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A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: PTEN loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 Kinase pathway. Temsirolimus blocks mTOR/TORC1, a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer is unknown. Methods: We conducted a single arm trial of weekly IV temsirolimus in men with chemorefractory metastatic CRPC who had >=5 circulating tumor cells (CTCs) at baseline (Cellsearch). The primary endpoint was change in CTCs at 8 weeks; secondary endpoints were composite progression-free survival (excluding PSA), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. Results: Eleven patients were accrued out of a planned 20; the trial was stopped prematurely due to lack of efficacy/feasibility. Median age was 61, with 55% African-Americans and 36% Caucasians. Median baseline PSA was 390 ng/dl, median baseline CTC was 14 cells, 50% had significant pain, and 63% had >2 prior chemotherapy regimens. The median decline in CTC enumeration at week 8 was 48% and three patients experienced a decline in CTCs to <5. However, 73% of men had persistently unfavorable CTCs (>=5) over time and only 1 patient had a >=30% PSA decline. Median PFS was 1.9 months (95% CI 0.9-3.1) and median OS was 8.8 months (95% CI 3.1-15.6). Toxicities included grade 4 hypophosphatemia and grade 4 CNS hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Persistently high N-cadherin expression on longitudinal CTC analysis was observed as a marker of epithelial plasticity and treatment resistance. Conclusions: Temsirolimus lacked sufficient clinical activity in men with metastatic CRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors. Clinical trial information: NCT00887640.