Development of Drugs That Target Prostate Cancer

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Following the publication of two landmark randomized trials, docetaxel chemotherapy is now the standard of care for men with metastatic CRPC. However, the benefit of this treatment is limited. Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biological agents. Several new docetaxel-based combinations are under evaluation and promising results have been found for the combination of docetaxel with angiogenesis inhibitors. We are attempting to develop novel agents that alter the biology of the cancer. In order to accomplish this goal, we have initiated a collaboration with a unique computational chemistry company to design compounds that abrogate key molecular targets in the development, progression and metastasis of cancer. These studies are just being initiated but could provide valuable new agents. Following previous experiments demonstrating increased efficacy of microtubule-active drugs when combined with ketoconazole in vitro, when tested in multiple prostate cancer cell lines, we initiated a Phase I trial of ketoconazole plus weekly docetaxel in patients with androgen independent prostate cancer (AIPC). The primary objective of this study is to determine the side effect profile and MTD. In recognition of possible drug-drug interations, starting doses of 5 mg/m2 and 1200 mg/d were used for docetaxel and ketoconazole, respectively. Significant hepatotoxicity was noted with a docetaxel dose of 10 mg/m2. The dosing regimen was modified to 600 mg/d of ketoconazole and 10 mg/m2 of docetaxel. A total of 30 patients have been treated with this combination to date and pharmacokinetic analyses are currently ongoing. A randomized Phase II trial of ketoconazole plus alendronate versus ketoconazole alone has been completed with 72 patients with progressive AIPC metastatic to bone. There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC. A Phase II study in AIPC has recently been completed with perifosine. Treatment with this agent was complicated by fatigue and gastrointestinal toxicity. No significant clinical activity against prostate cancer was observed. Perifosine does not merit further study in the setting of monotherapy in this population. Sorafenib for castration-resistant prostate cancer (CRPC): To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, we conducted a phase 2 trial in patients with metastatic CRPC. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49-85) years, the on-study prostate-specific antigen level was 68.45 (5.8-995) ng/mL, the Gleason score 8 (6-9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15-48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer. Thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation: We determined whether thalidomide can prolong progression-free survival in men with biochemically recurrent prostate cancer treated with limited androgen deprivation therapy. A total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing prostate specific antigen after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of prostate specific antigen progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). Testosterone and dihydroxytestosterone were likewise monitored throughout the study. During oral phase A the median time to prostate specific antigen progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to prostate specific antigen progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients. Despite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy. Oral lenalidomide in patients with refractory metastatic cancer: The objectives of this study were to determine the maximum tolerated dose and to characterize the side effect profile and pharmacokinetics of lenalidomide in patients with advanced refractory solid tumors. Patients were treated on a modified Fibronacci dose escalation scheme with an oral daily dose of lenalidomide. A total of 45 patients with 8 different tumor types were accrued. Doses administered included 5, 10, and 20 mg continuous daily doses, every 28 days (n = 15), later modified to intermittent doses of 15, 20, 25, 30, 35, and 40 mg, with a 21 days-on and 7 days-off schedule, due to observed side effects. Lenalidomide exhibited a linear pharmacokinetics over a wide range of doses with the mean half-life of 3.9 hours. The renal function affected lenalidomide clearance, resulting in 50% reduction in patients with mild renal impairment compared with patients with normal function (CL/F = 243 mL/min). Stable disease was documented in 12 of 44 evaluable patients, of whom 9 patients had prostate cancer. Most frequent grade 1 and 2 toxicities included fatigue, nausea, pruritus/rash, neutropenia, and neuropathy. Grade 3/4 events were predominantly hematologic. Lenalidomide was well tolerated up to a 35-mg/d intermittent dosing schedule at doses higher than previously indicated for hematologic malignancies.