Targeting the Microenvironment
Tasquinimod: In addition to the approval of some small molecule inhibitors, several novel inhibitors are, at the time of publication, in various phases of clinical trials for mCRPC. Tasquinimod, a quinoline-3-carboxamide derivative, is being investigated in men with mCRPC (NCT01234311, NCT00560482).
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Tasquinimod provides an antiangiogenic effect by upregulating thrombospondin-1 (TSP-1) and downregulating the gene expression of vascular endothelial growth factor (VEGF), the C-X-C chemokine receptor (CXCR) 4, and lysyl oxidase.60
It has also been shown to reduce the expression levels of C-X-C chemokine motif (CXCL) 12 and inhibit S100A9, both of which are important molecules implicated in tumorigenesis and angiogenesis.50,60-63 The results of a phase 2 trial in patients naive to chemotherapy showed improved rates of median progression-free survival (7.6 months vs 3.3 months).57
In addition, the study showed bone alkaline phosphatase levels, a correlate of bone turnover, were stabilized in patients receiving tasquinimod. Following the favorable outcome of the phase 2 trial, a phase 3 trial comparing tasquinimod to placebo was initiated in patients with mCRPC naive to chemotherapy.50
Cabozantinib: Cabozantinib is a tyrosine kinase inhibitor that blocks c-MET and VEGF receptor 2 and is already approved for the treatment of medullary thyroid cancer. This fact, combined with its oral administration, makes it a favorable candidate for further investigation and development in mCRPC. Phase 2 clinical trials have shown that cabozantinib results in partial resolution of bone lesions in 56% of patients and provided complete resolution in 19%.51
A total of 64% had an improvement in pain and 46% were able to decrease or discontinue narcotics.51 An additional exploratory analysis updated the results of this phase 2 trial and indicated a reduction of more than 30% in the bone scan lesion area and also indicated a reduction in circulating tumor cells.64
Multiple phase 3 trials focused on the treatment of mCRPC with cabozantinib are either ongoing or in the recruiting stages (NCT01428219, NCT01703065, NCT01995058, NCT01605227, NCT01834651, NCT01599793, NCT01522443, NCT01683994). At the time of publication, NCT01605227 failed to reach efficacy in men with mCRPC.
Custirsen: Custirsen is an antisense oligonucleotide that targets clusterin, a chaperone induced by stress and detected at elevated levels in several tumor types, including prostate cancer.65
Studies of clusterin have demonstrated its antiapoptotic and prosurvival activities in prostate cancer that are believed to be associated with docetaxel resistance.66 As such, inhibiting clusterin concomitantly with docetaxel may increase the time until docetaxel resistance in mCRPC. Phase 2 trials of weekly intravenous custirsen plus docetaxel extended median survival rates from 16.9 months to 23.8 months compared with single-agent docetaxel.67,68
Subsequent to treatment, significant decreases in clusterin levels were noted in patients treated with custirsen.67,68 A second phase 2 trial evaluating custirsen plus prednisone compared with mitoxantrone plus prednisone in patients with mCRPC who previously failed first-line docetaxel showed an increase of 4.3 months in median overall survival and a 3.8-month increase in progression-free survival as well as improved declines in PSA.52
Phase 3 trials of custirsen are ongoing (NCT01578655), although its benefits may be limited to patients expressing high levels of clusterin.69
Prostvac-VF: The use of cancer vaccines aims to generate an immune response to specific tumor antigens. The Prostvac vaccine uses a fowlpox and vaccinia platform to deliver the PSA transgene to antigen-presenting cells, which, in turn, express and present the antigen to T cells and T-cell activation.70
In addition to PSA, the vaccine has been engineered to include B7-1, ICAM-1, and LFA-3 antigen-presenting cell costimulatory molecules.71 Phase 2 trials in patients with mCRPC have shown improvements of 8 to 9 months in median survival rates.56,72
The results of these trials suggest that Prostvac offers an improvement compared with sipuleucel-T and have resulted in the initiation of a phase 3 trial (NCT01322490).
Nivolumab: Blocking the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunosuppressive axis has received much attention in recent years. Nivolumab is a monoclonal antibody that inhibits the interaction between PD-L1 and T-cell expressed PD-1, preventing tumor-induced loss of T-cell effector function.73 In trials of melanoma, 80% of patients responded to nivolumab therapy.74
However, limited studies in CRPC have not been as promising; phase 1 studies have failed to reach objective responses and others have shown limited or lack of PD-L1 expression by CRPCs or the immune infiltrates.53,73 However, it is possible that prospective, individual patients with mCRPC with high levels of PD-L1 could benefit from nivolumab.
Ipilimumab: As cancer progresses, it can express inhibitory ligands such as B7-1, B7-2, and PD-L1 to suppress the immune system. Ipilimumab is a monoclonal antibody that inhibits T-cell–expressed cytotoxic T-lymphocyte antigen 4 from interacting with antigen-presenting cell B7-1 and B7-2 ligands but not those on tumor cells, allowing for the continued immune-mediated destruction of tumor cells.
Ipilimumab has been studied in melanoma and is the only FDA-approved immune checkpoint inhibitor on the market.40 Despite encouraging results in early clinical trials, the results of a phase 3 trial of patients with mCRPC receiving bone-directed radiotherapy prior to 10 mg/kg ipilimumab or placebo revealed no significant improvement in overall survival rates.54,55
However, individual analysis of patient subsets indicated that ipilimumab may benefit men with low disease burden, thus emphasizing the importance of appropriate patient selection.16,55
