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Olaparib for Metastatic Castration-Resistant Prostate Cancer.

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Publication Date
2020-05
ICR Author
De Bono, Johann
Author
de Bono, J
Mateo, J
Fizazi, K
Saad, F
Shore, N
Sandhu, S
Chi, KN
Sartor, O
Agarwal, N
Olmos, D
Thiery-Vuillemin, A
Twardowski, P
Mehra, N
Goessl, C
Kang, J
Burgents, J
Wu, W
Kohlmann, A
Adelman, CA
Hussain, M
Type
Journal Article
Metadata
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Abstract
BACKGROUND:Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS:We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS:In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS:In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
URL
https://repository.icr.ac.uk/handle/internal/3836
Collections
  • Clinical Studies
Licenseref URL
http://www.rioxx.net/licenses/under-embargo-all-rights-reserved
Version of record
10.1056/nejmoa1911440
Subject
Humans
Neoplasm Metastasis
Phenylthiohydantoin
Piperazines
Phthalazines
Androstenes
Antineoplastic Agents
Genes, BRCA1
Genes, BRCA2
Aged
Aged, 80 and over
Middle Aged
Male
Ataxia Telangiectasia Mutated Proteins
Prostatic Neoplasms, Castration-Resistant
Poly(ADP-ribose) Polymerase Inhibitors
Loss of Function Mutation
Progression-Free Survival
Research team
Prostate Cancer Targeted Therapy Group
Language
eng
License start date
2020-05
Citation
The New England journal of medicine, 2020, 382 (22), pp. 2091 - 2102

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