18 (5%) 157 (42%) Thrombocytopeniab 176 (48%) 15 (4%) 160 (43%) 6 (2%) ≥5% of patients. on laboratory values: JEVTANA® (n=369), mitoxantrone (n=370). b Based • Protocol did not permit primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) at cycle 1 JEVTANA® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010. Data on file. Clinical study report/EFC6193 (TROPIC). Cabazetaxel: How do we use it? 1. Cabazitaxel significantly improved survival when compared to mitoxantrone, in patients with metastatic CRPC who had received prior docetaxel. 2. It may prolong sensitivity to taxane chemotherapy in patients with acquired docetaxel resistance 3. Its use in the overtly taxane refractory patient may be limited UCSF Cabazitaxel: Where do we go? 1. As an incremental step forward, it merits testing as front line chemotherapy 2. Combination studies are also warranted. 3. As before, a study of the mechanisms of resistance to this therapy are warranted. (Friedlander/Paris project) 4. FDA mandated 25mg/m2 vs 20 mg/m2 study. UCSF XL184: Cabozantanib XLOral Multi-targeted TKI RET MET VEGFR2 KIT 3.8 nM 1.8 nM 0.035 nM 4.6 nM How do we use it? Where do we go? Stay tuned…. New Treatments for Advanced Prostate Cancer Radium 223 UCSF Radium-223 Targets Bone Metastases • Radium-223 acts as a calcium mimic • Naturally targets new bone growth in and around bone metastases • Radium-223 is excreted by the small intestine Ca Ra Radium-223 Targets Bone Metastases Range of alpha-particle Radium-223 Bone surface • Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1 – Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS STRATIFICATION • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No • Post-docetaxel or unfit for docetaxel R A N D O M I S E D 2:1 N = 922 Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751. 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + Best standard of care Placebo (saline) + Best standard of care ALSYMPCA Patient Demographics and Baseline Characteristics (ITT; N = 809) Radium-223 (n = 541) Placebo (n = 268) 70.2 70.7 Race, n (%) Caucasian 507 (94) 252 (94) Baseline ECOG score, n (%) ≤1 2 467 (86) 71 (13) 229 (85) 37 (14) Extent of disease, n (%) < 6 metastases 6-20 metastases > 20 metastases/superscan 88 (16) 235 (44) 217 (40) 33 (12) 129 (48) 106 (40) WHO ladder, cancer pain index ≥ 2, n (%) 294 (54) 142 (53) Parameter Age, y Mean ALSYMPCA Patient Baseline Characteristics, cont (ITT; N = 809) Parameter Median (min, max) Radium-223 (n = 541) Placebo (n = 268) Haemoglobin, g/dL 12.2 (8.5-15.7) 12.1 (8.4-16.4) 40 (24-53) 40 (23-50) Total ALP, µg/L 213 (32-4661) 224 (29-3225) LDH, U/L 317 (76-2171) 328 (132-3856) PSA, µg/L 159 (3.78-6026) 195 (1.5-14500) Albumin, g/L ALSYMPCA Overall Survival 100 HR 0.695; 95% CI, 0.552-0.875 P = 0.00185 90 80 70 60 % Radium-223, n = 541 Median OS: 14.0 months 50 40 30 Placebo, n = 268 Median OS: 11.2 months 20 10 0 Month Radium- 223 Placebo 0 3 6 9 12 15 18 21 24 27 541 268 450 218 330 147 213 89 120 49 72 28 30 15 15 7 3 3 0 0 The Future – My predictions 1. Oral, Well tolerated therapies will extend the option of treatment for m CRPC to more patients than previous….(only about 50% of CRPC pts get docetaxel) 2. Prostate cancer will become a model for ( or a victim of ?) cost effectiveness research. 3. Management of CRPC will be done by those most capable of understanding biology and the integration of therapies – no matter what their prior training. 4. Combined oral therapies will push therapy and survival further – e.g with better survival more patients will be available for therapy (“If you build it, they will come”)_ 5. New targeted therapies will need to be developed in conjunction with biomarkers that predict response (e.g. Her 2 trastuzumab in breast cancer) UCSF Thank You UCSF