Evolution or revolution in the treatment of prostate cancer
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1 Evolution or revolution in the treatment of prostate cancer de Johann Sebastian de Bono, MB, ChB, FRCP, MSc, PhD Professor of Experimental Cancer Medicine Department of Medicine/ Drug Development Unit Institute of Cancer Research Honorary Consultant Medical Oncologist Department of Medicine and Drug Development Royal Marsden Hospital NHS Foundation Trust Sutton, Surrey, United Kingdom Vancouver March 2012 Disclosure Johann Sebastian de Bono, MB, ChB, FRCP, MSc, PhD Served as an advisor or consultant for: Cougar Biotechnology, Inc.; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; AstraZeneca Pharmaceuticals LP; Medivation, Inc.; Astellas Pharma, Inc. Served as a speaker or a member of a speakers bureau for: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; sanofi-aventis Received grants for clinical research from: Pfizer Inc. Employed by a commercial interest: Institute of Cancer Research. Dr. de Bono does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr. de Bono does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. 1
2 Advanced Prostate Cancer Unprecedented Progress In the last 2 years, 5 treatments shown to improve OS Abiraterone [a] Sipuleucel-T [b] Cabazitaxel [c] Alpharadin [d] MDV3100 [e] a. de Bono J, et al. N Engl J Med. 2011;364: b. Kantoff PW, et al. N Engl J Med. 2010;363: c. de Bono JS, et al. Lancet. 2010;376: d. Parker C, et al. ESMO e. Scher HI & de Bono J, Press Release 11/2011; GU ASCO 2012 Presentation Overview Insight into disease biology: key therapeutic targets Improving treatment: changing landscape Future challenges 2
3 Prostate Carcinogenesis Increased Insight Into Disease Biology NORMAL CELLULAR FUNCTION Hormones induce DNA cleavage at specific sites GENERATION OF HIJACKED HORMONE DRIVEN GENES Hormone-Driven Genetic Switches HORMONES HIJACKED! CANCER GENES More than 20 different types of prostate cancers: all with different drivers 3
4 Prostate Cancer Biology Yap TA, et al. Nat Rev Clin Oncol. 2011;8: Presentation Overview Insight into disease biology: Key therapeutic targets Improving treatment: changing landscape Future challenges 4
5 Treatment of Advanced PCa Few Advances Before 2010 Only 2 therapies showed improved survival Blockers of testicular testosterone synthesis Docetaxel chemotherapy Charles Huggins: Nobel Prize 1966 Hypothesis in 2004 Hormone refractory prostate cancer was NOT hormone refractory but frequently remained driven by a ligand-activated androgen receptor Attard G, et al. BJU Int. 2005;96: de Bono JS, et al. Nature. 2010;467:
6 Androgen Receptor Addiction Hard Habit to Break Hormonal treatments continue to have antitumor activity High levels of intratumoral androgens despite castration Preclinical and clinical evidence of intracrine synthesis Castration resistance associated with AR amplification (increased gene dose) AR mutations that increase AR (transcriptional) activity AR (< 2x) expression (ligand driven) in isogenic resistant lines AR still switched on in Abiraterone- and MDV3100-resistant PCa Identification of oncogenic translocations/fusions driven by androgens + estrogen-response elements (ETS genes; TMPRSS2/ERG in 50% to 70% of PCa) Attard G, et al. Cancer Cell. 2009;16: Abiraterone Acetate Androgen Biosynthesis Inhibitor Androgens produced at 3 critical sites lead to tumor proliferation Testes Adrenal gland Prostate tumor cells Abiraterone inhibits biosynthesis of androgens that stimulate tumor cell growth PSA and radiographic responses in phase 1-2 studies Chemotherapy-naive and postchemotherapy patients [a-e] a. Attard G, et al. J Clin Oncol. 2008;26: ; b. Attard G, et al. J Clin Oncol. 2009;27: ; c. Reid AH, et al. J Clin Oncol. 2010;28: ; d. Ryan C, et al. J Clin Oncol. 2010;28: ; e. Danila D, et al. J Clin Oncol. 2010;28:
