Pazopanib as Second Line Therapy in Patients With Metastatic Prostate Cancer Refractory to Total Androgen Blockade

VEGF expression is low in all normal prostate tissue, but markedly increased in tumor
tissue, and has a positive association with MVD (micro vessel density) tumor stage, grade,
and disease-specific survival in patients with prostate cancer. VEGF is known to be under
the influence of HIF-1α, which is also up-regulated in the majority of prostate cancer
tissue. It has been shown that complete androgen blockade down-regulates VEGF expression
via the HIF-1α pathway with concomitant up-regulation of thrombospondin and induction of
endothelial cell apoptosis. The VEGF pathway appears to be the dominant vascular formation
pathway in prostate cancer with bFGF having a lesser role.

Pazopanib , a hydrochloride salt, is a small molecule inhibitor of several tyrosine kinases,
ie: VEGF 1, 2, 3, c-KIT and platelet-derived growth factor receptors. The broad blockade
of the VEGF receptors should interfere with the VEGF/VEGF-receptor pathway, and have an
impact on cell growth.

According to the NCCN guidelines , first line therapy for metastatic prostate cancer is
considered total androgen blockade, either utilizing orchiectomy and/or LH/RH agonists plus
Casodex.

Second line therapy would depend on the patient's response to first line therapy, urgency of
a response, and the location of metastatic disease.

Pazopanib has been explored in several settings. It has recently been looked at with
Bicalutamide in hormone refractory prostate cancer. The second study was with earlier
disease, i.e. D-0 relapse androgen-sensitive patients. The University of Chicago has a
study looking at the sub-population of prostate cancer patients that have a "chemical
relapse" in which patients are given one shot of Lupron, and if the PSA is adequately
suppressed, the patients are randomized between pazopanib and placebo.