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

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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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