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% – 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

Natural History of Rising PSA

Makarov, et al; J Urol:179:156, 2008

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

Endocrine Axis in Prostate Cancer

GnRH agonist Adrenal Blockade Antiandrogens Orchiectomy Tumor Androgens

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

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%

EORTC 30891: Survival

HR: 1.25 (1.05 – 1.48)

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)

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)

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 (?)

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

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.

Fatigue, Muscle Loss and Elderly Prostate Cancer Patients

Bylow, et al, Cancer, 2007

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

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

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

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.

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

Abiraterone Phase II

Attard JCO 2009 Pre-Chemo Ryan ASCO 2009 Danila ASCO 2009 Post-Chemo Reid ASCO 2009

COU-AA-301 Study Design

Patients

• 1195 patients with progressive mCRPC • Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel

R A N D O M I Z E D 2:1

Abiraterone 1000 mg daily Prednisone 5 mg BID n=797 Placebo daily Prednisone 5 mg BID n=398

Efficacy endpoints (ITT) 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)

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.

COU-AA-301 Patient Disposition Subjects treated Median number of cycles of therapy (range) Treatment ongoing, n (%) Treatment discontinued, n (%) Abiraterone (n=797) 791 8 (1-21) 222 (28.1) 569 (71.9) Placebo (n=398) 394 4 (1-21) 54 (13.7) 340 (86.3)

COU-AA-301 Baseline Demographics Median age, years (range) Race, % White Black Asian ECOG PS 2, % Significant pain present, % 2 Prior chemotherapies, % Abiraterone (n=797) 69.0 (42-95) 93.3

3.5

1.4

10.7

44.3

28.2

Placebo (n=398) 69.0 (39-90) 92.7

3.8

2.3

11.1

44.0

28.4

Total (n=1195) 69.0

(39-95) 93.1

3.6

1.7

10.8

44.2

28.3

COU-AA-301 Baseline Disease Characteristics Primary site of disease, % Bone Node Liver Lung Abiraterone (n=797) 89.2

45.4

11.3

13.0

Placebo (n=398) 90.4

41.5

7.6

11.4

100 COU-AA-301: Abiraterone Acetate Improves OS in mCRPC HR=0.646 (0.54-0.77) P <0.0001

Abiraterone: 14.8 months (95% CI: 14.1, 15.4) 80 60 40 20 Abiraterone Placebo 0 0 797 398 100 728 352 Placebo: 10.9 months (95% CI: 10.2, 12.0) 1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo 200 631 296 300 400 500 Days from Randomization 475 204 25 180 69 8 600 0 1 700

Survival Benefit Consistently Observed Across Patient Subgroups Variable All subjects Baseline ECOG Baseline BPI No. of prior chemo regimens Type of progression Baseline PSA above median Visceral disease at entry Baseline LDH above median Baseline ALK-P above median Region Abbreviations

: HR=hazard ratio; ALK-P=alkaline phosphatase.

Subgroup All 0-1 2 <4



4 1 2 PSA only Radiographic YES YES YES YES North America Other N 1195 1068 127 659 536 833 362 363 832 591 709 581 587 652 543 Favors Abiraterone 0.5 0.75

1 HR 0.66

0.64

0.81

0.64

0.68

0.63

0.74

0.59

0.69

0.65

0.60

0.71

0.60

0.64

0.69

1.5

Favors Placebo 95% CI 0.56-0.79

0.53-0.78

0.53-1.24

0.50-0.82

0.53-0.85

0.51-0.78

0.55-0.99

0.42-0.82

0.56-0.84

0.52-0.81

0.48-0.74

0.58-0.88

0.48-0.74

0.51-0.80

0.54-0.90

COU-AA-301: Secondary End Points Achieved Statistical Significance TTPP, mo rPFS, mo PSA response rate (>50% reduction), % Total Abiraterone (n=797) 10.2 5.6

38.0

Placebo (n=398) 6.6 3.6

HR (95% CI) 0.58

(0.46, 0.73) 0.67

(0.59, 0.78) P Value <0.0001

<0.0001

10.1

<0.0001

COU-AA-301: Summary of AEs

All treatment-emergent AEs, % Serious AEs, % AEs leading to discontinuation, % Deaths within 30 days of last dose, % Underlying disease Other specified cause Drug-related AEs Abiraterone (n=791) All Grades Grades 3/4 98.9

54.5

37.5

32.1

18.7

10.5

7.5

2.9

0 10.5

Placebo (n=394) All Grades Grades 3/4 99.0

58.4

41.4

35.3

22.8

13.5

13.2

9.9

3.3

0

COU-AA-301: AEs of Special Interest AE, % Fluid retention Hypokalemia LFT abnormalities Hypertension Cardiac disorders Abiraterone (n=791) All Grades Grades 3/4 All Grades Placebo (n=394) Grades 3/4 30.5

