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

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

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

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

Multimodality Therapy Urology Radiation Oncology Medical Oncology Pathology Radiology

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

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

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

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

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

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.

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

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

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.

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

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.

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])

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

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.

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

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

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

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.

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

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

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

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