PARP (Poly ADP‐Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer

Amelia M Taylor; David Lok Hang Chan; Martin Tio; Sujata M Patil; Tiffany A Traina; Mark E Robson; Mustafa Khasraw

doi:10.1002/14651858.CD011395.pub2

Cochrane Database of Systematic Reviews

Inhibidores de la PARP (poli ADP‐ribosa polimerasa) para el cáncer de mama localmente avanzado o metastásico

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DOI:

https://doi.org/10.1002/14651858.CD011395.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

22 abril 2021see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Cáncer de mama

Copyright:

Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Amelia M Taylor

Medical Oncology, Royal North Shore Hospital, Sydney, Australia
David Lok Hang Chan

Medical Oncology, Royal North Shore Hospital, Sydney, Australia

Faculty of Medicine and Health, Northern Clinical School, University of Sydney, Sydney, Australia
Martin Tio

Medical Oncology, Royal North Shore Hospital, Sydney, Australia
Sujata M Patil

Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA
Tiffany A Traina

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, USA
Mark E Robson

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, USA
Mustafa Khasraw

Correspondencia a: NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, Australia

[email protected]

[email protected]

Contributions of authors

Draft the protocol: MK, SMP, MR
Study selection: AT, DC, MT, MK
Extract data from studies: AT, DC, MK
Enter data into RevMan: AT, DC, MK
Carry out the analysis: AT, DC, MK
Interpret the analysis: AT, DC, MK
Draft the final review: AT, DC, MK, MR
Disagreement resolution: AT, DC, MT, SP, TT, MR, MK
Update the review: AT, DC, MT, SP, TT, MR, MK

Declarations of interest

Dr Taylor: none known.

Dr Tio: none known.

Dr Patil: none known.

Dr Chan: none related to this review topic. Dr Chan has received honoraria for preparing and delivering education work from Novartis and Ipsen; this activity is outside the scope of the submitted work. The drug companies listed do not appear to be associated with PARP inhibitors or chemotherapy drugs listed in this review.

Dr Traina: Dr Traina's institution has received research support for a distant phase 1 trial of olaparib in combination with platinum in metastatic breast cancer and a clinical trial of olaparib with durvalumab in metastatic triple‐negative breast cancer from AstraZeneca. Dr Traina reports consultancy or advisory roles for Genentech/Roche, Pfizer, AstraZeneca, Merck, Puma Biotechnology, Advaxis, Celgene, Innocrin Pharma, Genomic Health, Bristol‐Myers Squibb, Samsung, Athenex, Aduro Biotech, Halozyme, Daiichi Sankyo, Ionis and Seattle Genetics. Dr Traina's institution also received funding from Eisai, Pfizer, Novartis, Innocrin Pharma, AstraZeneca, Astellas Pharma, Immunomedics, Genentech/Roche, Daiichi Sankyo and Carrick Pharm; these consultancy activities relate to work outside the scope of the submitted work.

Dr Robson: Dr Robson's institution has received funding for an underlying trial related to this topic from AstraZeneca and for a PARP inhibitor studies from AbbVie, Biomarin, Medivation and Pfizer. Dr Robson reports financial support for investigator meetings, global principal investigator compensation and editorial assistance from AstraZeneca. Dr Robson reports advisory roles for Tesaro, AbbVie, Bayer Health, Pfizer, Daiichi‐Sankyo, Merck and Zenith Pharmaceuticals however this activity is outside the scope of the submitted work. Dr Robson conducts studies, unrelated to the scope of the submitted work, that receive funding from Merck and Pfizer where payments have been made to the institution.

Dr Khasraw: none related to this review topic. Dr Khasraw reports consultant or advisory roles for Ipsen, Bristol‐Myers Squibb, Roche, Janssen and Janssen; grants to the institution from AbbVie and Bristol‐Myers Squibb; educational presentations for AbbVie and Novartis; travel expenses for unrelated to activities listed from Roche. These roles relate to work outside the scope of the submitted work.

Declaration of potential conflict of interest by one of the peer‐reviewers:

Dr Andrew Redfern (peer‐reviewer) has served on advisory boards for Astra Zeneca and Pfizer and he is Principal Investigator on the Brightness trial exploring the use of veliparib in neoadjuvant TNBC treatment.

Acknowledgements

The authors would like to thank Melina Willson from the Cochrane Breast Cancer Group for her assistance and co‐ordinating this review.

