Tuesday, September 17, 2013

Current, New and Novel Therapy for Castration-Resistant Prostate Cancer part 6

Novel Targets & Trials

Several agents attenuating new biological targets are in clinical trials. Each drug targets different pathways, with effects ranging from immune modulation, cytotoxicity, hormonal manipulation and bone turnover.

Drugs With Antiangiogenic Activity

Angiogenesis is the most important target of the novel treatment, measures of microvessel density and VEGF levels correlate with metastatic disease, Gleason grade and clinical outcome.[6] However, antiangiogenic agents have yet to prove an OS benefit for men with prostate cancer.
VEGF Receptor Inhibitors. Recently, bevacizumab and sunitinib both showed improvements in PFS, but not OS.[53,54]Sunitinib is a multitargeted tyrosine kinase inhibitor with known selectivity for VEGF receptors (VEGFR). In a Phase II trial of men with CRPC who had progressed after chemotherapy, 12.1% of the patients had more than 50% decline in PSA, with 11% showing a 30% decline in measurable disease by RECIST criteria.[55]
Aflibercept is a VEGF-Trap fusion protein that has both the VEGFR-1 and VEGFR-2 domains fused to the Fc domain of IgG1. The Phase III VENICE trial randomized 1200 patients to either docetaxel, prednisone and aflibercept or docetaxel and prednisone with results expected in 2013 (ClinicalTrials.gov identifier: NCT00532155).[101]
Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis and angiogenesis. Cabozantinib was approved by the FDA in November 2012 for the treatment of medullary thyroid cancer. A Phase II trial of cabozantinib (XL184) in patients with CRPC metastatic to bone (ClinicalTrials.gov identifier: NCT01428219) enrolled 171 patients who were randomly assigned to cabozantinib or placebo. Cabozantinib showed clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans and reductions in bone turnover markers, pain and narcotic use.[56]
Finally, tasquinimod is a quinoline-3-carboxamide derivative that has antiangiogenic effects and direct antitumor activity. PFS was prolonged in a Phase II randomized trial, leading to a 2:1 Phase III randomized trial for patients with asymptomatic or minimally symptomatic metastatic CRPC with radiographic PFS as the primary end point.[57]
Endothelin-receptor Antagonists. Endothelins are involved in proliferation, vasomotor tone and angiogenesis. The interactions between endothelins and their receptors (endothelin-A and endothelin-B) have been shown to be implicated in tumor growth, proliferation, apoptosis, angiogenesis and bone metastasis. Elevated levels of endothelins are found in patients with CRPC.[58] Atrasentan, an endothelin-A receptor antagonist, was evaluated in a Phase III trial showing that atrasentan did not reduce the risk of disease progression, but was associated with lower bone alkaline phosphatase and PSA levels.[59]
Zibotentan (ZD4054) is a highly selective endothelin-A receptor antagonist. A Phase II study of ZD4054 compared with placebo in 312 patients showed an OS benefit of 6 months.[60] However, three Phase III studies with this drug have not shown any survival benefit in an initial report.

Drugs With Antiapoptotic Activity (Bcl-2 Inhibitors)

Cytoplasmic clusterin is associated with antiapoptotic functions through mechanisms which include inhibition of the proapoptotic Bcl-2. Forced overexpression of clusterin in cancer models confers resistance to radiation, hormone and chemotherapy whereas inhibition enhances apoptotic death of tumor cells.[57]

Custirsen is a novel intravenously administered antisense oligonucleotide that inhibits clusterin at the mRNA level, increasing sensitivity to androgen deprivation as well as chemotherapy in prostate cancer cell lines and xenograft models. In a randomized Phase II study (OGX-011) of docetaxel+prednisone with or without custirsen in 82 patients with metastatic CRPC, PSA responses (58 vs 54%) and PFS (7.3 vs 6.1 months) were similar in both arms. However, OS trended in favor of the combination arm (23.8 vs 16.9 months; p = 0.06).[62] A randomized, open-label, two-arm (custirsen vs cabazitaxel) Phase III study in 630 patients with CRPC who have documented disease progression after prior first-line docetaxel treatment was recently launched, with OS being the primary end point.

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