Optimization of trial design and dose selection based on the quantitative assessment of the efficacy of TAK-385, an investigational, oral GnRH antagonist, in patients with prostate cancer

Aims: To select a dose for confirmatory trials using prospective simulations based on a PK/PD model of testosterone (T) suppression with the non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist TAK-385, resulting in >90% of patients with Testosterone ≤ 50 ng/dL (medical castration) for 48 weeks.

Methods: Pharmacokinetic (PK) and Testosterone (T) data were obtained from 3 phase I/II clinical trials. In total, 104 healthy males and 174 prostate cancer patients contributed 2465 PK and 3445 T observations, after treatment with various TAK-385 maintenance doses (40-160 mg daily) for up to max 48 weeks. A PK/PD model was developed using non-linear mixed-effects modelling in NONMEM V7.2.0 [1]. Simulations were performed to construct the exposure-effect curve, and predict the fraction of subjects with sustained T ≤ 50 ng/dL over a 48-week treatment period (80-120 mg OD, after a loading dose on day 1).

Results: A three-compartment model with first-order delayed absorption and first-order elimination and an exponential error model adequately described TAK-385 PK. T levels were described using a semi-mechanistic PK/PD model, which combined indirect response-based modelling of production and degradation processes (GnRH, testosterone) with competitive and reversible inhibition of endogenous GnRH binding by TAK-385, and down-regulation mechanisms of GnRH receptors. Age was included as a covariate for the endogenous agonist (GnRH) concentration at baseline to account for different baseline T between healthy men and prostate cancer patients. Simulations showed that the proportion of patients with sustained medical castration reached a maximum at doses of 100 mg OD and above, with minimal added benefit beyond 120 mg OD. Higher doses were associated with a more robust T lowering response vs lower dose regimens, taking the 95% CI of expected responders into account. Large variability in PK and PD responses required a sufficiently high maintenance dose to ensure that >90% pts achieve and maintain T ≤ 50 ng/dL.

Conclusion: This analysis provided an integrated understanding of the relationships between TAK-385 dose, exposure and efficacy to inform trial design and decision-making in oncology drug development. A clinical trial of 610 patients receiving TAK-385 120 mg OD, which can produce a larger and consistent treatment effect, has a prospective power of >90%, even when allowing for a 15% dropout.


1. Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.