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Antitumour Activity of the Parp Inhibitor Olaparib in Unselected Sporadic Castration-Resistant Prostate Cancer (Crpc) in the Toparp Trial
Annals of Oncology 25 (Supplement 5): v1–v41, 2014 doi:10.1093/annonc/mdu438.20
LBA20
J. Mateo1, E. Hall2, S. Sandhu1, A.G. Omlin1, S. Miranda3, S. Carreira3, J. Goodall3, A. Gillman2, H. Mossop2, C. Ralph4, Z. Zafeiriou1, R. Perez Lopez1, N. Tunariu1, R. Ferraldeschi3, D. Nava Rodrigues3, L.P. Kunju5, D. Robinson5, G. Attard1, A. Chinnaiyan5, J.S. de Bono1 1 Prostate Targeted Therapy Group, The Institute of Cancer Research and The Royal Marsden NHS Trust, London, UK 2 Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK 3 Cancer Biomarkers Group, The Institute of Cancer Research, London, UK 4 Medical Oncology, St James’s Institute of Oncology-Leeds University, Leeds, UK 5 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Aim: Next generation sequencing studies have identified defects in DNA repair machinery in 20-40% of sporadic castration resistant prostate cancer (CRPC) patients ( pt). We hypothesized that single agent PARP inhibition would have antitumour activity based on synthetic lethality in CRPC. Methods: An investigator initiated adaptive multi-part Phase II trial (TOPARP; CR-UK/11/029) was pursued to assess olaparib antitumour activity and identify
Table: LBA20. Response assessment (PSA, CTC count and radiological response) for the patients who achieved a response per protocol definition (10 out of 30, response rate 33%) Responder patient ID
Maximum PSA decline from baseline
Measurable disease at baseline
Best RECIST response (if measurable disease)
1 2 3 4 5 6 7 8 9 10
No decline 47.3% 94.6% 58.7% 80.1% 79.9% 29.3% 82.6% 51.2% No decline
Yes No Yes Yes No Yes Yes No No Yes
PD PR SD PR SD SD
Confirmed CTC conversion
Yes Yes Yes Yes Unconfirmed Yes Yes Yes Yes Yes
Baseline CTC count (cells/7.5ml blood)
6 38 8 22 87 18 105 102 24 38
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Maximum CTC decline from baseline 83.3% 94.7% 100% 100% 100% 100% 97.1% 100% 100% 100%
Time on treatment (weeks) (+: on-going) 12 62 24 36 + 42 + 36 17 39 32 + 12 +
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ANTITUMOUR ACTIVITY OF THE PARP INHIBITOR OLAPARIB IN UNSELECTED SPORADIC CASTRATION-RESISTANT PROSTATE CANCER (CRPC) IN THE TOPARP TRIAL
abstracts
genitourinary tumours, prostate
predictive biomarkers for response in CRPC. Part A is a 2-stage open labeled multi-centre study [ po = 0.05; p1= 0.20; α = 0.02; β = 0.10; 30/45 pt]. Olaparib dosing was with 400mg tablets BID continuously. The primary endpoint was response, defined as a confirmed radiological response (RECIST 1.1), confirmed PSA decline ≥50% and/or confirmed circulating tumour cells (CTC) count fall from ≥5 to <5/7.5ml blood. Paired tumour biopsies at screening and day 8-28 of treatment were mandated for biomarker studies, including exome, transcriptome and functional DNA repair studies. Results: Preliminary results are available for the first stage after 30 pt have been evaluated for the primary endpoint. Prior lines of treatment include docetaxel (n = 30, 100%), cabazitaxel (17, 57%), abiraterone (29, 97%) and enzalutamide (5, 17%). CRPC biopsies for biomarker studies were acquired from bone marrow (17), nodal/soft tissue disease (10) or visceral metastasis (3). The most common grade > 3 adverse events (AE) were anaemia (6, 20%) and fatigue (3, 10%). Olaparib was well tolerated; 6 (20%) pt required a dose reduction, with no permanent discontinuations due to drug-related AEs. Response rate was 33% (10/30 pt, Table 1). Median time on treatment for responding pt was 6.9 months (range 2.8m-14.4m). Somatic cell exome and transcriptome analyses have identified loss of function of genes involved in DNA repair including BRCA2 and ATM among the responding patients. Conclusions: Olaparib has antitumour activity in sporadic mCRPC with DNA repair defects; multiple durable responses have led to continuation to the next stage of this trial, which is nearing completion. Disclosure: A.G. Omlin: has served as advisor for Astra-Zeneca; J.S. de Bono: has served as paid advisor for Astra-Zeneca. All other authors have declared no conflicts of interest.
