Pilot study of rapamycin in patients with hormone-refractory prostate cancer

Background: currently, no second-line treatment for hormone-refractory prostate cancer (HRPC) cases that fail docetaxel regimens. Rapamycin, an immunosuppressive macrolide, inhibits metastatic prostate tumor growth and angiogenesis in in vivo mouse models. This pilot study assessed the antitumor activity, safety, and toxicity of rapamycin in patients with HRPC. Patients and Methods: Eligible patients had HRPC and disease progression. The initial dose of rapamycin was 0.15 mg/kg followed by 0.04 mg/kg daily without interruption. Rapamycin levels were measured every 28 days with dose adjustments of 0.04-0.06 mg/kg as necessary to maintain levels between 6-10 ng/mL. Patients were evaluated every 4 weeks for prostate-specific antigen (PSA) and safety and every 8 weeks for radiographic response. Results: Thirteen patients were enrolled from January 2005 to February 2006. One was not evaluable for response. Responses were seen in 2 of 12 evaluable patients (17%). One patient experienced a 50% decrease in absolute PSA and partial radiographic response; another experienced a PSA response only. Four patients had stable disease (33%). The median progression-free survival was 4.2 months (range, 1.9-23.3 months), and overall survival was 23.3+ months (range, 1.9-34.3+ months). Diarrhea (69%), fatigue (46%), and nausea (46%) were the most common adverse events. Rapamycin was well tolerated and showed signs of antitumor activity. Conclusion: Rapamycin and other inhibitors of mammalian targets of rapamycin warrant further study in developing combination therapies with chemotherapy or radiation.