17.1

10.4

9.7

13.3

2.3

3.8

3.5

1.3

4.1

22.3

8.4

8.1

7.9

10.4

1.0

0.8

3.0

0.3

2.3

Novel More Potent AR Antagonists

• • BMS-641988 (development discontinued) MDV3100 – Phase I/II trial – Phase III trial initiated (docetaxel refractory)

60 mg (n=22) 150 mg (n=23) 2 pt off study <12 wk 3 pt off study <12 wk 240 mg (n=28) 7 pt off study <12 wk

Scher, et al, ASCO 2009

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

Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein

Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC

Active T-cell

Fully activated, the APC is now sipuleucel-T INFUSE PATIENT

Inactive 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.

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Sipuleucel-T: Logistics of Therapy

Day 1

Leukapheresis

Day 2-3

sipuleucel-T is manufactured

Day 3-4

Patient is infused Apheresis Center Central Processing Doctor’s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4 45

Randomized Phase 3 IMPACT Trial

(IMmunotherapy Prostate AdenoCarcinoma Treatment) Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate Cancer (N=512)

2:1

Sipuleucel-T Q 2 weeks x 3 Placebo Q 2 weeks x 3 P R O G R E S S I O N Treated at Physician Discretion Treated at Physician Discretion and/or Salvage Protocol S U R V I V A L Primary Endpoint: Overall Survival Secondary Endpoint: Objective Disease Progression

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IMPACT Overall Survival Final 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% No. at Risk Sipuleucel-T Placebo 341 171 274 123 142 59 56 22 18 5 3 2

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Adverse Events More Commonly

1

Reported in Sipuleucel-T Group

Preferred Term Chills Pyrexia Headache Influenza-Like Illness Myalgia Hypertension Hyperhidrosis Groin Pain Sipuleucel-T N = 338 % 54.1

29.3

16.0

9.8

9.8

7.4

5.3

5.0

Placebo N = 168 % 12.5

13.7

4.8

3.6

4.8

3.0

0.6

2.4

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.

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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

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

Other Immune Therapy Approaches (2)

• A true vaccine: PSA-TRICOM – “Prime” and “boost” vaccinations – Castrate/Docetaxel resistant patients – Quadramet ± PSA-TRICOM

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

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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) *Oral prednisone/prednisolone: 10 mg daily.

mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377 )

Primary endpoint:

OS

Secondary endpoints:

Progression-free survival (PFS), response rate, and safety

Inclusion:

Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

Summary of Demographics and Patient Characteristics

MP (n=377) CBZP (n=378) Age

Median (years) ≥65 (%)

ECOG PS (%)

0, 1 2

PSA (ng/mL)

Median

Measurability of disease (%)

Measurable disease Non-measurable disease

Disease Site (%)

Bone Lymph node Visceral PSA: Prostate-specific antigen.

67.0

57.0

91.2

8.8

127.5

54.1

45.9

87.0

44.8

24.9

68.0

64.9

92.6

7.4

143.9

53.2

46.8

80.2

45.0

24.9

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Primary Endpoint: Overall Survival Proportion of OS (%) 100 80 Median OS (months) 95% CI P-value MP CBZP

12.7

15.1

0.70

0.59

–0.83

<.0001

60 40 20 Number at risk MP CBZP 0 0 months

377 378 55

6 months

300 321

12 months

188 231

18 months

67 90

24 months

11 28

30 months

1 4

Most Frequent Grade ≥3 Treatment Emergent AEs* Any adverse event

Febrile neutropenia Diarrhea Fatigue Asthenia Back pain Nausea Vomiting Hematuria Abdominal pain

MP (n=371) All grades (%) Grade ≥3 (%) 88.4

1.3

10.5

27.5

12.4

12.1

22.9

10.2

3.8

3.5

39.4

1.3

0.3

3 2.4

3 0.3

0 0.5

0

CBZP (n=371) All grades (%) Grade ≥3 (%) 95.7

7.5

46.6

36.7

20.5

16.2

34.2

22.6

16.7

11.6

57.4

7.5

6.2

4.9

4.6

3.8

1.9

1.9

1.9

1.9

*Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.

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Total Deaths During Study Safety Population

Total deaths during study Due to progression Due to AEs Due to other reasons MP (n=371)

275 (74.1%) 253 (68.2%) 7 (1.9%) 15 (4.0%)

CBZP (n=371)

227 (61.2%) 197 (53.1%) 18 (4.9%) 12 (3.2%)

XL184

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

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