Treatment of Advanced Disease

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 Symptomatic Asymptomatic 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.

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): 745-55.

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; 363:411-422.

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 • 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. 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 - Abbreviations: ACTH=adrenocorticotropic hormone; DHEA=dehydroepiandrosterone; DHT=dihydrotestosterone.

24. Abiraterone Blocks Androgen Production at All 3 Sources • 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