A Phase II Trial of Temsirolimus in Men With Castration-Resistant Metastatic Prostate Cancer

Given the highly prevalent molecular aberrations in phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3-kinase (PI3K) signaling in men with metastatic prostate cancer, we evaluated the target of rapamycin complex 1 (TORC1) inhibitor temsirolimus in a phase II trial of heavily pretreated men with metastatic castration-resistant disease. Given the low level of observed clinical activity in this trial, as measured by short clinical and radiographic progression-free survival (PFS) and overall survival (OS) times and uncommon improvements in prostate-specific antigen (PSA) levels or circulating tumor cell (CTC) levels, combination strategies addressing compensatory oncogenic pathways induced by PI3K blockade are suggested. Background: Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown. Methods: We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had >= 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [ 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 because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone >= 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (>= 5) and only 1 patient had a >= 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [ CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Conclusion: Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors.