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SYSTEMIC THERAPY OF PROSTATE CANCER: Androgen Receptor and Immune System Targeting

SYSTEMIC THERAPY OF PROSTATE CANCER: Androgen Receptor and Immune System Targeting. Walter Stadler, MD, FACP University of Chicago. Androgen Ablation . Androgen Ablation & Prostate Ca. The androgen receptor is the most important therapeutic target in PCa Targeting AR is effective in >90%

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SYSTEMIC THERAPY OF PROSTATE CANCER: Androgen Receptor and Immune System Targeting

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  1. SYSTEMIC THERAPY OF PROSTATE CANCER: Androgen Receptor and Immune System Targeting Walter Stadler, MD, FACP University of Chicago

  2. Androgen Ablation

  3. Androgen Ablation & Prostate Ca • The androgen receptor is the most important therapeutic target in PCa • Targeting AR is effective in >90% • The AR is critical even in the “hormone refractory” state • Targeting AR is not curative • Androgen ablation has toxicity • Bone, muscle, sex • Toxicity minimal in comparison to other cancer therapies

  4. Natural History of Rising PSA Makarov, et al; J Urol:179:156, 2008

  5. Prostate Ca System Therapy Philosophy • Natural history can be very long • Chronic disease management • Competing mortality/morbidity • Therapy toxicity can have significant functional signficance • Natural history is highly variable • Some patients have rapid disease progression • Disease mortality and morbidity not insignificant • Care is often fragmented • Urologists • Medical oncologists • Primary care

  6. Endocrine Axis in Prostate Cancer GnRH agonist Adrenal Blockade Orchiectomy Tumor Androgens Antiandrogens

  7. Androgen Ablation: Early vs Late • VA studies early vs delayed orchiectomy (1960’s) • Advanced metastatic cancer • No survival differences • MRC trial of delayed vs immediate hormonal therapy • 934 pts, asymptomatic clinical mets • Immediate LHRH/orchiectomy vs at symptoms • Decreased morbidity, improved survival with immediate • DOD prostate cancer database • Early hormonal therapy delayed clinical metastases in patients with Gleason >7 and PSA doubling < 12 mo • Swiss immediate vs delayed orchiectomy • 197 pts no primary tumor therapy, most without mets • Immediate delayed time to pain, urinary obstruction, or mets

  8. EORTC 30891: Immediate vs Delayed • T0-4, N0-2, no mets • Refused or ineligible for definitive local rxn • Immediate androgen ablation vs. at symptomatic progression • 1002 pts randomized • Reasons for starting deferred (n=245) • Symptoms  objective findings: 56% • Asymptomatic objective findings: 10% • Asymptomatic marker rise: 26%

  9. EORTC 30891: Survival HR: 1.25 (1.05 – 1.48)

  10. EORTC 30891: Causes of Mortality Prostate Ca Mortality Non-Prostate Ca Mortality But in meta-analysis of RT  ADT pts on ADT had higher incidence of fatal MI (D’Amico, et al, JCO 25:2420, 2007)

  11. Adjuvant Data Supports “Early” ADT • Prostatectomy LN positive immediate vs delayed ADT • Improved survival (Messing, et al, Lancet Oncol, 2006) • Clinical T3 (or high risk) radiotherapy • Survival advantage with long term adjuvant (EORTC, RTOG 85-31) (Bolla, et al, Lancet, 2002; Pilepich, et al Int J Rad Oncol Biol Phy, 2005) • Survival advantage with long vs short term ADT (EORTC) (Bolla, et al NEJM, 2009) • Disease-free and metastases-free survival advantage with combined plus long term versus combined plus short term (RTOG 92-02) (Horwitz, et al, J Clin Oncol, 2008)

  12. Morbidity of Androgen Ablation • Hot flashes • Loss of libido and impotence • Gynecomastia • Weight gain and loss of muscle mass • Exacerbation of hypertension and diabetes • Fatigue • Osteoporosis and fractures • Cognitive effects (?)

  13. Unadjusted Fracture-free Survival among Patients with Prostate Cancer Shahinian, V. et al. N Engl J Med 2005;352:154-164

  14. Timing of Bisphosphonates • Risk of osteonecrosis and renal failure • Increases with duration of exposure • Risk benefit of use for hormone sensitive disease unclear • CALGB 90202 • Immediate versus delayed zoledronate for hormone sensitive bone scan positive pts.