We would also like to thank:

Clinical editor: Dr Alessandra Gennari, University of Eastern Pietmont, Novara, Italy
External clinical reviewer: Dr Andrew Redfern, Fiona Stanley Hospital and University of Western Australia
Consumer reviewer: Sara Whiting
Statistical editor: Professor Dianne O’Connell, Senior Epidemiologist, Methods Group Lead, Cancer Council NSW

Version history

Published

Title

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Authors

Version

2021 Apr 22

PARP (Poly ADP‐Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer

Review

Amelia M Taylor, David Lok Hang Chan, Martin Tio, Sujata M Patil, Tiffany A Traina, Mark E Robson, Mustafa Khasraw

https://doi.org/10.1002/14651858.CD011395.pub2

2014 Nov 26

Poly(ADP‐Ribose) Polymerase (PARP) Inhibitors for locally advanced or metastatic breast cancer

Protocol

Mustafa Khasraw, Sujata M Patil, Tiffany A Traina, Mark E Robson

https://doi.org/10.1002/14651858.CD011395

Differences between protocol and review

The authors initially stated they would perform subgroup analysis on line of therapy and performance status; however, these subgroups were not specifically reported on and the data were not available for analysis from any of the five studies. The authors also stated they would compare PARP inhibitors as monotherapy, maintenance therapy or in combination with chemotherapy and by their position in the breast cancer treatment paradigm (first‐line, second‐line or third‐line), as well as different PARP inhibitors. Of the five studies, three used veliparib, one used olaparib and one used talazoparib. Two studies compared single‐agent PARP inhibitors to chemotherapy as the control and three compared PARP inhibitor plus chemotherapy to chemotherapy alone. Given the small number of studies and the heterogeneity described, these aforementioned subgroup analyses were not able to be performed in a meaningful way.

Although not prespecified, we examined progression‐free survival outcomes for patients who had received prior platinum chemotherapy compared to those who had not as this is a clinically relevant distinction. We know that platinum results in improved first‐line response rate (Tutt 2018) in BRCA carriers and so it was useful to gain insight into whether those who had received platinum chemotherapy in prior lines of treatment would still gain benefit from PARP inhibitors.

The authors initially stated if there was evidence of substantial heterogeneity between studies, we would use a random‐effects model to account for heterogeneity. Otherwise, we would use a fixed‐effect model for the meta‐analysis. On further review, it was deemed this approach was inappropriate. Instead, fixed‐effect analysis was chosen a priori and used for all outcomes.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 PARPi‐containing regimen vs non‐PARPi regimen, outcome: 1.1 Overall survival

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Figure 4

Forest plot of comparison: 1 PARPi‐containing regimen vs non‐PARPi regimen, outcome: 1.2 Progression‐free survival

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Figure 5

Forest plot of comparison: 1 PARPi‐containing regimen vs non‐PARPi regimen, outcome: 1.3 Response rate

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Figure 6

Forest plot of comparison: 1 PARPi‐containing regimen vs non‐PARPi regimen, outcome: 1.4 Grade ≥ 3 AEs

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Analysis 1.1

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 1: Overall survival

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Analysis 1.2

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 2: Progression‐free survival

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Analysis 1.3

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 3: Progression‐free survival: BRCA

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Analysis 1.4

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 4: Progression‐free survival: receptor status

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Analysis 1.5

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 5: Progression‐free survival: prior chemo for advanced breast cancer

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Analysis 1.6

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 6: Progression‐free survival: prior platinum exposure

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Analysis 1.7

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 7: Response rate

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Analysis 1.8

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 8: Grade ≥ 3 adverse events

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Analysis 1.9

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 9: Neutropenia (any grade)

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Analysis 1.10

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 10: Anaemia (any grade)

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Analysis 1.11

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 11: Fatigue (any grade)

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Analysis 1.12

Comparison 1: PARPi‐containing regimen vs non‐PARPi regimen, Outcome 12: Thrombocytopenia (any grade)

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Summary of findings 1. PARPi‐containing regimen compared to non‐PARPi regimen for locally advanced or metastatic breast cancer

