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

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.

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 (160 mg orally, once daily) with capivasertib (400 mg)/ 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.

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 %).

Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

European journal of cancer (Oxford, England : 1990). 2024 May 08 [Epub ahead of print]

Pasquale Rescigno, Nuria Porta, Laura Finneran, Ruth Riisnaes, Ines Figueiredo, Suzanne Carreira, Penny Flohr, Susana Miranda, Claudia Bertan, Ana Ferreira, Mateus Crespo, Daniel Nava Rodrigues, Bora Gurel, Jenny Nobes, Simon Crabb, Zafar Malik, Christy Ralph, Ursula McGovern, Peter Hoskin, Robert J Jones, Alison Birtle, Joanna Gale, Peter Sankey, Suneil Jain, Duncan McLaren, Eliot Chadwick, Aude Espinasse, Emma Hall, Johann de Bono

The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK; Newcastle University, Newcastle upon Tyne, UK., The Institute of Cancer Research, London, UK., Norfolk & Norwich Hospital, Norwich, UK., University Hospital Southampton NHS Foundation Trust, Southampton, UK., The Clatterbridge Cancer Centre, Liverpool, UK., St James's University Hospital, Leeds, UK., University College Hospital, London, UK., Mount Vernon Cancer Centre, Northwood, UK., University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK., Rosemere Cancer Centre, Lancashire Teaching Hospitals, Preston, UK; University of Manchester, Manchester, UK; University of Central Lancashire, Preston, UK., Queen Alexandra Hospital, Portsmouth, UK., University Hospitals Plymouth, Plymouth, UK., Queen's University Belfast, Belfast, UK., Western General Hospital, Edinburgh, UK., Nottingham City Hospital, Nottingham, UK., The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: .