  15. Fatigue, Muscle Loss and Elderly Prostate Cancer Patients Bylow, et al, Cancer, 2007

  16. Diabetes and CV Risk ADT • Case control, • Ontario (Alibhai, JCO, 2009) • Median 6.5 yr follow up • DM HR (time to event): 1.16 (1.12 – 1.21) • MI HR: 0.91 (0.84 – 1.00) • US claims based • Incident DM HR: 1.36 (Lage, et al; Urology, 2007) • Incident DM HR: 1.44 (p<0.001), MI HR: 1.11 (p=0.03) • Adjuvant ADT (RTOG 85-31) (Efstatstiou, JCO, 2009) • Median 8.1 yr follow up • No increased risk MI/sudden death

  17. Intermittent ADT As a New Drug Screen • Drug x vs. placebo during “off” period • Need to monitor testosterone and DHT recovery • Drugs in study • Thalidomide – no major effect (Figg, ASCO 2008) • Pazopanib (VEGFR/PDGFR TKI) • Closed, too toxic • Dutasteride (5- reductase inhibitor) • UC/NU SPORE clinical trial and others

  18. Castrate Resistant Disease • Not really “hormone refractory” • AR still a relevant target • Other potential targets • Immune system • DNA and DNA repair • Mechanisms of castrate resistance • AR amplification • AR mutation • AR modification • Ligand availability • AR interactions

  19. What we know… • Prostate cancer requires AR signaling for development and sustenance. • AR activation is required throughout the natural history of prostate cancer. • AR activation in CRPC occurs via many mechanisms. • Successful blockade of the receptor pathways will confer greater therapeutic control on metastatic prostate cancer.

  20. Testosterone • Actually a growth inhibitory and differentiating agent in normal prostate • Cells adapted to androgen depleted environment • AR upregulation • Growth inhibited by androgen • Tumor shrinkage in xenograft models • Randomized phase II trial initiated

  21. Abiraterone Phase II Attard JCO 2009 Pre-Chemo Ryan ASCO 2009 Danila ASCO 2009 Post-Chemo Reid ASCO 2009

  22. COU-AA-301 Study Design RANDOMIZED 2:1 Abiraterone1000 mg daily Prednisone 5 mg BID n=797 Efficacy endpoints (ITT) Patients • Primary end point • OS (25% improvement; HR 0.8) • Secondary endpoints (ITT) • TTPP • PFS • PSA response • Phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) • Stratification according to • ECOG performance status (0-1 vs 2) • Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present]) • Prior chemotherapy (1 vs 2) • Type of progression (PSA only vs radiographic progression with or without PSA progression) • 1195 patients with progressive mCRPC • Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel Placebo daily Prednisone 5 mg BID n=398 Abbreviations: BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastatic castrate-resistant prostate cancer. Source: Clinicaltrials.gov identifier: NCT00638690.

  23. COU-AA-301 Patient Disposition

  24. COU-AA-301 Baseline Demographics

  25. COU-AA-301 Baseline Disease Characteristics

  26. COU-AA-301: Abiraterone Acetate Improves OS in mCRPC 100 HR=0.646 (0.54-0.77) P <0.0001 Abiraterone: 14.8 months (95% CI: 14.1, 15.4) 80 60 Overall Survival, % 40 Placebo: 10.9 months (95% CI: 10.2, 12.0) 20 1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo 0 300 500 0 400 600 700 100 200 Days from Randomization

  27. Survival Benefit Consistently Observed Across Patient Subgroups 0.5 0.75 1 1.5 Favors Abiraterone FavorsPlacebo Abbreviations: HR=hazard ratio; ALK-P=alkaline phosphatase.

  28. COU-AA-301: Secondary End Points Achieved Statistical Significance

  29. COU-AA-301: Summary of AEs

  30. COU-AA-301: AEs of Special Interest

  31. 240 mg (n=28) 60 mg (n=22) 150 mg (n=23) 7 pt off study <12 wk 2 pt off study <12 wk 3 pt off study <12 wk Novel More Potent AR Antagonists • BMS-641988 (development discontinued) • MDV3100 • Phase I/II trial • Phase III trial initiated (docetaxel refractory) Scher, et al, ASCO 2009

  32. Castrate Resistant Disease Non-Hormonal Treatment Options • Good prognosis (asymptomatic, “low volume”) • Standard docetaxel chemotherapy • ? Immunotherapy (Provenge, sipuleucel-T) • Investigational therapy • Poor prognosis • Standard docetaxel chemotherapy • Standard cabazitaxel • Investigational chemotherapy combinations

  33. Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein APC takes up the antigen Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC) Fully activated, the APC is now sipuleucel-T Antigen is processed and presented on surface of the APC Inactive T-cell INFUSE PATIENT Active T-cell T-cells proliferate and attack cancer cells sipuleucel-T activates T-cells in the body The precise mechanism of sipuleucel-T in prostate cancer has not been established.