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
PARPi‐containing regimen compared to non‐PARPi regimen for locally advanced or metastatic breast cancer
Patient or population: locally advanced or metastatic breast cancer Setting: Intervention: PARPi‐containing regimen Comparison: non‐PARPi regimen
Outcomes	Risk with non‐PARPi regimen	Risk with PARPi‐containing regimen	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Overall Survival** follow up: 24 months	Study population		HR 0.84 (0.76 to 1.00)	1435 (4 RCTs)	⊕⊕⊕⊕ HIGH ^{1 2 3 4}
Overall Survival** follow up: 24 months	550 per 1,000	497 per 1,000 (446 to 550)	HR 0.84 (0.76 to 1.00)	1435 (4 RCTs)	⊕⊕⊕⊕ HIGH ^{1 2 3 4}
Progression Free Survival** follow up: 12 months	Study population		HR 0.63 (0.56 to 0.71)	1474 (5 RCTs)	⊕⊕⊕⊕ HIGH ^{1 3 5 6}
Progression Free Survival** follow up: 12 months	625 per 1,000	461 per 1,000 (423 to 502)	HR 0.63 (0.56 to 0.71)	1474 (5 RCTs)	⊕⊕⊕⊕ HIGH ^{1 3 5 6}
Response Rate	Study population		RR 1.39 (1.24 to 1.54)	1185 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 3 6 7}
Response Rate	489 per 1,000	695 per 1,000 (636 to 749)	RR 1.39 (1.24 to 1.54)	1185 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 3 6 7}
Grade ≥3 AEs	Study population		RR 0.98 (0.91 to 1.04)	1443 (5 RCTs)	⊕⊕⊕⊝ MODERATE ^{1 3 8 9}
Grade ≥3 AEs	645 per 1,000	620 per 1,000 (555 to 684)	RR 0.98 (0.91 to 1.04)	1443 (5 RCTs)	⊕⊕⊕⊝ MODERATE ^{1 3 8 9}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Given i) overall survival and progression‐free survival are continuous endpoints in clinical practice but ii) that continuous measures are not easily quantifiable (even if the HR is available), we opted to estimate the percentage of patients with this outcome (e.g. death) at a predefined time interval to practically estimate the size of treatment benefit for readers. We extrapolated this information from Kaplan‐Meier curves from the included studies. We started with the OS at 2 years, then subtracted this from 1 to arrive at incidence of death at 2 years and similarly for PFS at 1 year (BROCADE 2; BROCADE 3; EMBRACA; Kummar 2016; OLYMPIAD). CI: Confidence interval; HR: Risk ratio; OR:** Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ All studies mostly graded as low to unclear risk of bias. This is based on the scores from each domain including 3/5 studies which had high risk of bias in terms of performance bias due to being open‐label. Also, detection bias for adverse events (3/5 studies) were judged as having high risk of bias. Overall, judged as unclear but not serious risk of bias. ² I²=0%, indicating low heterogeneity. ³ No indirectness present. ⁴ 95% CI did not extend past HR of 1.0 and the total number of patients exceeded 400. ⁵ I²=2%, indicating low heterogeneity. ⁶ 95% CI excluded a HR of 1.0 and the total number of events exceeded 400. ⁷ Significant heterogeneity (I²=90%) without an obvious clinical explanation arising from differences in included trials. ⁸ Significant heterogeneity (I²=73%). ⁹ 95% CI crosses both 1 (the point of no effect) and 0.75 (the point of significantly reduced toxicity)

Summary of findings 1. PARPi‐containing regimen compared to non‐PARPi regimen for locally advanced or metastatic breast cancer

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Comparison 1. PARPi‐containing regimen vs non‐PARPi regimen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Overall survival Show forest plot	4	1435	Hazard Ratio (IV, Fixed, 95% CI)	0.87 [0.76, 1.00]

1.2 Progression‐free survival Show forest plot	5	1474	Hazard Ratio (IV, Fixed, 95% CI)	0.63 [0.56, 0.71]

1.3 Progression‐free survival: BRCA Show forest plot	4	1414	Hazard Ratio (IV, Fixed, 95% CI)	0.63 [0.55, 0.73]

1.3.1 BRCA 1	4	717	Hazard Ratio (IV, Fixed, 95% CI)	0.65 [0.53, 0.78]
1.3.2 BRCA 2	4	697	Hazard Ratio (IV, Fixed, 95% CI)	0.62 [0.51, 0.76]
1.4 Progression‐free survival: receptor status Show forest plot	4	1435	Hazard Ratio (IV, Random, 95% CI)	0.63 [0.54, 0.75]

1.4.1 Not triple negative	4	771	Hazard Ratio (IV, Random, 95% CI)	0.66 [0.53, 0.82]
1.4.2 Triple Negative	4	664	Hazard Ratio (IV, Random, 95% CI)	0.61 [0.47, 0.80]
1.5 Progression‐free survival: prior chemo for advanced breast cancer Show forest plot	4	1435	Hazard Ratio (IV, Fixed, 95% CI)	0.65 [0.57, 0.74]

1.5.1 Prior chemo	4	729	Hazard Ratio (IV, Fixed, 95% CI)	0.64 [0.53, 0.77]
1.5.2 No prior chemo	4	706	Hazard Ratio (IV, Fixed, 95% CI)	0.66 [0.55, 0.79]
1.6 Progression‐free survival: prior platinum exposure Show forest plot	3	1242	Hazard Ratio (IV, Fixed, 95% CI)	0.64 [0.55, 0.74]

1.6.1 Previous platinum	3	205	Hazard Ratio (IV, Fixed, 95% CI)	0.71 [0.50, 1.01]
1.6.2 No previous platinum	3	1037	Hazard Ratio (IV, Fixed, 95% CI)	0.63 [0.53, 0.73]
1.7 Response rate Show forest plot	5	1185	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [1.24, 1.54]

1.8 Grade ≥ 3 adverse events Show forest plot	5	1443	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.91, 1.04]

1.9 Neutropenia (any grade) Show forest plot	5	1443	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.60, 0.76]

1.10 Anaemia (any grade) Show forest plot	5	1443	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [1.04, 1.41]

1.11 Fatigue (any grade) Show forest plot	5	1443	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.78, 1.05]

1.12 Thrombocytopenia (any grade) Show forest plot	4	1147	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.84, 1.15]

Comparison 1. PARPi‐containing regimen vs non‐PARPi regimen

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Inhibidores de la PARP (poli ADP‐ribosa polimerasa) para el cáncer de mama localmente avanzado o metastásico

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