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

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

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

PATIENTS AND METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

1527-7755
JCO2001576
Crabb, Simon J
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Griffiths, Gareth
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Marwood, Ellice
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Dunkley, Denise
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Downs, Nichola
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Martin, Karen
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Light, Michelle
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Northey, Josh
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Wilding, Sam
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Whitehead, Amy
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Shaw, Emily
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Birtle, Alison J
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Bahl, Amit
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Elliott, Tony
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Westbury, Charlotte
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Sundar, Santhanam
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Robinson, Angus
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Jagdev, Satinder
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Kumar, Satish
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Rooney, Claire
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Salinas-Souza, Carolina
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Stephens, Christine
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Khoo, Vincent
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Jones, Robert J
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Crabb, Simon J
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Griffiths, Gareth
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Marwood, Ellice
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Dunkley, Denise
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Downs, Nichola
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Martin, Karen
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Light, Michelle
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Northey, Josh
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Wilding, Sam
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Whitehead, Amy
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Shaw, Emily
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Birtle, Alison J
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Bahl, Amit
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Elliott, Tony
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Westbury, Charlotte
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Sundar, Santhanam
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Robinson, Angus
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Jagdev, Satinder
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Kumar, Satish
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Rooney, Claire
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Salinas-Souza, Carolina
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Stephens, Christine
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Khoo, Vincent
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Jones, Robert J
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Crabb, Simon J, Griffiths, Gareth, Marwood, Ellice, Dunkley, Denise, Downs, Nichola, Martin, Karen, Light, Michelle, Northey, Josh, Wilding, Sam, Whitehead, Amy, Shaw, Emily, Birtle, Alison J, Bahl, Amit, Elliott, Tony, Westbury, Charlotte, Sundar, Santhanam, Robinson, Angus, Jagdev, Satinder, Kumar, Satish, Rooney, Claire, Salinas-Souza, Carolina, Stephens, Christine, Khoo, Vincent and Jones, Robert J (2020) Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). Journal of clinical oncology : official journal of the American Society of Clinical Oncology, JCO2001576. (doi:10.1200/JCO.20.01576).

Record type: Article

Abstract

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

PATIENTS AND METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

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Crabb (JCO 2020) ProCAID phase II - Version of Record
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Accepted/In Press date: 20 October 2020
e-pub ahead of print date: 16 December 2020

Identifiers

Local EPrints ID: 445663
URI: http://eprints.soton.ac.uk/id/eprint/445663
ISSN: 1527-7755
PURE UUID: 43c8c32d-2d22-4fba-a8bf-412db37af7d9
ORCID for Simon J Crabb: ORCID iD orcid.org/0000-0003-3521-9064
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021
ORCID for Karen Martin: ORCID iD orcid.org/0000-0002-6362-0501
ORCID for Sam Wilding: ORCID iD orcid.org/0000-0003-4184-2821

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Date deposited: 05 Jan 2021 17:33
Last modified: 17 Mar 2024 03:48

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Contributors

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

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