A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration resistant prostate cancer
Mené sur 16 patients atteints d'un cancer de la prostate résistant à la castration et de stade métastatique, cet essai de phase I évalue la dose maximale tolérée du capivasertib (un inhibiteur d'AKT) en combinaison avec l'enzalutamide, et analyse les caractéristiques pharmacocinétiques et l'activité antitumorale de cette combinaison
Résumé en anglais
Background : Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss.
Patients and Methods: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320mg twice daily (bid) given 4-days on and 3-days off, in combination with enzalutamide 160mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose (MTD) and recommended phase II dose; pharmacokinetics, antitumor activity, and exploratory biomarker analysis were also evaluated.
Results : Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320mg bid, 400mg bid, and 480mg bid dose-levels of capivasertib. The recommended phase II dose (RP2D) identified for capivasertib was 400mg bid, with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 AE’s were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met criteria for response (defined as PSA decline ≥50%, CTC conversion and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in pERK in post-exposure samples.
Conclusions : The combination of capivasertib and enzalutamide is tolerable and has antitumor activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway.
