S'abonner

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial - 02/07/18

Doi : 10.1016/S1470-2045(18)30365-6 
Noel Clarke, ProfChM a, , Pawel Wiechno, MD b, Boris Alekseev, ProfMD c, Nuria Sala, MD d, Robert Jones, MRCP e, Ivo Kocak, MD f, Vincenzo Emanuele Chiuri, MD g, Jacek Jassem, ProfMD h, Aude Fléchon, MD i, Charles Redfern, MD j, Carsten Goessl, MD k, Joseph Burgents, PhD k, Robert Kozarski, PhD l, Darren Hodgson, PhD m, Maria Learoyd, PhD l, Fred Saad, ProfMD FRCS n
a The Christie and Salford Royal Hospitals, Manchester, UK 
b Maria Skłodowska-Curie Memorial Cancer Centre, Warsaw, Poland 
c Hertzen Moscow Cancer Research Institute, Moscow, Russia 
d Catalan Institute of Oncology, Hospital Josep Trueta, Girona, Spain 
e Velindre Cancer Centre, Cardiff University, Cardiff, UK 
f Masaryk Memorial Cancer Institute, Brno, Czech Republic 
g Ospedale Vito Fazzi, Lecce, Italy 
h Medical University of Gdańsk, Gdańsk, Poland 
i Centre Léon Bérard, Lyon, France 
j Sharp HealthCare, San Diego, CA, USA 
k AstraZeneca, Gaithersburg, MD, USA 
l AstraZeneca, Cambridge, UK 
m AstraZeneca, Macclesfield, UK 
n Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada 

* Correspondence to: Prof Noel Clarke, Department of Surgery, Christie NHS Foundation Trust, Manchester M20 4BX, UK Department of Surgery Christie NHS Foundation Trust Manchester M20 4BX UK

Summary

Background

Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status.

Methods

We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients.

Findings

Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8–20·4) with olaparib and abiraterone and 8·2 months (5·5–9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44–0·97, p=0·034). The most common grade 1–2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group.

Interpretation

Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer.

Funding

AstraZeneca.

Le texte complet de cet article est disponible en PDF.

Plan


© 2018  Elsevier Ltd. Tous droits réservés.
Ajouter à ma bibliothèque Retirer de ma bibliothèque Imprimer
Export

    Export citations

  • Fichier

  • Contenu

Vol 19 - N° 7

P. 975-986 - juillet 2018 Retour au numéro
Article précédent Article précédent
  • Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study
  • Bo Jan Noordman, Manon C W Spaander, Roelf Valkema, Bas P L Wijnhoven, Mark I van Berge Henegouwen, Joël Shapiro, Katharina Biermann, Ate van der Gaast, Richard van Hillegersberg, Maarten C C M Hulshof, Kausilia K Krishnadath, Sjoerd M Lagarde, Grard A P Nieuwenhuijzen, Liekele E Oostenbrug, Peter D Siersema, Erik J Schoon, Meindert N Sosef, Ewout W Steyerberg, J Jan B van Lanschot, SANO study group, Michael Doukas, Nanda C Krak, Jan-Werner Poley, Caroline M van Rij, Jaques JGHM Bergman, Suzanne S Gisbertz, Hanneke WM van Laarhoven, Sybren L Meijer, Lucas Goense, Nadia Haj Mohammad, Monique GG Hobbelink, G Johan A Offerhaus, Frank Vleggaar, Wouter L Curvers, Geert-Jan Creemers, Mark J Roef, Maurice JC van der Sangen, Jeroen Buijsen, Robert G Riedl, Wendy MJ Schreurs, Fabienne ARM Warmerdam, MJR Janssen, Chella van der Post, Sandra A Radema, Camiel Rosman, Heidi Rütten
| Article suivant Article suivant
  • Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial
  • Gunter von Minckwitz, Marco Colleoni, Hans-Christian Kolberg, Serafin Morales, Patricia Santi, Zorica Tomasevic, Nan Zhang, Vladimir Hanes

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

Mon compte


Plateformes Elsevier Masson

Déclaration CNIL

EM-CONSULTE.COM est déclaré à la CNIL, déclaration n° 1286925.

En application de la loi nº78-17 du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés, vous disposez des droits d'opposition (art.26 de la loi), d'accès (art.34 à 38 de la loi), et de rectification (art.36 de la loi) des données vous concernant. Ainsi, vous pouvez exiger que soient rectifiées, complétées, clarifiées, mises à jour ou effacées les informations vous concernant qui sont inexactes, incomplètes, équivoques, périmées ou dont la collecte ou l'utilisation ou la conservation est interdite.
Les informations personnelles concernant les visiteurs de notre site, y compris leur identité, sont confidentielles.
Le responsable du site s'engage sur l'honneur à respecter les conditions légales de confidentialité applicables en France et à ne pas divulguer ces informations à des tiers.


Tout le contenu de ce site: Copyright © 2024 Elsevier, ses concédants de licence et ses contributeurs. Tout les droits sont réservés, y compris ceux relatifs à l'exploration de textes et de données, a la formation en IA et aux technologies similaires. Pour tout contenu en libre accès, les conditions de licence Creative Commons s'appliquent.