Naomi B Haas, MDAssociate Professor of Medicine

Abramson Cancer CenterApril 24, 2013

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 :non-

castrate (not previously treated with androgen deprivation therapy)

Metastatic castrate prostate cancer

Orchiectomy LHRH (GHRH) (Luteinizing hormone

releasing hormone) agonists Anti-androgens

Anti-androgen LHRH Pills 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 hormone-refractory 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.

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.

78 patients 0 1 to 3, >3 lesions bone scan25, 35, and 18 patients

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 variantsMDV3100Aragon agent

Other AR ModulatorsHSP 90 inhibitorsHDAC 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

Decline docetaxel or are not suitable for docetaxel

1:1 randomization MDV3100

Something else

? patients

Coming soon

Failed 1 or 2 prior chemotherapies (docetaxel)

2:1 randomization MDV3100

Placebo

1170 patients

Improvement in overall survival of more than 5 months

AsymptomaticCastrate metastatic disease

2:1 randomization MDV3100

Placebo

850 patients

Closed to accrual in the US

ARN-509 versus MDV3100

ARN-509 versus MDV3100

PK week Continuous Daily Dosing

Wk 1 2 3 4 5 9 13

Cycle 1 2 3

ARN-509Single Dose

Tumor EvaluationQ 12 wks

Disease Progression

DLT period for dose escalation

PSA and CTCQ 4 wks

ARN-509 dose escalation cohorts (n=3-6/cohort): 30, 60, 90, 120, 180, 240, 300, 390 and 480 mg

ARN-509 once daily until progression

PK D1-6

Optional FDHT-PET

at Baseline, 4 and 12

wks

Phase 1 Study Design

14 out of 29 patients (48.3%) experienced ≥ 50% reduction in PSA at 12 weeks

30 mg 60 mg 90 mg120 mg180 mg240 mg300 mg390 mg480 mg

Dose

PSA Response Rates

Baseline

4 Weeks

F-DHT-PET: Pharmacodynamic Marker

OF AR INHIBITION IN RESPONSE TO ARN-509

Ongoing Phase 2 Trial

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

Original Normalized CAD Annotated

Screening

Week 6

XL 1129-2408XL 1129-2408

Original CAD AnnotatedNormalized

Screening

Week 6

Original CAD AnnotatedNormalized

Screening

Week 6

XL 1521-2565XL 1521-2565

Original Normalized

Screening

Week 6

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 CabazetaxelDocetaxel ECOG 2809 ketoconazole mitoxantrone and

prednisone

abiraterone abiraterone

docetaxel enzalutamideStrivePrevail

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

Hormone Sensitive

Hormone Refractory

Biology

Clinical TrialsOpen or Planned at

UPENN

1. High risk RT+ ADT+/- docetaxel trial

2. everolimus + salvage XRT3. Phase I Docetaxel/ cmet

inhibitor trial4. CAR-T cells in advanced disease5. TKI258 plus INC280

Combines VEGFR+ FGF inhibitor with a C-met inhibitor.

Phase I/II planned