7 P450c17 Inhibitors Chemical Development N Abiraterone N N HO HO HO 2-pyridyl IC 50 (nm) lyase 76 hydroxylase pyridyl IC 50 (nm) lyase 2.9 hydroxylase 4 4-pyridyl IC 50 (nm) lyase 1000 hydroxylase 4000 Designed at The Institute of Cancer Research: Jarman M, Potter G, Barrie E Abiraterone Mechanism of Action ACTH Positive drive x 5 Pregnenolone Deoxycorticosterone x 10 Corticosterone x 40 Aldosterone x 1.5 CYP17: 17α-hydroxylase Hypokalemia Hypertension Fluid overload Suppression of renin Negative feedback 17OH-Pregnenolone 17OH-Progesterone x 3 11-deoxycortisol x 4 Cortisol x 2 DHEA CYP17: C17,20-lyase x 3 Androstenedione < 2 ng/dl Testosterone < 1 ng/dl Estradiol < 80 ng/dl Attard G, et al. J Clin Oncol. 2008;26:
8 Abiraterone Phase 1 Study in CRPC Continuous daily dosing (N = 21) mg daily to fasted chemotherapy-naive patients Abiraterone administered without steroids Mineralocorticoid antagonist eplerenone utilized No dose-limiting toxicity Satisfactory dose-proportional pharmacokinetics Pharmacodynamic endocrine data Suppression of hormone levels downstream of CYP17; increases in hormone levels upstream of CYP17; PSA decline; CTC decline Attard G, et al. J Clin Oncol. 2008;26: Abiraterone Acetate PSA Declines Patients Who Failed All Hormonal Therapy Maximal % PSA Change PSA is a pharmacodynamic endpoint of AR signaling blockade Attard G, et al. J Clin Oncol. 2009;27:
9 Abiraterone Acetate Antitumor Activity Patient Receiving Abiraterone Regressing Pelvic Nodes Prestudy: 20 mm After 6 mos: 4 mm Previous progression on several hormone treatments PSA decline from 34.3 ng/ml 0.21 ng/ml (99%) within 3 mos Shrinkage of lymph glands shown above on CT scan 9
10 Postchemotherapy PSA Data Abiraterone + Prednisolone 10 mg/day Maximal Response (%) Week 12 PSA Response (%) Patient Patient 90% 50% 30% 90% 50% 30% PSA value clipped Reid AH, et al. J Clin Oncol. 2010;28: COU-AA-301 Phase 3 Study of Abiraterone in mcrpc Patients with mcrpc progressing after 1-2 chemotherapy regimens, 1 of which contained docetaxel (N = 1195) Randomized 2:1 Abiraterone acetate 1000 mg/day + Prednisone 5 mg BID (n = 797) Stratified by ECOG PS, worst pain over previous 24 hrs, previous chemotherapy, type of progression Placebo + Prednisone 5 mg BID (n = 398) de Bono J, et al. N Engl J Med. 2011;364:
11 COU-AA-301 Improved OS at Interim Analysis HR: (95% CI: ; P <.0001) Survival (%) Placebo: 10.9 mos (95% CI: ) Abiraterone acetate: 14.8 mos (95% CI: ) Median OS with 2 prior chemo: Median OS with 1 prior chemo 14.0 mos AA vs 10.3 mos placebo mos AA vs 11.5 mos placebo Days From Randomization AA Placebo de Bono J, et al. N Engl J Med. 2011;364: COU-AA-301 Updated Analysis (775 Events) OS Benefit Increased From 3.9 to 4.6 Months Median duration of follow-up: 20.2 months Median duration of treatment: AA, 8 months vs placebo, 4 months 11
12 COU-AA-301 Survival Across Patient Subgroups Variable Subgroup n HR 95% CI All subjects All Baseline ECOG Baseline BPI < No. of prior chemo regimens Type of progression PSA only Radiographic Baseline PSA above median Yes Visceral disease at entry Yes Baseline LDH above median Yes Baseline ALK-P above median Yes Region North America Other Favors abiraterone Favors placebo de Bono J, et al. N Engl J Med. 2011;364: COU-AA-301 Secondary Endpoints Endpoint Characteristic Abiraterone (n = 797) Placebo (n = 398) TTPP, mos ( ) rpfs, mos ( ) PSA response rate, % HR (95% CI) P Value <.0001 <.0001 Total <.0001 Confirmed <.0001 de Bono J, et al. N Engl J Med. 2011;364:
13 COU-AA-301 Summary of AEs AE, % Abiraterone (n = 791) All Grades Grades 3/4 All Grades Placebo (n = 394) Grades 3/4 All treatment-emergent AEs Serious AEs AEs leading to discontinuation AEs leading to death Deaths within 30 days of last dose Underlying disease Other specified cause de Bono J, et al. N Engl J Med. 2011;364: COU-AA-301 AEs of Special Interest Abiraterone (n = 791) Placebo (n = 394) AE, % All Grades Grades 3/4 All Grades Grades 3/4 Fluid retention Hypokalemia LFT abnormalities Hypertension Cardiac disorders de Bono J, et al. N Engl J Med. 2011;364:
