Managing Castrate-Resistant Metastatic Prostate Cancer

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

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

Provenge AR ModulatorsDenosumab

Clinical States of Prostate Cancer

Cabazitaxel

Definition of Castrate-Resistant Disease

Prostate Cancer Working Group 2 (PCWG2) PSA 2.0 ng/mL Rising PSA minimum 1 week apart LN > 2 cm used for assessment Bone scan: 2 more new lesions

Howard Scher et al. Design and End Points of Clinical Trials for Patients WithProgressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate CancerClinical Trials Working Group J Clin Oncol 26:1148-1159.

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

Androgen Deprivation Therapy

Maintain castrate levels of testosterone ADT important in controlling castrate-

sensitive population Supportive therapy for bone health

including calcium and vitamin D still indicated

Supportive therapy for symptoms of androgen suppression also indicated

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

Secondary Hormonal Therapy

Add anti-androgen Subtract anti-androgen Add ketoconazole Add steroid Add Diethylstilbesterol (DES) Consider clinical trial

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 or 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])

IMPACT Study

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.

Current Challenges

Leukopheresis Venous access Location of center

Increasing public demand First year only in select sites Manufacturing centers being developed

Biologic Targets for Cancer Therapy

1. Growth Factors andGrowth-Factor Receptors(HER family, VEGFR, c-kit/SCFR)

2. Signal Transduction Pathways(Ras, raf, MAPK, MEK, ERK PKC, P13K)

3. Tumor-AssociatedAntigens/Markers(gangliosides, CEA, MAGE, CD20, CD22)

4. Proteasome

6. Extracellular Matrix/Angiogenic Pathways(MMPs, VEGF, integrins)

5. Cell-Survival Pathways(cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2)

HER = human epidermal growth factor receptor; MMPs = matrix metalloproteinases; SCFR = stem cell growth factor receptor. Adapted with permission from Perez-Soler R, Miller V. Presented at: New Advances in the Management of Advanced NSCLC: the Expanding Role of Targeted Therapies [live Web conference]; April 20, 2005.

Tumor Cell

Targeted Agents

Compounds that target cellular pathways abnormal in cancer cells, not in normal cells

Potentially more effective and less toxic Better understanding of genetic and

biologic changes underlying prostate cancer progression has led to growing research and development of rational prostate-specific drug targets1

1 Heath EI, Carducci MA. Hematol Oncol Clin North Am 2006 Aug;20(4):985-999.

Novel Agents

VEGF inhibitors Src inhibitors HSP90 inhibitors AKT inhibitors PI3 kinase inhibitors MTOR inhibitors Jak/Stat inhibitors Encourage enrollment into clinical trials