DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Joaquin Mateo; Suzanne Carreira; Shahneen Sandhu; Susana Miranda; Helen Mossop; Raquel Perez-Lopez; Daniel Nava Rodrigues; Dan Robinson; Aurelius Omlin; Nina Tunariu; Gunther Boysen; Nuria Porta; Penny Flohr; Alexa Gillman; Ines Figueiredo; Claire Paulding; George Seed; Suneil Jain; Christy Ralph; Andrew Protheroe; Syed Hussain; Robert Jones; Tony Elliott; Ursula McGovern; Diletta Bianchini; Jane Goodall; Zafeiris Zafeiriou; Chris T Williamson; Roberta Ferraldeschi; Ruth Riisnaes; Bernardette Ebbs; Gemma Fowler; Desamparados Roda; Wei Yuan; Yi-Mi Wu; Xuhong Cao; Rachel Brough; Helen Pemberton; Roger A'Hern; Amanda Swain; Lakshmi P Kunju; Rosalind Eeles; Gerhardt Attard; Christopher J Lord; Alan Ashworth; Mark A Rubin; Karen E Knudsen; Felix Y Feng; Arul M Chinnaiyan; Emma Hall; Johann S de Bono

doi:10.1056/NEJMoa1506859

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Joaquin Mateo, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues, Dan Robinson, Aurelius Omlin, Nina Tunariu, Gunther Boysen, Nuria Porta, Penny Flohr, Alexa Gillman, Ines Figueiredo, Claire Paulding, George Seed, Suneil Jain, Christy Ralph, Andrew ProtheroeSyed Hussain, Robert Jones, Tony Elliott, Ursula McGovern, Diletta Bianchini, Jane Goodall, Zafeiris Zafeiriou, Chris T Williamson, Roberta Ferraldeschi, Ruth Riisnaes, Bernardette Ebbs, Gemma Fowler, Desamparados Roda, Wei Yuan, Yi-Mi Wu, Xuhong Cao, Rachel Brough, Helen Pemberton, Roger A'Hern, Amanda Swain, Lakshmi P Kunju, Rosalind Eeles, Gerhardt Attard, Christopher J Lord, Alan Ashworth, Mark A Rubin, Karen E Knudsen, Felix Y Feng, Arul M Chinnaiyan, Emma Hall, Johann S de Bono

Research output: Contribution to journal › Article › peer-review

1759 Citations (Scopus)

286 Downloads (Pure)

Abstract

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.

RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.

CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

Original language	English
Pages (from-to)	1697-1708
Number of pages	12
Journal	New England Journal of Medicine
Volume	373
Issue number	18
DOIs	https://doi.org/10.1056/NEJMoa1506859
Publication status	Published - 29 Oct 2015

Keywords

Adult
Aged
Anemia
Antineoplastic Agents
Ataxia Telangiectasia Mutated Proteins
DNA Repair
Drug Resistance, Neoplasm
Enzyme Inhibitors
Fatigue
Genes, BRCA2
Genes, Tumor Suppressor
Humans
Male
Middle Aged
Mutation
Neoplasm Metastasis
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Prostatic Neoplasms

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1056/NEJMoa1506859Licence: Unspecified

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer
© 2015 Massachusetts Medical Society. This work is made available online in accordance with the publisher’s policies. Please refer to any applicable terms of use of the publisher.
Final published version, 872 KBLicence: Unspecified

Suneil Jain
- s.jainqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Patrick G Johnston Centre for Cancer Research
Person: Academic

Cite this

Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., Nava Rodrigues, D., Robinson, D., Omlin, A., Tunariu, N., Boysen, G., Porta, N., Flohr, P., Gillman, A., Figueiredo, I., Paulding, C., Seed, G., Jain, S., Ralph, C., ... de Bono, J. S. (2015). DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine, 373(18), 1697-1708. https://doi.org/10.1056/NEJMoa1506859

@article{cef1c2a1523c4143ad1e0e4617746da5,

title = "DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer",

abstract = "BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).",

keywords = "Adult, Aged, Anemia, Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, DNA Repair, Drug Resistance, Neoplasm, Enzyme Inhibitors, Fatigue, Genes, BRCA2, Genes, Tumor Suppressor, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Prostatic Neoplasms",

