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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

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

Walter Stadler, MD, FACP

University of Chicago

androgen ablation prostate ca
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
Natural History of Rising PSA

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

prostate ca system therapy philosophy
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
Endocrine Axis in Prostate Cancer

GnRH agonist

Adrenal Blockade

Orchiectomy

Tumor Androgens

Antiandrogens

androgen ablation early vs late
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
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
EORTC 30891: Survival

HR: 1.25 (1.05 – 1.48)

eortc 30891 causes of mortality
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
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
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 (?)
slide13

Unadjusted Fracture-free Survival among Patients with Prostate Cancer

Shahinian, V. et al. N Engl J Med 2005;352:154-164

timing of bisphosphonates
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.
diabetes and cv risk adt
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
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
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
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
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
slide21

Abiraterone Phase II

Attard JCO 2009

Pre-Chemo

Ryan ASCO 2009

Danila ASCO 2009

Post-Chemo

Reid ASCO 2009

cou aa 301 study design
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.

cou aa 301 abiraterone acetate improves os in mcrpc
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

survival benefit consistently observed across patient subgroups
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.

novel more potent ar antagonists

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

castrate resistant disease non hormonal treatment options
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
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.

sipuleucel t logistics of therapy
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

randomized phase 3 impact trial immunotherapy prostate adenocarcinoma treatment
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

impact overall survival final analysis 349 events
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%

adverse events more commonly 1 reported in sipuleucel t group
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.

challenges
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
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
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
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
cabazitaxel phase iii
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

primary endpoint overall survival

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

most frequent grade 3 treatment emergent aes
Most Frequent Grade ≥3 Treatment-Emergent AEs*

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

xl184
XL184
  • MET/VEGF pathway targeted
  • Dramatic changes in bone scan
  • Clinical implications to be determined
conclusions
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