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Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study

Date

29 Sep 2019

Session

Poster Discussion – Genitourinary tumours, prostate

Presenters

Johann de Bono

Citation

Annals of Oncology (2019) 30 (suppl_5): v325-v355. 10.1093/annonc/mdz248

Authors

J.S. de Bono1, K. Fizazi2, F. Saad3, N. Shore4, S.K. Sandhu5, N. Mehra6, M. Kolinsky7, G. Roubaud8, M. Ӧzgüroǧlu9, N. Matsubara10, C. Gedye11, Y.D. Choi12, C. Padua13, C. Goessl14, A. Kohlmann15, C. Corcoran15, C.A. Adelman15, A. Allen14, J. Burgents16, M. Hussain17

Author affiliations

  • 1 Department Of Medical Oncology, The Institute of Cancer Research and Royal Marsden, SW7 3RP - London/GB
  • 2 Department Of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 94805 - Villejuif/FR
  • 3 Department Of Urology, Centre Hospitalier de l’Université de Montréal/CRCHUM, H2X 3J4 - Montreal/CA
  • 4 Department Of Medical Oncology, Carolina Urologic Research Center, 29572 - Myrtle Beach/US
  • 5 Division Of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne/AU
  • 6 Department Of Medical Oncology, Radboud University Medical Center, Nijmegen/NL
  • 7 Department Of Medical Oncology, University of Alberta Cross Cancer Institute, T6G 1Z2 - Edmonton/CA
  • 8 Department Of Medical Oncology, Institute Bergonié, 33076 - Bordeaux/FR
  • 9 Department Of Medical Oncology, Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul/TR
  • 10 Department Of Breast And Medical Oncology, National Cancer Center Hospital East, 104-0045 - Chiba/JP
  • 11 Department Of Medical Oncology, School of Medicine and Public Health, University of Newcastle, Callaghan/AU
  • 12 Department Of Medical Oncology, Yonsei University College of Medicine, Seoul/KR
  • 13 Department Of Medical Oncology, Cetus Medicina Oncológica, Betim/BR
  • 14 Drug Development Department, AstraZeneca, Gaithersburg/US
  • 15 Drug Development Department, AstraZeneca, Cambridge/GB
  • 16 Drug Development Department, Merck, Sharpe & Dohme NA, Kenilworth/US
  • 17 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 60611 - Chicago/US
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Resources

Abstract 5118

Background

A proportion of patients (pts) with mCRPC have tumour cells harbouring HRRm that may confer sensitivity to PARP inhibition. The PROfound study (NCT02987543) is a phase III, randomized, multicentre trial evaluating the efficacy and safety of the PARP inhibitor olaparib versus physician’s choice of enzalutamide or abiraterone acetate in pre-treated mCRPC pts with a qualifying HRRm. Here we report the prevalence of HRRm and co-occurring HRRm in pts screened for PROfound.

Methods

An investigational next-generation sequencing assay developed in partnership with Foundation Medicine Inc. (FMI) was used to prospectively select patients harbouring HRRm in their tumour tissue. This tumour tissue test reports deleterious or suspected deleterious alterations (‘qualifying mutations’) in 15 HRR genes. Tissue samples were clinically heterogenous regarding location and timing. Pts that had a qualifying mutation and who met the remaining eligibility requirements were randomized to the trial. The study comprised two cohorts; Cohort A: pts with mutations in BRCA1, BRCA2 or ATM (assigned regardless of any co-occurring mutation in other genes); Cohort B: 12 other HRR genes.