author = "Joaquin Mateo and Suzanne Carreira and Shahneen Sandhu and Susana Miranda and Helen Mossop and Raquel Perez-Lopez and {Nava Rodrigues}, Daniel and Dan Robinson and Aurelius Omlin and Nina Tunariu and Gunther Boysen and Nuria Porta and Penny Flohr and Alexa Gillman and Ines Figueiredo and Claire Paulding and George Seed and Suneil Jain and Christy Ralph and Andrew Protheroe and Syed Hussain and Robert Jones and Tony Elliott and Ursula McGovern and Diletta Bianchini and Jane Goodall and Zafeiris Zafeiriou and Williamson, {Chris T} and Roberta Ferraldeschi and Ruth Riisnaes and Bernardette Ebbs and Gemma Fowler and Desamparados Roda and Wei Yuan and Yi-Mi Wu and Xuhong Cao and Rachel Brough and Helen Pemberton and Roger A'Hern and Amanda Swain and Kunju, {Lakshmi P} and Rosalind Eeles and Gerhardt Attard and Lord, {Christopher J} and Alan Ashworth and Rubin, {Mark A} and Knudsen, {Karen E} and Feng, {Felix Y} and Chinnaiyan, {Arul M} and Emma Hall and {de Bono}, {Johann S}",

year = "2015",

month = oct,

day = "29",

doi = "10.1056/NEJMoa1506859",

language = "English",

volume = "373",

pages = "1697--1708",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "18",

}

Mateo, J, Carreira, S, Sandhu, S, Miranda, S, Mossop, H, Perez-Lopez, R, Nava Rodrigues, D, Robinson, D, Omlin, A, Tunariu, N, Boysen, G, Porta, N, Flohr, P, Gillman, A, Figueiredo, I, Paulding, C, Seed, G, Jain, S, Ralph, C, Protheroe, A, Hussain, S, Jones, R, Elliott, T, McGovern, U, Bianchini, D, Goodall, J, Zafeiriou, Z, Williamson, CT, Ferraldeschi, R, Riisnaes, R, Ebbs, B, Fowler, G, Roda, D, Yuan, W, Wu, Y-M, Cao, X, Brough, R, Pemberton, H, A'Hern, R, Swain, A, Kunju, LP, Eeles, R, Attard, G, Lord, CJ, Ashworth, A, Rubin, MA, Knudsen, KE, Feng, FY, Chinnaiyan, AM, Hall, E & de Bono, JS 2015, 'DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer', New England Journal of Medicine, vol. 373, no. 18, pp. 1697-1708. https://doi.org/10.1056/NEJMoa1506859

TY - JOUR

T1 - DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

AU - Mateo, Joaquin

AU - Carreira, Suzanne

AU - Sandhu, Shahneen

AU - Miranda, Susana

AU - Mossop, Helen

AU - Perez-Lopez, Raquel

AU - Nava Rodrigues, Daniel

AU - Robinson, Dan

AU - Omlin, Aurelius

AU - Tunariu, Nina

AU - Boysen, Gunther

AU - Porta, Nuria

AU - Flohr, Penny

AU - Gillman, Alexa

AU - Figueiredo, Ines

AU - Paulding, Claire

AU - Seed, George

AU - Jain, Suneil

AU - Ralph, Christy

AU - Protheroe, Andrew

AU - Hussain, Syed

AU - Jones, Robert

AU - Elliott, Tony

AU - McGovern, Ursula

AU - Bianchini, Diletta

AU - Goodall, Jane

AU - Zafeiriou, Zafeiris

AU - Williamson, Chris T

AU - Ferraldeschi, Roberta

AU - Riisnaes, Ruth

AU - Ebbs, Bernardette

AU - Fowler, Gemma

AU - Roda, Desamparados

AU - Yuan, Wei

AU - Wu, Yi-Mi

AU - Cao, Xuhong

AU - Brough, Rachel

AU - Pemberton, Helen

AU - A'Hern, Roger

AU - Swain, Amanda

AU - Kunju, Lakshmi P

AU - Eeles, Rosalind

AU - Attard, Gerhardt

AU - Lord, Christopher J

AU - Ashworth, Alan

AU - Rubin, Mark A

AU - Knudsen, Karen E

AU - Feng, Felix Y

AU - Chinnaiyan, Arul M

AU - Hall, Emma

AU - de Bono, Johann S

PY - 2015/10/29

Y1 - 2015/10/29

N2 - BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

AB - BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

KW - Adult

KW - Aged

KW - Anemia

KW - Antineoplastic Agents

KW - Ataxia Telangiectasia Mutated Proteins

KW - DNA Repair

KW - Drug Resistance, Neoplasm

KW - Enzyme Inhibitors

KW - Fatigue

KW - Genes, BRCA2

KW - Genes, Tumor Suppressor

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neoplasm Metastasis

KW - Phthalazines

KW - Piperazines

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Prostatic Neoplasms

U2 - 10.1056/NEJMoa1506859

DO - 10.1056/NEJMoa1506859

M3 - Article

C2 - 26510020

SN - 0028-4793

VL - 373

SP - 1697

EP - 1708

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 18

ER -

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Profiles

Suneil Jain

Cite this