Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID).

Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel.

ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status.

One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash.

The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 Dec 16 [Epub ahead of print]

Simon J Crabb, Gareth Griffiths, Ellice Marwood, Denise Dunkley, Nichola Downs, Karen Martin, Michelle Light, Josh Northey, Sam Wilding, Amy Whitehead, Emily Shaw, Alison J Birtle, Amit Bahl, Tony Elliott, Charlotte Westbury, Santhanam Sundar, Angus Robinson, Satinder Jagdev, Satish Kumar, Claire Rooney, Carolina Salinas-Souza, Christine Stephens, Vincent Khoo, Robert J Jones

Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom., University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom., Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom., Bristol Oncology and Haematology Centre, Bristol, United Kingdom., The Christie NHS Foundation Trust, Manchester, United Kingdom., Mount Vernon Cancer Centre, Northwood, United Kingdom., Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom., Royal Sussex County Hospital, Brighton, United Kingdom., Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom., Velindre Cancer Centre, Cardiff, United Kingdom., Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Early Oncology Clinical, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., The Royal Marsden NHS Foundation Trust, London, United Kingdom., University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.

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