A phase I/II study of safety and efficacy of orteronel (TAK-700), an oral, investigational, nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC): Updated phase II results.

Abstract

59 Background: Orteronel is an investigational non-steroidal, selective inhibitor of 17,20-lyase, a key enzyme in the production of steroidal hormones. DP is currently an approved therapy in mCRPC; this phase 1/2 study examined orteronel + DP in men with mCRPC. Methods: Castrate men (testosterone [T] <50 ng/dL) with mCRPC, no prior chemotherapy and no ketoconazole/abiraterone received orteronel (400 mg BID) + D (75 mg/m2 q3w) + P (5 mg BID). The primary phase 2 objectives were tolerability, PK, serum PSA declines, and best PSA response. Secondary objectives included time to progression of PSA ± radiographic disease, response by RECIST 1.1. Results: At data cutoff (July 23, 2012), 24 men had been treated and 12 remained on study: median age was 66 yrs (n=24, range 53–87), ECOG PS 0/1 (88%/13%). At baseline, median PSA was 46 ng/mL (4.5–813) and T was 6.8 ng/dL (2.6–13.8). 9 men discontinued due to AEs (the most common was fatigue [13%]). All men reported at least 1 Gr ≥3 AE (23 were drug-related). Drug-related Gr ≥3 AEs ≥10% were neutropenia (38%); WBC decreased (25%); fatigue (21%); decreased neutrophil count (17%); blood alkaline phosphatase increased, and leukopenia (each 13%). The most common drug-related SAE was dehydration (13%). There were 2 on-study deaths, due to disease progression and respiratory distress, both considered unrelated to treatment. At 3 mo, PSA response was evaluable in 18 men; PSA30/50/90 rates were 83%/72%/28%. Best PSA decline (median) was -76% (n=23; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Response was evaluable in 9 men; 5 achieved a PR; ORR was 56% (n=9; 80% CI: 30, 79). Median time to PSA progression was 6.1 mo (95% CI: 4.6, not reached); median time to radiologic progression was not reached. The Cmax of orteronel + DP was similar to that of DP alone with no evidence of DDI. Conclusions: Orteronel 400 mg BID + DP appears tolerable and shows androgen-lowering activity, and strong PSA and partial tumor response in mCRPC. There was no evidence of DDI between orteronel and DP. Updated data, including a detailed PK analysis, will be presented. Clinical trial information: NCT01084655.

Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

“…A second phase I/II study (NCT01084655) was conducted to evaluate orteronel (200 mg or 400 mg given twice daily) in combination with docetaxel given every 3 weeks at 75 mg m −2 and prednisone 5 mg twice pre day, in patients with mCRPC 66. The combination was generally well-tolerated with no dose-limiting or unexpected toxicities reported.…”

Phase II Study of Single-Agent Orteronel (TAK-700) in Patients with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen

“…Whether concomitant steroids would have prevented some of the AEs that led to discontinuation of therapy is unclear. Data from other orteronel trials in different patient populations and disease settings showed rates of discontinuation due to AEs of 42% in a phase II study of orteronel plus docetaxel and prednisone in 24 patients with chemotherapy-na€ ve mCRPC (26), 21% overall in a phase I/II study of orteronel with or without prednisone in 123 patients with mCRPC, in which the discontinuation rates due to AEs were similar between the 2 treatment groups (27), and 26% in a phase III study of orteronel plus prednisone in 734 patients with mCRPC that progressed post-docetaxel treatment (28).…”

Orteronel for the Treatment of Prostate Cancer

“…Petrylak et al presented a Phase I study of docetaxel in combination with orteronel at the 2012 American Society of Clinical Oncology annual meeting [18]. In this study, orteronel was given b.i.d.…”

“…plus docetaxel/prednisone [19]. The primary end points were: safety, pharmacokinetics and PSA response.…”

“…In Phase I clinical studies, the only dose-limiting toxicity was grade 3 febrile neutropenia with orteronel 400 mg b.i.d. in combination with docetaxel chemotherapy [18]. In Phase II studies, the most common AEs were fatigue, nausea and constipation [18,20].…”