PURPOSE: The androgen receptor pathway remains active in men with prostate cancer whose disease has progressed following surgical or medical castration.
Orteronel (TAK-700) is an investigational, oral, non-steroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones.
EXPERIMENTAL DESIGN: We conducted a phase 1/2 study in men with progressive, chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) and serum testosterone < 50 ng/dL. In the phase 1 part, patients received orteronel 100-600 mg twice-daily (BID) or 400 mg BID plus prednisone 5 mg BID. In phase 2, patients received orteronel 300 mg BID, 400 mg BID plus prednisone, 600 mg BID plus prednisone or 600 mg once-daily without prednisone.
RESULTS: In phase 1 (n = 26), no dose-limiting toxicities were observed and 13/20 evaluable patients (65%) achieved ≥50% prostate-specific antigen (PSA) decline from baseline at 12 weeks. In phase 2 (n = 97), 45/84 evaluable patients (54%) achieved a ≥50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (-7.5 ng/dL) and dehydroepiandrosterone-sulfate (DHEA-S; -45.3 μg/dL) were observed. Unconfirmed partial responses were reported in 10/51 evaluable phase 2 patients (20%). Decreases in circulating tumor cells were documented. Fifty-three percent of phase 2 patients experienced grade ≥3 adverse events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea.
CONCLUSIONS: 17,20-lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses.
Written by:
Dreicer R, Maclean D, Suri A, Stadler WM, Shevrin D, Hart L, Macvicar GR, Hamid O, Hainsworth J, Gross ME, Shi Y, Webb IJ, Agus DB. Are you the author?
Solid Tumor Oncology and Urology, Cleveland Clinic.
Reference: Clin Cancer Res. 2014 Jan 13. Epub ahead of print.
doi: 10.1158/1078-0432.CCR-13-2436
PubMed Abstract
PMID: 24418642
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