Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males

Abstract

Context: TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment.

Objective: The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone.

Design, setting, and participants: This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers.

Interventions: Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years.

Main outcome measures: Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone.

Results: Oral TAK-385 was readily absorbed, and steady state was reached in ≤ 14 days. Food reduced TAK-385 systemic exposure by 47-52%. Mean serum testosterone levels declined ≤ 6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥ 7 to <3 days. TAK-385 doses ≥ 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤ 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤ 2).

Conclusions: Oral TAK-385 (40-180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone-sensitive prostate cancer are 80 and 120 mg/d.

Figures

Figure 1.

Study design.

Figure 2.

Mean plasma concentration-time profiles of TAK-385. A, Semilogarithmic plot of the mean (+SD) concentration-time profiles from subjects in Part 2 who received daily doses of TAK-385 for 14 days. B, Semilogarithmic plot of the mean (+ SD) concentration-time profiles from subjects in Parts 3 and 3a who received daily doses of TAK-385 for 28 days.

Figure 3.

Mean (+ SD) serum concentration-time profiles of testosterone. A and B, Data from subjects who received single (A) or multiple (B) doses of TAK-385 or placebo in Parts 1 and 2, respectively. C and D, Data from subjects who received multiple doses of TAK-385 or placebo for 28 days in Parts 3 and 3a, respectively. Dashed and solid lines represent medical castration levels of 1.73 and 0.69 nmol/L, respectively. Note: All testosterone values for Figure 3 were measured by LC/MS/MS, with the upper range of the standard assay curve (ULQ) of 3000 pg/mL (10.4 nmol/L). All baseline values above 10.4 nmol/L (3000 pg/ml) were thus set to the ULQ.