A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration resistant prostate cancer.

Abstract 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.