A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Armstrong, AJ; Shen, T; Halabi, S; Kemeny, G; Bitting, RL; Kartcheske, P; Embree, E; Morris, K; Winters, C; Jaffe, T; Fleming, M; George, DJ

Published Date

  • December 2013

Published In

Volume / Issue

  • 11 / 4

Start / End Page

  • 397 - 406

PubMed ID

  • 23830964

Pubmed Central ID

  • 23830964

Electronic International Standard Serial Number (EISSN)

  • 1938-0682

Digital Object Identifier (DOI)

  • 10.1016/j.clgc.2013.05.007

Language

  • eng

Conference Location

  • United States