Results

Of 4426 screened pts, 4047 had samples tested at FMI, of whom 2793 (69%) yielded an interpretable result. A qualifying HRRm was detected in 778 (27.9%) pts and the prevalence of HRRm in genes included in Cohort A was 17.1%. A co-occurring qualifying HRRm alteration in ≥ 1 gene was detected in 59 (7.6%) patients, most commonly BRCA2 (n = 30), CDK12 (n = 24) or ATM (n = 13; Table).Table:

847PD

GeneNo. of patientsPrevalence in pts successfully tested, % (n = 2793)Prevalence in all HRRm-detected patients, % (n = 778)Co-occurring qualifying HRRm (no. of patients)
BRCA22729.735.0ATM (5); BARD1 (3); CDK12 (9); CHEK2 (7); PPP2R2A (6); RAD51B (1); RAD51C (1); RAD51D (1)
ATM1776.322.8BARD1 (1); BRCA1 (1); BRCA2 (5); CDK12 (2); CHEK2 (1); FANCL (1); PALB2 (1); PPP2R2A (1); RAD51B (2)
BRCA1351.34.5ATM (1); BARD1 (1); CDK12 (3); PPP2R2A (1); RAD54L (2)
CDK121997.125.6ATM (2); BARD1 (3); BRCA1 (3); BRCA2 (9); BRIP1 (1); CHEK1 (2); CHEK2 (3); PALB2 (2); PPP2R2A (2); RAD51B (1)
CHEK2441.65.7ATM (1); BRCA2 (7); CDK12 (3); RAD51D (1)
PPP2R2A411.55.3ATM (1); BRCA1 (1); BRCA2 (6); CDK12 (2); PALB2 (1); RAD54L (1)
PALB2150.51.9ATM (1); BRIP1 (1); CDK12 (2); PPP2R2A (1); RAD51D (1)
BRIP1140.51.8CDK12 (1); PALB2 (1)
RAD54L110.41.4BRCA1 (2); PPP2R2A (1)
BARD1110.41.4BRCA1 (1); BRCA2 (3); CDK12 (3)
RAD51B100.41.3ATM (2); BRCA2 (1); CDK12 (1)
RAD51D60.20.8BRCA2 (1); CHEK2 (1); PALB2 (1)
CHEK140.10.5CDK12 (2)
FANCL20.10.3ATM (1)
RAD51C10.040.1BRCA2 (1)
*

Pts with a mutation in more than one gene are re-counted for each co-occurring mutation

Conclusions

This is the largest study to date with central prospective HRRm tissue testing in prostate cancer. HRRm were most common in BRCA2, followed by ATM and CDK12. Further analyses are warranted to help understand if there is any correlation between clinical/demographic characteristics and HRRm.

Clinical trial identification

NCT02987543.

Editorial acknowledgement

Sarah Bulman, Mudskipper Business Ltd; funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).

Legal entity responsible for the study

AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Funding

AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Disclosure

J.S. de Bono: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: GSK; Licensing / Royalties, Abiraterone rewards to Inventors with royalties paid to institution, no personal income: Janssen Oncology; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Genmab, Orion Pharma, Qiagen, Taiho Pharma, Vertex; Licensing / Royalties, A patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income: N/A. K. Fizazi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AAA; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Curevac; Honoraria (self), Advisory / Consultancy: Essa; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Orion; Honoraria (self), Advisory / Consultancy: Sanofi. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen. N. Shore: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. S.K. Sandhu: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche Genentech; Research grant / Funding (institution): Endocyte. N. Mehra: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi. M. Kolinsky: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Novartis. M. Özgüroǧlu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Janssen; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel / Accommodation / Expenses: BMS. N. Matsubara: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (institution): Eisai. C. Gedye: Non-remunerated activity/ies: AbbVie, Astellas, Amgen, Bristol-Myers Squibb, AstraZeneca, Merck, Sharp & Dohme, Pfizer, Losen; Travel / Accommodation / Expenses: Astellas, Bristol-Myers Squibb, Merck, Sharp & Dohme. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Corcoran: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C.A. Adelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Burgents: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. M. Hussain: Honoraria (self): Sanofi/Genzyme; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self): Research to Practice; Honoraria (self): Aptitude Health; Honoraria (self): Epics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest.

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