Efficacy and safety exposure-response relationships of apalutamide in patients with metastatic castration-sensitive prostate cancer: results from the phase 3 TITAN study.

Apalutamide plus androgen-deprivation therapy (ADT) has been approved for treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on data from phase 3 TITAN study. This analysis was conducted to describe pharmacokinetics of apalutamide and N-desmethyl-apalutamide and explore relationships between apalutamide exposure and selected clinical efficacy and safety observations.

1052 patients were randomized to apalutamide + ADT (n = 525) or placebo + ADT (n = 527). A previously developed population pharmacokinetic model was applied. Cox regression analysis investigated the relationships between apalutamide exposure and overall survival (OS; n = 1004) and radiographic progression-free survival (rPFS; n = 1003). Logistic regression analysis assessed the relationships between apalutamide exposure and selected clinically relevant adverse events (n = 1051).

Apalutamide + ADT treatment was efficacious in extending rPFS and OS versus placebo + ADT. Within a relatively narrow apalutamide exposure range (coefficient of variation: 22%), no statistical association was detected between rPFS, OS and apalutamide exposure quartiles. Incidence of skin rash and pruritus increased significantly with increasing apalutamide exposure.

Differences in apalutamide exposure were not associated with clinically relevant differences in rPFS or OS in patients with mCSPC. Patients with increased apalutamide exposure are more likely to develop skin rash and pruritus. Dose reductions may improve these adverse events, based on an individual risk-benefit approach.

Cancer chemotherapy and pharmacology. 2022 Apr 02 [Epub ahead of print]

Huybrecht T'jollyn, Oliver Ackaert, Caly Chien, Angela Lopez-Gitlitz, Sharon McCarthy, Carlos Perez Ruixo, Lawrence Karsh, Kim Chi, Simon Chowdhury, Juan-Jose Perez Ruixo, Neeraj Agarwal

Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium., Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium. ., Clinical Pharmacology, Hutchison MediPharma International, Florham Park, NJ, USA., Janssen Research & Development, Los Angeles, USA., Janssen Research and Development, Raritan, NJ, USA., The Urology Center of Colorado, Denver, CO, USA., BC Cancer and Vancouver Prostate Centre, Vancouver, Canada., Guy's, King's, and St. Thomas' Hospitals and the Sarah Cannon Research Institute, London, UK., Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.

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