1. Treatment of Advanced Disease
Elisabeth I. Heath, MD
Associate Professor of Medicine and Oncology
Wayne State University/Karmanos Cancer Institute
August 28, 2010

2. Prostate Cancer Annual incidence in the USA slowly increasing
Longer life expectancy
Widespread use of PSA leading to early detection
15% present with advanced disease
20-30% of localized disease eventually progress to metastatic disease

3. Clinical States of Prostate Cancer
Under the care of ONCOLOGIST
Androgen
Deprivation
Death
Therapies After LHRH Agonists and AA
Local
Therapy
Chemotherapy
Postchemo
Asymptomatic
Symptomatic
Non Metastatic
Metastatic
Castrate Sensitive
Castrate Resistant
Typical presentation of patient as they move through the different stages. The line represents level burden of disease. Time is not proportional
Abbreviations: AA = antiandrogen; LHRH=luteinizing hormone-releasing hormone. 3

4. Definition of Advanced Disease
Locally advanced
Extracapsular extension
Seminal vesicles
Lymph nodes
Castration sensitivity
Orchiectomy
LHRH suppression
Prior therapy
Surgery
Radiation therapy
Chemotherapy

5. Multimodality Therapy
Urology
Radiation Oncology
Medical Oncology
Pathology
Radiology

6. Hormone Therapy Male menopause
Lutenizing Hormone Releasing Hormone (LHRH) Agonist
Leuprolide acetate (Lupron)
Goserelin acetate (Zoladex)
Decrease testosterone level
Not permanent, although testosterone recovery may take months depending on length of hormone therapy and age

7. Side Effects of Hormonal Therapy
Hot flashes
Sweats
Weight gain
Change in mood
Sexual dysfunction
Bone metabolism changes

8. Length of Hormonal Therapy
Continuous versus intermittent therapy
Clinical trials not definitive as of yet
Discuss with your physician pros/cons of both approaches
Issues for discussion include short and long term side effects of therapy

9. Radiology April 2007 vol 243 no 1, 28-53.

10. Therapy for Bone Metastasis
Zoledronic acid administered IV q 4 weeks
Monitor renal function and perform close evaluations for osteonecrosis of the jaw
Prevent disease related skeletal complications including
Pathological fractures
Spinal cord compression
Radiation therapy
Surgery

11. Denosumab (Amgen)
Another bone strengthening compound in advanced clinical trials
Monoclonal antibody targeting and binding against anti-RANK ligand
Given subcutaneously
Increases bone mineral density and reduces risk of fractures in men who received androgen-deprivation therapy for non-metastatic prostate cancer
Smith MR, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
NEJM 2009 Aug 20: 361(8):

12. Immunotherapy
Sipuleucel-T (Provenge)(Dendreon) FDA approved on April 29, 2010
Approval for treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer
Provenge designed to induce an immune response against prostate cancer
First in class to be approved

13. Sipuleucel-T (Provenge)(Dendreon)
Sipuleucel-T is composed of autologous antigen presenting cells (APCs) cultured with a fusion protein (PA2024) consisting of prostatic acid phosphatase (PAP) linked to GM-CSF
Sipuleucel-T is designed to stimulate T-cell immunity to PAP
PAP is expressed in the vast majority of prostate cancers but not in non-prostate tissue
PA2024 provides efficient loading and processing of antigens by APCs

14. Cellular Immunotherapy
Recombinant Prostatic Acid Phosphatase (PAP) antigen combines with resting antigen presenting cell (APC)
APC takes up the antigen
Fully activated, the APC is now sipuleucel-T
Antigen is processed and presented on surface of the APC
INFUSE PATIENT
Active T-cell
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.

