Phase 1/2 Trial of Orteronel (TAK-700) - an Investigational 17,20-Lyase Inhibitor - in Patients with Metastatic Castration-Resistant Prostate Cancer
Mené sur 26 et 97 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cet essai de phase I/II évalue la toxicité et l'activité antitumorale d'un composé appelé orteronel, un inhibiteur d'une enzyme impliquée dans la production des androgènes, en combinaison avec la prednisone
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.