14 QOL Time to FACT-P Deterioration Patients Without Progression (%) AA + prednisone Placebo + prednisone p < Days on Study The median time to functional status degradation (FACT-P total score) was 12.1 months in the AA + prednisone group vs 8.4 months in the placebo + prednisone group MDV3100 Novel, Oral AR antagonist Inhibits Multiple Steps in the AR Signaling Pathway AR Signaling Cascade AR Binding Testosterone Pure Agonist MDV3100 Pure Antagonist Nuclear Translocation Stimulation Inhibition DNA Binding Stimulation Inhibition Gene Transcription Stimulation Inhibition Functional Consequence Proliferation Apoptosis Mukherji D, et al. Expert Opin Investig Drugs. 2012;21:
15 MDV3100 Phase 1/2 Study in Advanced PCa Phase 1/2 trial conducted to determine safety, PK, and antitumor activity of MDV3100 [b] N = 140 patients with progressive CRPC, pre- or postchemotherapy Cohorts treated with sequentially escalating doses of MDV3100 ( mg/day) a. Tran C, et al. Science. 2009;324: b. Scher HI, et al. Lancet. 2010;375: Slows tumor growth and causes cell death in cancers resistant to bicalutamide [a] Testosterone synthesis Tumor death Testosterone T 3 X DNA binding and activation blocked Cell nucleus No prednisone required X T X MDV3100 AR 1 AR binding blocked 2 Nuclear translocation impaired MDV3100 Long-term Follow-up Antitumor activity durable both before and after chemotherapy Outcome Chemotherapy Naive (n = 65) Post Chemotherapy (n = 75) 50% PSA decline from baseline, % Median time to PSA progression, days Per protocol* NYR 316 PCCTWG 2 criteria Median time to radiographic progression, days * 25% increase in PSA from baseline with increase 5 ng/ml. 25% increase in PSA from nadir with increase 2 ng/ml. Higano CS, et al. ASCO GU Abstract 134. Higano CS, et al. ASCO GU Abstract
16 MDV3100 AFFIRM: Study Design Phase 3, multinational, double-blind, placebocontrolled MDV mg/day vs placebo (2:1 randomization) Enrollment completed November 2010 N = 1,199 enrolled Patient population: Progressive mcrpc Ongoing ADT or orchiectomy Previously treated with chemotherapy ( 2 regimens) at least one of which was docetaxel-based ECOG Performance Status 0-2 ClinicalTrials.gov Identifier: NCT AFFIRM Post-Chemotherapy Phase 3 trial 2 MDV mg daily R 1 Placebo daily OS primary endpoint Interim analyses after 520 deaths Steroid use was optional for MDV3100 ClinicalTrials.gov Identifier: NCT
17 AFFIRM Study Objectives Primary objective Overall survival Key Secondary objectives Radiographic progression-free survival Time to first skeletal-related event QoL FACT-P and EQ-5D PSA Progression Pain Palliation Safety Pharmacokinetics ClinicalTrials.gov Identifier: NCT AFFIRM Planned Interim Analysis Independent Data Monitoring Committee recommended stopping the study early: 520 events at the time of the interim analysis Statistically significant improvement in overall survival MDV3100 compared to placebo Met pre-determined stopping criteria Favorable benefit-risk ratio Placebo patients should be crossed over to MDV3100 ClinicalTrials.gov Identifier: NCT
18 MDV3100 Prolonged Survival by a Median of Months in the Phase 3 AFFIRM Trial HR = (0.529, 0.752) P < % Reduction in Risk of Death 80 MDV3100: 18.3 months (95% CI: 17.3, NYR) Survival (%) Placebo: 13.6 months (95% CI: 11.3, 15.8) Duration of Overall Survival, Months MDV Placebo Survival benefit observed across subgroups *Based on data analysis cutoff date for the planned interim analysis. 18
19 Patients on MDV3100 received therapy longer and a higher percentage remain on study MDV3100 Placebo Patients treated (n) Median duration of treatment (months) Treatment ongoing (%) Median duration of follow up was 14.4 months Both MDV3100 and placebo patients received additional therapies when off study MDV3100 Placebo Patients treated (n) Median duration of treatment (months) Treatment ongoing 28.9% 4.8% Median duration of follow up was 14.4 months MDV3100 treatment Median 8.3 months Eligible for subsequent therapies Placebo Median 3.0 Months Eligible for subsequent therapies 19
