Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer.

Background: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. Results: In phase 1 ( n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 ( n = 23). After 4 cycles, 68, 59, and 23 % of patients achieved ≥30, ≥50, and ≥90 % PSA reductions, respectively; median best PSA response was −77 %. Seven of 10 (70 %) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78 %), alopecia (61 %), diarrhea (48 %), nausea (43 %), dysgeusia (39 %), and neutropenia (39 %). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. Conclusions: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses. [ABSTRACT FROM AUTHOR]

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