15. Sipuleucel-T Manufacturing
Day 1
Leukapheresis
Day 1-2
Sipuleucel-T is manufactured
Day 2
Patient is infused
Apheresis Center
1.5 – 2.0 ml mononuclear cells
Dendreon
Doctor’s Office
COMPLETE COURSE OF THERAPY:
3 CYCLES
WEEKS 0, 2, and 4
# cells infused was the maximum # of cells that could be prepared from the leukapheresis product. Median # of nucleated cells per infusion = 3.65 x 109 and median # of CD54+ bright cells per infusion = 7.45 x 108. Patients premedicated 30 minutes before each infusion with Tylenol (650 mg) and Benadryl (50 mg). Sipuleucel-T or placebo administered IV over 30 minutes, and patients observed 30 minutes

16. IMPACT Study
Phase 3 clinical trial of Provenge compared to patient’s non-activated immune cells
512 patients in 2:1 randomization
Administered IV q 2 weeks for a total of 3 infusions
Primary endpoint: overall survival
Philip W. Kantoff et al for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:

17. IMPACT Study
Men who received Provenge lived an average of 4.1 months longer and had a 22.5% reduction in the risk of death compared to men in control group (P=0.032, HR=0.77, [95% CI: 0.614,0.979])

18. Current Challenges Leukopheresis Increasing public demand
Venous access
Location of center
Increasing public demand
First year only in select sites
Manufacturing centers being developed

19. Cabazitaxel (Jevtana)(Sanofi-Aventis)
FDA approved on June 17, 2010 in combination with prednisone for the treatment of patients with metastatic castrate-resistant prostate cancer
Phase 3 TROPIC study
755 patients previously treated with docetaxel
30% risk reduction in risk of death from cabazitaxel/prednisone versus mitoxantrone/prednisone (P<0.0001)
Sartor AO, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). GU ASCO 2010, #9.

20. Androgens Synthesized Within the Tumor Itself
Tumor cells use androgen along with androgen precursors from their microenvironment to convert them into testosterone and dihydrotestosterone
In this way, the tumor produces androgen de novo to fuel its own growth and proliferation

21. Prostate Tumor Cell Activates Itself
In CRPC, it is believed that the tumor itself is capable of synthesizing its own source of androgen growth factors, while circulating levels of testosterone remain low
This, in combination with hypersensitivity of the androgen receptor, could result in “self-activation” of the tumor

22. 3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene
Abiraterone
Molecular modeling was used to design a compound that could act as a substrate for CYP17
Inhibition of CYP17 has been shown to block production of androgens from all sources in the body—testes, adrenal glands, and the CaP tumor
Dehydroepiandrosterone-acetate converted into a pyridyl analog of pregnenolone, which is the preferred substrate for the CYP17 enzyme
The resulting analog, abiraterone, was not only highly specific for CYP17, but also was extremely potent
3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene
Molecular Weight=391.55

23. Androgenic Steroidogenesis
Abiraterone is a selective and potent inhibitor of CYP17 enzymes
Blocks production of androgens, including testosterone and DHT -
CYP17 is a key enzyme in the generation of androgens and oestrogens in the adrenal glands and tumor tissue
It specifically inhibits 17α hydroxylase which converts pregnenalone to 170H-pregnenalone → DHEA
Abbreviations: ACTH=adrenocorticotropic hormone; DHEA=dehydroepiandrosterone; DHT=dihydrotestosterone.

24. Abiraterone Blocks Androgen Production at All 3 Sources
Inhibits production of androgens needed to fuel prostate tumor cell growth

25. Other Novel AR Modulators
MDV3100 (Medivation)
TAK700 (Millenium)
TOK-001 (Tokia Pharmaceuticals)

26. Treatment Advancements
Sipuleucel-T (Provenge)
Cabazitaxel (Jevtana)
Denosumab
AR modulators
Abiraterone
MDV3100
TAK700
TOK-001

27. Treatment Advancements
Recognition of importance of multidisciplinary care in treatment of advanced stage prostate cancer
Role of hormonal therapy being optimized
Immunotherapy for treatment of advanced disease
Second-line therapy for patients who fail docetaxel
Encourage enrollment in clinical trials