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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).
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; Jones, Robert J.
Afiliação
  • Crabb SJ; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Griffiths G; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Marwood E; Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
  • Dunkley D; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Downs N; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Martin K; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Light M; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Northey J; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Wilding S; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Whitehead A; Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
  • Shaw E; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Birtle AJ; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Bahl A; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Elliott T; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Westbury C; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Sundar S; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Robinson A; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Jagdev S; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Kumar S; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Rooney C; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Salinas-Souza C; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.
  • Stephens C; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Khoo V; University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  • Jones RJ; Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom.
J Clin Oncol ; 39(3): 190-201, 2021 01 20.
Article em En | MEDLINE | ID: mdl-33326257
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 (11) 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Pirróis / Prednisolona / Protocolos de Quimioterapia Combinada Antineoplásica / Inibidores de Proteínas Quinases / Proteínas Proto-Oncogênicas c-akt / Neoplasias de Próstata Resistentes à Castração / Docetaxel Tipo de estudo: Clinical_trials Limite: Aged / Aged80 / Humans / Male / Middle aged País como assunto: Europa Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Pirróis / Prednisolona / Protocolos de Quimioterapia Combinada Antineoplásica / Inibidores de Proteínas Quinases / Proteínas Proto-Oncogênicas c-akt / Neoplasias de Próstata Resistentes à Castração / Docetaxel Tipo de estudo: Clinical_trials Limite: Aged / Aged80 / Humans / Male / Middle aged País como assunto: Europa Idioma: En Ano de publicação: 2021 Tipo de documento: Article