20 A large proportion of patients received post-study antineoplastic therapy Patients with 1 post-study drug antineoplastic therapy Most common post-protocol treatment MDV3100 (n = 800) Placebo (n = 399) 41.1% 58.4% Abiraterone 20.9% 24.3% Cabazitaxel 9.8% 13.8% Docetaxel 8.5% 14.3% Mitoxantrone 2.6% 11.0% 39 The benefits of MDV3100 were supported by changes in the secondary outcome measures: PSA response and progression Response MDV3100 Placebo P-value Confirmed PSA decline 50% from baseline 90% from baseline 54.0% 24.8% 1.5% 0.9% < < Progression Median time to PSA progression (months) MDV3100 Placebo Hazard Ratio (95% CI) P-value (0.204, 0.303) <
21 The benefits of MDV3100 were supported by changes in the secondary outcome measures: Radiographic responses and progression Response MDV3100 Placebo P-value Soft Tissue Response by CT/MRI Imaging 28.9% 3.8% < Progression MDV3100 Placebo Hazard Ratio (95% CI) P-value Median radiographic PFS (months) (0.350, 0.466) < AFFIRM: Summary of AEs MDV3100 (n = 800) All Grades Grades >3* Placebo (n = 399) MDV3100 (n = 800) Placebo (n = 399) AEs 98.1% 97.7% 45.3% 53.1% Serious AEs 33.5% 38.6% 28.4% 33.6% Discontinuations due to AEs 7.6% 9.8% 4.6% 7.0% AEs leading to death 2.9% 3.5% 2.9% 3.5% *AEs graded for severity with grades 1 and 2 being milder and grades 3-5 being more severe 21
22 AFFIRM: AEs of Special Interest All Grades Grade 3 Events MDV3100 (n = 800) Placebo (n = 399) MDV3100 (n = 800) Placebo (n = 399) Fatigue 33.6% 29.1% 6.3% 7.3% Cardiac Disorders 6.1% 7.5% 0.9% 2.0% Myocardial Infarction 0.3% 0.5% 0.3% 0.5% LFT Abnormalities* 1.0% 1.5% 0.4% 0.8% Seizure 0.6% 0.0% 0.6% 0.0% *Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased. 43 Overall survival benefit in post-docetaxel CRPC trials Trial/ Agent/ Date Approved AFFIRM MDV3100 COU-AA-301 Abiraterone + prednisone 2011 TROPIC Cabazitaxel + prednisone 2010 Mechanism Androgen Receptor Signaling Inhibitor CYP17 Inhibitor Cytotoxic Comparator Hazard Ratio P-value Placebo < Placebo + prednisone Mitoxantrone + prednisone < <
23 Presentation Overview Insight into disease biology: Key therapeutic targets Improving treatment: Changing landscape Future challenges CRPC Current Landscape Multiple lines of treatment for advanced prostate cancer that improve OS: Sipuleucel-T, docetaxel, abiraterone, cabazitaxel, MDV3100, alpharadin Optimal sequence of administration now needs defined: Combinations! Cross-resistance: taxanes, abiraterone and MDV3100? Abiraterone will move into prechemotherapy space and now also being evaluated in large adjuvant trial (STAMPEDE) MDV αra Yap TA, et al. Nat Rev Clin Oncol. 2011;8:
24 Combining Abiraterone and MDV3100 Resistance mechanisms to abiraterone! Residual steroids can activate promiscuous AR Upstream of CYP17 Eplerenone Prednisolone, dexamethasone! Increased androgenic steroid levels induce resistance to MDV3100 Richards et al, Cancer Res 2012 AR promiscuous activation: Spironolactone, eplerenone and prednisone D Spironolactone, eplerenone, activate AR Pred levels at 5mg bid in patients high enough to activate AR 24
25 Increased steroid ligand levels in patients can result in resistance to MDV3100 Resistance mechanisms to MDV3100: Androgen levels may increase after MDV3100 due to decreased AR transcriptional activity and can result in acquired resistance (Efstathiou et al) AR Signaling as Therapeutic Target Conclusion Advanced prostate cancer Not hormone refractory Nor androgen independent Remains nuclear steroid receptor driven even after AA and MDV3100 Hormone therapy works after chemotherapy Important since OS remains only robust registration endpoint Maximal androgen blockade is a misnomer 25
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