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A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.
Kolinsky, M P; Rescigno, P; Bianchini, D; Zafeiriou, Z; Mehra, N; Mateo, J; Michalarea, V; Riisnaes, R; Crespo, M; Figueiredo, I; Miranda, S; Nava Rodrigues, D; Flohr, P; Tunariu, N; Banerji, U; Ruddle, R; Sharp, A; Welti, J; Lambros, M; Carreira, S; Raynaud, F I; Swales, K E; Plymate, S; Luo, J; Tovey, H; Porta, N; Slade, R; Leonard, L; Hall, E; de Bono, J S.
Afiliação
  • Kolinsky MP; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK; Cross Cancer Institute, Edmonton, Canada.
  • Rescigno P; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK; Department of Clinical Medicine and Surgery, Department of Translational Medical Sciences, AOU Federico II, Naples, Italy.
  • Bianchini D; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Zafeiriou Z; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Mehra N; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Mateo J; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Michalarea V; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Riisnaes R; The Institute of Cancer Research, London, UK.
  • Crespo M; The Institute of Cancer Research, London, UK.
  • Figueiredo I; The Institute of Cancer Research, London, UK.
  • Miranda S; The Institute of Cancer Research, London, UK.
  • Nava Rodrigues D; The Institute of Cancer Research, London, UK.
  • Flohr P; The Institute of Cancer Research, London, UK.
  • Tunariu N; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Banerji U; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Ruddle R; The Institute of Cancer Research, London, UK.
  • Sharp A; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
  • Welti J; The Institute of Cancer Research, London, UK.
  • Lambros M; The Institute of Cancer Research, London, UK.
  • Carreira S; The Institute of Cancer Research, London, UK.
  • Raynaud FI; The Institute of Cancer Research, London, UK.
  • Swales KE; The Institute of Cancer Research, London, UK.
  • Plymate S; University of Washington School of Medicine, Seattle, USA.
  • Luo J; Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, USA.
  • Tovey H; The Institute of Cancer Research, London, UK.
  • Porta N; The Institute of Cancer Research, London, UK.
  • Slade R; The Institute of Cancer Research, London, UK.
  • Leonard L; The Institute of Cancer Research, London, UK.
  • Hall E; The Institute of Cancer Research, London, UK.
  • de Bono JS; The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK. Electronic address: johann.de-bono@icr.ac.uk.
Ann Oncol ; 31(5): 619-625, 2020 05.
Article em En | MEDLINE | ID: mdl-32205016
ABSTRACT

BACKGROUND:

Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND

METHODS:

mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated.

RESULTS:

Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples.

CONCLUSIONS:

The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER NCT02525068.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Humans / Male Idioma: En Revista: Ann Oncol Assunto da revista: NEOPLASIAS Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Humans / Male Idioma: En Revista: Ann Oncol Assunto da revista: NEOPLASIAS Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Canadá