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  • Several tertiary prevention studies are currently underway

    2023-11-18

    Several tertiary prevention studies are currently underway examining the use of dutasteride for prostate cancer treatment: (1) during expectant management of prostate cancer, (2) after radical prostatectomy in men at high risk for relapse, and (3) in men with metastatic disease. The Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) [49] trial is a 3-year study testing whether dutasteride can be used in men with localized prostate cancer to delay progression to a more aggressive form. To avoid the complications of unwanted side effects, men in this study with low-grade cancer are undergoing “watchful waiting” or what is currently termed expectant management of their disease, with the possibility of intervention upon evidence of disease progression. This is a randomized, double-blind, placebo-controlled study involving 302 men enrolled in 2006–2007. To be enrolled, men must have low-grade, low-risk, localized prostate cancer (Gleason score≤6, PSA≤10ng/ml) and a TPV of <80cm3. Men were randomized to receive placebo or 0.5mg/d dutasteride and have been followed up with visits every 3 months for the first year and every 6 months for the remaining 2 years. The primary endpoint for the REDEEM trial is the interval to disease progression, which has been defined as either kobe2602 of therapy for prostate cancer or pathologic progression. The results and evaluation of data are expected in 2010 and if proven successful, dutasteride could become an effective treatment for men undergoing expectant management. Two other studies are looking at dutasteride treatment in patients who have failed previous therapies. The Avodart® after Radical Therapy for Prostate Cancer Study (ARTS) [50] is exploring the use of dutasteride in patients who have increasing PSA levels after either radical prostatectomy or radiotherapy, but have not yet progressed to metastatic disease. Study endpoints are time to PSA doubling, time to disease progression, treatment response (PSA decrease), changes in PSA and PSA doubling time, and changes in anxiety, as measured by the Memorial Anxiety Scale for Prostate Cancer. Combination therapies with 5ARIs and various agents are also being explored. The Therapy Assessed by Rising PSA (TARP) [51] study will be examining the use of combination therapy in patients with castrate-refractory prostate cancer (CRPC). This is a multicenter trial in the US and Canada where patients will be randomized to receive treatment with bicalutamide alone or bicalutamide plus dutasteride. The primary endpoint of this study will be time to disease progression. This will be the first trial using both an anti-androgen and a 5ARI in an attempt to reduce the rate of progression in CRPC. A Phase II study of 57 patients with CPRC receiving dutasteride in addition to ketoconazole, which was reported last year, concluded that dutasteride may improve the response rate to ketoconazole and also increases the duration of the response significantly [52]. Ketoconazole is one of a group of inhibitors of CYP17A1, the enzyme that mediates androgen precursor synthesis. This study demonstrated the validity of combining therapies targeting multiple steps in the androgen synthesis pathway and supports the concept of further combination trials. Table 3 lists the major chemoprevention trials and a number of the ongoing prostate cancer treatment trials using 5ARIs. The results of several studies are expected to be reported this year that may add to our knowledge regarding use of 5ARIs in treatment of prostate cancer.
    Gene expression analysis of 5ARI action in prostate cells Gene expression analyses are enhancing knowledge of the mechanism(s) of action of 5ARIs in prostate cells. A number of laboratories, including our own, have examined changes in gene expression in prostate cancer cells treated with finasteride and/or dutasteride. These studies have discovered pathways in addition to the androgen pathway that are affected with treatment, such as those involved in cytoskeletal remodeling, cell cycle, and Rho GTPase signaling [43], [47], [53], [54], [55], [56]. Recently, gene expression patterns were examined in benign epithelium of patients with localized prostate cancer. It was found that pre-treatment AR levels may predict the response to or success of chemoprevention with dutasteride [56] and that patients with high levels of AR can compensate for androgen depletion better than those having lower endogenous levels, leading to differing responses to 5AR inhibition. A carefully designed clinical study can determine if these levels do indeed predict response to therapy. Gaining insights into the pathways affected by finasteride and dutasteride within the prostate tumor microenvironment should lead to development of additional agents that can be used in combination with 5ARIs leading to more effective use in prevention or treatment of prostate cancer in the near future.