LBA20
J. Mateo1, E. Hall2, S. Sandhu1, A.G. Omlin1, S. Miranda3, S. Carreira3, J. Goodall3, A. Gillman2, H. Mossop2, C. Ralph4, Z. Zafeiriou1, R. Perez Lopez1, N. Tunariu1, R. Ferraldeschi3, D. Nava Rodrigues3, L.P. Kunju5, D. Robinson5, G. Attard1, A. Chinnaiyan5, J.S. de Bono1 1 Prostate Targeted Therapy Group, The Institute of Cancer Research and The Royal Marsden NHS Trust, London, UK 2 Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK 3 Cancer Biomarkers Group, The Institute of Cancer Research, London, UK 4 Medical Oncology, St James’s Institute of Oncology-Leeds University, Leeds, UK 5 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Aim: Next generation sequencing studies have identified defects in DNA repair machinery in 20-40% of sporadic castration resistant prostate cancer (CRPC) patients ( pt). We hypothesized that single agent PARP inhibition would have antitumour activity based on synthetic lethality in CRPC. Methods: An investigator initiated adaptive multi-part Phase II trial (TOPARP; CR-UK/11/029) was pursued to assess olaparib antitumour activity and identify
Table: LBA20. Response assessment (PSA, CTC count and radiological response) for the patients who achieved a response per protocol definition (10 out of 30, response rate 33%) Responder patient ID
Maximum PSA decline from baseline
Measurable disease at baseline
Best RECIST response (if measurable disease)
1 2 3 4 5 6 7 8 9 10
No decline 47.3% 94.6% 58.7% 80.1% 79.9% 29.3% 82.6% 51.2% No decline
Yes No Yes Yes No Yes Yes No No Yes
PD PR SD PR SD SD
Confirmed CTC conversion
Yes Yes Yes Yes Unconfirmed Yes Yes Yes Yes Yes
Baseline CTC count (cells/7.5ml blood)
6 38 8 22 87 18 105 102 24 38
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Maximum CTC decline from baseline 83.3% 94.7% 100% 100% 100% 100% 97.1% 100% 100% 100%
Time on treatment (weeks) (+: on-going) 12 62 24 36 + 42 + 36 17 39 32 + 12 +
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/mdu438.20/1746470 by guest on 13 November 2018
ANTITUMOUR ACTIVITY OF THE PARP INHIBITOR OLAPARIB IN UNSELECTED SPORADIC CASTRATION-RESISTANT PROSTATE CANCER (CRPC) IN THE TOPARP TRIAL
abstracts
genitourinary tumours, prostate
predictive biomarkers for response in CRPC. Part A is a 2-stage open labeled multi-centre study [ po = 0.05; p1= 0.20; α = 0.02; β = 0.10; 30/45 pt]. Olaparib dosing was with 400mg tablets BID continuously. The primary endpoint was response, defined as a confirmed radiological response (RECIST 1.1), confirmed PSA decline ≥50% and/or confirmed circulating tumour cells (CTC) count fall from ≥5 to <5/7.5ml blood. Paired tumour biopsies at screening and day 8-28 of treatment were mandated for biomarker studies, including exome, transcriptome and functional DNA repair studies. Results: Preliminary results are available for the first stage after 30 pt have been evaluated for the primary endpoint. Prior lines of treatment include docetaxel (n = 30, 100%), cabazitaxel (17, 57%), abiraterone (29, 97%) and enzalutamide (5, 17%). CRPC biopsies for biomarker studies were acquired from bone marrow (17), nodal/soft tissue disease (10) or visceral metastasis (3). The most common grade > 3 adverse events (AE) were anaemia (6, 20%) and fatigue (3, 10%). Olaparib was well tolerated; 6 (20%) pt required a dose reduction, with no permanent discontinuations due to drug-related AEs. Response rate was 33% (10/30 pt, Table 1). Median time on treatment for responding pt was 6.9 months (range 2.8m-14.4m). Somatic cell exome and transcriptome analyses have identified loss of function of genes involved in DNA repair including BRCA2 and ATM among the responding patients. Conclusions: Olaparib has antitumour activity in sporadic mCRPC with DNA repair defects; multiple durable responses have led to continuation to the next stage of this trial, which is nearing completion. Disclosure: A.G. Omlin: has served as advisor for Astra-Zeneca; J.S. de Bono: has served as paid advisor for Astra-Zeneca. All other authors have declared no conflicts of interest.