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

Abstract

Summary 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/m2 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 radio-graphic 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.

Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer?

“…For these eight successful phase 3 trials, there were nine preceding phase 2 trials [44][45][46][47][48][49][50][51][52]. For the 23 failed phase 3 trials there were 20 preceding phase 2 trials [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] (Table 1b). Trials were published from January 1994 to April 2017.…”

Chemotherapy in Prostate Cancer

“…Docetaxel has been combined with the Cyp17A inhibitor orteronel [55] and the antiandrogen enzalutamide [56]. Mateo et al [57] reported in abstract form that the combination of cabazitaxel and abiraterone after docetaxel and abiraterone separately had a 46 % PSA response rate and a 20 % partial response rate.…”

Physiologically based and population PK modeling in optimizing drug development: A predict–learn–confirm analysis

“…In this study, we present an application of PBPK modeling to a simpler system for orteronel, a drug that is primarily cleared by the kidneys (decreasing the impact of uncertainty in system parameters with respect to RI effects on metabolism) and has clinical data available for validation. Orteronel (TAK‐700) is an oral, nonsteroidal, reversible, selective 17,20‐lyase inhibitor that was, until recently, in development for the treatment of patients with metastatic castration‐resistant prostate cancer (mCRPC) . Data from a human radioactive carbon ( 14 C) mass balance and urine metabolite profiling study revealed that orteronel is predominantly cleared through renal excretion as the intact parent compound (unpublished data; Suri, A., Pusalkar, S., Li, Y., & Prakash, S. Clin.…”