Treatment of Advanced Disease

Elisabeth I. Heath, MDAssociate Professor of Medicine and OncologyWayne State University/Karmanos Cancer InstituteAugust 28, 2010

Prostate Cancer

Annual incidence in the USA slowly Annual incidence in the USA slowly increasing increasing Longer life expectancyLonger life expectancy Widespread use of PSA leading to early Widespread use of PSA leading to early

detectiondetection 15% present with advanced disease15% present with advanced disease 20-30% of localized disease eventually 20-30% of localized disease eventually

progress to metastatic diseaseprogress to metastatic disease

Abbreviations: AA = antiandrogen; LHRH=luteinizing hormone-releasing hormone.

• Typical presentation of patient as they move through the different stages. The line represents level burden of disease. Time is not proportional

Under the care of ONCOLOGIST

Under the care of ONCOLOGIST

Castrate Sensitive

Asymptomatic

Non Metastatic

Castrate Resistant

Metastatic

Symptomatic

Local Therapy

Androgen Deprivation

Therapies After LHRH Agonists

and AA ChemotherapyChemotherapy Postchemo

Death

Clinical States of Prostate Cancer

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

APC takes up the

antigen

Recombinant Prostatic Acid

Phosphatase (PAP) antigen combines

with resting antigen presenting cell (APC)

Fully activated, the APC is now sipuleucel-T

The precise mechanism of sipuleucel-T in prostate cancer has not been established.

Antigen is processed and presented on

surface of the APCINFUSE PATIENT

T-cells proliferate and

attack cancer cells

Sipuleucel-T activates T-cells in the

body

Active T-cell

Inactive T-cell

Sipuleucel-T Manufacturing

COMPLETE COURSE OF THERAPY:3 CYCLES

WEEKS 0, 2, and 4

Day 1Leukapheresis

Day 1-2Sipuleucel-T is manufactured

Day 2Patient is infused

Apheresis Center1.5 – 2.0 ml mononuclear cells

Dendreon Doctor’s Office

•# 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 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.

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

Androgens Synthesized Within the Tumor 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

Prostate Tumor Cell Activates Itself

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

Abiraterone

3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene

Molecular Weight=391.55

Androgenic Steroidogenesis

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

-

• Abiraterone is a selective and potent inhibitor of CYP17 enzymes

• Blocks production of androgens, including testosterone and DHT

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

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