  34. Sipuleucel-T: Logistics of Therapy Day 2-3 sipuleucel-T is manufactured Day 3-4 Patient is infused Day 1 Leukapheresis Apheresis Center Central Processing Doctor’s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4

  35. Randomized Phase 3 IMPACT Trial(IMmunotherapy Prostate AdenoCarcinoma Treatment) P R O G R E S S I O N SURVIVAL Treated at Physician Discretion Sipuleucel-T Q 2 weeks x 3 Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate Cancer (N=512) 2:1 Treated at Physician Discretion and/or Salvage Protocol Placebo Q 2 weeks x 3 Primary Endpoint: Overall Survival Secondary Endpoint: Objective Disease Progression

  36. IMPACT Overall SurvivalFinal Analysis (349 events) 36.5 mo median f/u HR = 0.759(95% CI: 0.606, 0.951) p = 0.017 (Cox model) Sipuleucel-T (n = 341) Median Survival: 25.8 mo. 36 mo. survival: 32.1% Placebo (n = 171) Median Survival: 21.7 mo. 36 mo. survival: 23.0%

  37. Adverse Events More Commonly1 Reported in Sipuleucel-T Group 1 Reported by ≥ 5% of sipuleucel-T patients and having a ≥ 2-fold difference from placebo. The majority of the most common AEs were mild or moderate in severity. Safety results obtained from primary analysis did not substantively change with additional data obtained after study closure.

  38. Challenges • Why no effect on prostate cancer progression? • Ability to measure disease progression sucks • Something “bad” happened in control group • Something “good” happened in treated group that is unrelated to cancer • Important: no effect on symptoms • Cost • $93,000 not include all apheresis and infusion costs • Logistics • Limited apheresis capacity • Limited processing capacity

  39. Other Immune Therapy Approaches • Anti-CTLA4: Ipilimumab • “Turn off the brake” • Potential for severe auto-immune disease • Auto-immune diarrhea • Anti-tumor activity in phase II trials • Castrate/Docetaxel resistant pts: • Phase II External beam RT ± ipilimumab • Based on possible immune enhancing effects of RT • Castrate resistant pre-chemo pts: • Placebo vs Ipilimumab

  40. Other Immune Therapy Approaches (2) • A true vaccine: PSA-TRICOM • “Prime” and “boost” vaccinations • Castrate/Docetaxel resistant patients • Quadramet ± PSA-TRICOM

  41. How do we Measure “Immune Activation” • Ongoing blood collection study to: • Analytically validate HMBG1 in serum as marker of “danger signal” • Analyze serum antibodies to identify new immune targets • Store serum for evaluating other possible biomarkers

  42. CABAZITAXEL PHASE III mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles (n=377) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint: OS Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

  43. Summary of Demographics and Patient Characteristics PSA: Prostate-specific antigen.

  44. 100 MP CBZP Median OS (months) 12.7 15.1 Hazard Ratio 0.70 80 95% CI 0.59–0.83 P-value <.0001 60 40 20 0 6 months 12 months 18 months 24 months 30 months 0 months Primary Endpoint: Overall Survival Proportionof OS (%) Numberat risk

  45. Most Frequent Grade ≥3 Treatment-Emergent AEs* *Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.

  46. Total Deaths During Study Safety Population

  47. XL184 • MET/VEGF pathway targeted • Dramatic changes in bone scan • Clinical implications to be determined

  48. Conclusions • Advanced prostate cancer pts can have a long history • Opportunity for multiple therapies • Toxicities and quality of life important • Issues of co-morbid disease and aging • Philosophy of chronic d. management • Androgen receptor pathway targeting is key • DNA targeted chemotherapy plays a role • Immunotherapy may play a role • New therapies need to be identified

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