April 24, 2013

Naomi B Haas, MD
Associate Professor of Medicine
Abramson Cancer Center

Modulation of androgen and testosterone

New therapies for castrate resistant
prostate cancer

Intratumoral testosterone
Androgen receptor (AR) mutations and splice
variants
Ligand modulation (things that influence the
AR)
Targets in advance disease

Castrate-treated with androgen deprivation

therapy
Non-castrate- not previously treated with
androgen deprivation therapy

Rising PSA after surgery or radiation or both

New metastatic disease and rising PSA :noncastrate (not previously treated with
androgen deprivation therapy)
Metastatic castrate prostate cancer

Orchiectomy
LHRH (GHRH) (Luteinizing hormone releasing
hormone) agonists
Anti-androgens

Anti-androgen
Pills

LHRH
Implants and shots

LHRH antagonist- degarelix

Tiredness
Metabolic syndrome- weight gain, high blood
pressure and high blood sugar
Osteopenia-decreased bone density
Secondary risks for heart attack, blood clot or
stroke
Mood changes
Loss of sex drive (libido)
Hot flashes

Prednisone 10 mg by mouth two times a day

can decrease PSA by more than 50% in
approximately 1/3 of patients with hormonerefractory progressive prostate cancer (Sartor O
et al, The Journal of Urology Vol161, Issue 1, January 1999,
Page 360

Scholz M et al. J Urol. 2005 Jun;173(6):1947-52.

78 patients
0 1 to 3, >3 lesions bone scan
25, 35, and 18 patients

Median and mean time to PSA progression was 6.7 and 14.5 months.
Median and mean survival time was 38.0 and 42.4 months, respectively.
Response time and survival were highly correlated (r = 0.799). A total of
34 (44%) men had a greater than 75% decrease in PSA. The median
survival times in men with more vs less than a 75% decrease were 60 vs
24 months, respectively.

Lyase inhibitors- get rid of intratumoral testosterone and

residual sources of testosterone/androgens

Abiraterone acetate and prednisone

Tax 700
Toc 1 (dual lyase and AR inhibitor)

AR inhibitors- address mutations in the receptor, splice variants

MDV3100
Aragon agent
Other AR Modulators
HSP 90 inhibitors
HDAC inhibitors

Prednisone
Ketoconazole
Abiraterone

AA (Zytiga) 1000mg qd + pred 5mg twice daily

14 of 35 pts had decrease in PSA of >50%
Phase III trial completed post chemotherapy showed overall
survival improvement of almost 5 months in a study of
1000+ patients, leading to FDA approval

Dizziness
Fatigue
Low or high blood pressure
Fluid retention
Elevation of liver enzymes
Low potassium

AR modulation

1:1 randomization
Decline docetaxel
or are not suitable
for docetaxel

? patients

Coming soon

MDV3100

Something else

2:1 randomization
Failed 1 or 2 prior
chemotherapies
(docetaxel)

MDV3100

Placebo

1170 patients

Improvement in overall survival of more than 5 months

2:1 randomization
Asymptomatic
Castrate
metastatic disease

850 patients

Closed to accrual in the US

MDV3100

Placebo

ARN-509 versus MDV3100

ARN-509 versus MDV3100

Phase 1 Study Design

ARN-509
Single
Dose

Optional
FDHT-PET
at
Baseline,
4 and 12
wks

PSA
and CTC
Q 4 wks

Tumor
Evaluation
Q 12 wks

Disease
Progression

ARN-509 once daily until progression

PK week

Continuous Daily Dosing

PK D1-6

Wk 1

Cycle

13

DLT period for dose escalation

ARN-509 dose escalation cohorts (n=3-6/cohort):

30, 60, 90, 120, 180, 240, 300, 390 and 480 mg

PSA Response Rates

100

Dose
30 mg
60 mg
90 mg
120 mg
180 mg
240 mg
300 mg
390 mg
480 mg

% PSA Change from Baseline

75
50
25
0

-25
-50
-75

-100

14 out of 29 patients (48.3%)

experienced 50% reduction in PSA at 12 weeks

F-DHT-PET: Pharmacodynamic
Marker
OF AR INHIBITION IN RESPONSE TO ARN-509

Baseline

4 Weeks

Ongoing Phase 2 Trial

Non-Metastatic (M0)
CRPC
patients
(n = 93)

Metastatic
Treatment-Nave
Metastatic
Post-Abiraterone

Primary Endpoint:
12-week PSA response
ASCO GU 2013

Provenge
Prostvac
CARs

randomized (2:1) to receive 3 doses of

sipuleucel-T (n = 341) or placebo (n = 171)
intravenously at 2-week intervals
median survival of 25.8 and 21.7 months
survival probability at 36 months of 32.1%
and 23.0% in the sipuleucel-T and placebo
arms
Kantoff GU ASCO 2010

Harness antigens expressed uniquely by a

cancer (for example Prostate specific
membrane antigen, prostate specific stem
cell antigen, F77, c-met ) and link to T cells
to turn on immunity against the antigen
ongoing trials in leukemia, pancreatic cancer
Can be given IV or into the tumor

Targets c-met and VEGFR2 both important

targets in prostate cancer
c-met is overexpressed in bone metastases
as a later event in men on androgen
deprivation therapy
VEGF expressed in aggressive prostate
cancer

RDT trial in patients previously treated with

docetaxel showed 86% had response in bone
scan; 65% had improvement in pain
Expanded prostate trial 64% (51/80 pts
evaluable) had a PR on bone scans, 24 pts
(30%) SD at 100mg daily
other cohort treated at 39 mg daily results
pending
Two new phase III trials of XL184 coming

XL 1129-2408

Screening

Week 6

Original

Normalized

CAD Annotated

Screening

Week 6

Original

Normalized

CAD Annotated

Screening

Week 6

Original

Normalized

CAD Annotated

XL 1521-2565

Screening

Week 6

Original

Normalized

CAD Annotated

Adjuvant/
Neoadjuvant

Rising PSA Only

Rising PSA
and
metastatic
disease
(noncastrate)

Progression
after ADT
(castrate)

Progression after
Docetaxel

TKIs +ADT

ADT

ADT

Provenge

Cabazetaxel

Docetaxel

ECOG 2809

ketoconazole

mitoxantrone and
prednisone

abiraterone

abiraterone

docetaxel

enzalutamide

Strive
Prevail

XL184?
Radium chloride

Biopsy with molecular profile

Treatment with chemotherapy or targeted
agents or more hormonal therapy depending
on your molecular profile

Hormone Sensitive v. Hormone Refractory Prostate Cancer

Clinical Trials
Open or Planned at
UPENN
Biology
Hormone Sensitive

Hormone Refractory

1. High risk RT+ ADT+/- docetaxel

trial
2. everolimus + salvage XRT
3. Phase I Docetaxel/ cmet
inhibitor trial
4. CAR-T cells in advanced disease
5. TKI258 plus INC280

Combines VEGFR+ FGF inhibitor with a C-met

inhibitor.
Phase I/II planned