Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: results from the randomized phase II RE-AKT trial

Background PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. Methods This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160mg orally, once daily) with capivasertib (400mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥50% PSA decrease from baseline, or circulating tumor cell count conversion (from ≥5 at baseline to <5 cells/7·5 mL). Subgroup analyses by PTENIHC status were pre-planned. Results Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1%) enzalutamide/capivasertib and 9/48 (18.8%) enzalutamide/placebo (absolute difference 0.4% 90%CI -12.8 to 13.6, p=0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95%CI: 4.6-13.9] vs 14.8 months [95%CI: 10.8-18]; p =0.02). Most common treatment-emergent grade≥3 adverse events for the combination were diarrhea (13% vs 2%) and fatigue (10% vs 6%). Conclusions Combined capivasertib/enzalutamide was well tolerated but didn’t significantly improve outcomes from abiraterone pre-treated mCRPC.