1. Prostate Cancer: What’s New
Prostate Cancer: What’s New? Treatment Options For Advanced Castrate Resistant Disease
Naomi B Haas, MD
Associate Professor of Medicine
Abramson Cancer Center
April 24, 2013

2. Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer
Modulation of androgen and testosterone
New therapies for castrate resistant prostate cancer

3. Overcoming resistance mechanisms in prostate cancer:
Intratumoral testosterone
Androgen receptor (AR) mutations and splice variants
Ligand modulation (things that influence the AR)
Targets in advance disease

4. Semantics Castrate-treated with androgen deprivation therapy
Non-castrate- not previously treated with androgen deprivation therapy

5. Conventional categories
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

6. Androgen deprivation Therapy
Orchiectomy
LHRH (GHRH) (Luteinizing hormone releasing hormone) agonists
Anti-androgens

7. ADT Anti-androgen LHRH Pills Implants and shots
LHRH antagonist- degarelix

8. Side Effects 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

9. Other Hormonal Manipulations
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

10. Other options: ketoconazole + prednisone or hydrocortisone
Scholz M et al. J Urol Jun;173(6):
78 patients
0 1 to 3, >3 lesions bone scan
25, 35, and patients
Fig. 5. Kaplan-Meier representation of survival time. Group 1 denotes men with less then 50% decrease in PSA. Group 2 denotes men with PSA decrease between 50% and 75%. Group 3 denotes men with log PSA decrease greater than 75%.
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.

11. NEW Hormonal Manipulations!
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

12. Other hormonal manipulations
Prednisone
Ketoconazole
Abiraterone

13. Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy. JClin Oncol 26: 2008 (May 20 suppl; abstr 5019)
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 patients, leading to FDA approval

16. Abiraterone side effects
Dizziness
Fatigue
Low or high blood pressure
Fluid retention
Elevation of liver enzymes
Low potassium

17. MDV3100/ Enzalutamide / Xtandi
AR modulation
MDV3100/ Enzalutamide / Xtandi
This is an AR receptor antagonist (oral ) which inhibits both the translocation of the AR receptor to the nucleus and the binding of the AR complex to DNA. Casodex does not do this. Induces apoptosis

18. MDV 3100 Phase II trial MDV3100 1:1 randomization Decline docetaxel
or are not suitable
for docetaxel
Something else
? patients
Coming soon

19. MDV 3100 Phase III “AFFIRM” trial
2:1 randomization
Failed 1 or 2 prior
chemotherapies
(docetaxel)
Placebo
1170 patients
Improvement in overall survival of more than 5 months

22. MDV 3100 Phase III “PREVAIL” trial
2:1 randomization
Asymptomatic
Castrate
metastatic disease
Placebo
850 patients
Closed to accrual in the US

23. ARN-509 versus MDV3100

24. ARN-509 versus MDV3100

25. Phase 1 Study Design Cycle 1 2 3
Optional FDHT-PET at Baseline, 4 and 12 wks
PSA and CTC
Q 4 wks
Tumor Evaluation
Q 12 wks
ARN-509
Single Dose
Disease Progression
ARN-509 once daily until progression
PK week Continuous Daily Dosing
PK D1-6 Wk
Cycle
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

26. experienced ≥ 50% reduction in PSA at 12 weeks
PSA Response Rates
Dose
30 mg
60 mg
90 mg
120 mg
180 mg
240 mg
300 mg
390 mg
480 mg
14 out of 29 patients (48.3%)
experienced ≥ 50% reduction in PSA at 12 weeks

27. OF AR INHIBITION IN RESPONSE TO ARN-509
F-DHT-PET: Pharmacodynamic Marker
OF AR INHIBITION IN RESPONSE TO ARN-509
Baseline
4 Weeks

28. Ongoing Phase 2 Trial
ASCO GU 2013

29. Immunotherapies
Provenge
Prostvac
CARs

30. IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer
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

32. CARs (Chimeric Antigen and T cell Receptor)(Carl June)
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

33. XL184 (Cabozantanib)
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

34. XL184 (Cabozantanib)
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

35. XL 184 Cases

36. XL
Screening
Week 6
Original
Normalized
CAD Annotated

37. XL
Screening
Week 6
Original
Normalized
CAD Annotated

38. XL
Screening
Week 6
Original
Normalized
CAD Annotated

39. XL
Screening
Week 6
Original
Normalized
CAD Annotated

40. The Landscape TKIs +ADT ADT Provenge Cabazetaxel Docetaxel ECOG 2809
Adjuvant/
Neoadjuvant
Rising PSA Only
Rising PSA and metastatic disease
(noncastrate)
Progression after ADT
(castrate)
Progression after Docetaxel
TKIs +ADT
ADT
Provenge
Cabazetaxel
Docetaxel
ECOG 2809
ketoconazole
mitoxantrone and prednisone
abiraterone
docetaxel
enzalutamide
Strive
Prevail
XL184?
Radium chloride

41. The future Biopsy with molecular profile
Treatment with chemotherapy or targeted agents or more hormonal therapy depending on your molecular profile

42. 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
And I would like to close with this slide which summarizes our research plan for the next year. We hope to open a number of clinical trials that will give new options for patients with
PSa recurrence and metastatic prostate cancer. We hope that we can be at the forefront of identifying new apporaches for this disease, but we need your help. Whether it is participation in clinical research, or participation in patient support groups in person or on line, continued progress in the treatment of this disease can only happen with the involvement of the corageous men with prostate cancer and their families.

43. TKI258 + INC280 Combines VEGFR+ FGF inhibitor with a C-met inhibitor.
Phase I/II planned