Lynparza (olaparib)

PAOLA-1

PAOLA-1 study design:2

PAOLA-1 was a randomised, double-blind, international Phase III trial which was academically led, conducted by the GINECO group2

Please note: PFS2 was met in the ITT population, however data for other secondary endpoints are immature. *NED, complete or partial response; †In combination with, and as maintenance after, platinum-based chemotherapy; §Patient must have received prior to randomisation a minimum of 3 cycles of bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy. Only in case of interval debulking surgery, it is allowed to realise only 2 cycles of bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy.

BD=twice daily; BRCAm=BRCA mutation; CDx=companion diagnostic; FIGO=Fédération Internationale de Gynécologie et d’Obstétrique; GINECO=Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens; HGEOC=high grade epithelial ovarian cancer; HRD=homologous recombination deficiency; NED=no evidence of disease; OS=overall survival; PFS=progression-free survival; PFS2=progression-free survival 2; Q3W=every 3 weeks; QoL=quality of life; tBRCA=tumour BRCA

PAOLA-1 baseline characterstics:2

Baseline characteristics were well balanced between arms

*ECOG performance was missing for six patients in the Lynparza arm and four patients in the placebo arm.   †Other includes clear cell, undifferentiated and other histology. ‡ No evidence of disease was defined as no measurable or assessable disease after cytoreductive surgery plus no radiologic evidence of disease and a normal CA-125 level after chemotherapy. § Clinical complete response was defined as the disappearance of all measurable or assessable disease and normalization of CA-125 levels. ∬ Partial response was defined as radiologic evidence of disease, an abnormal CA-125 level, or both.

​1L=first-line; CA-125=cancer antigen 125; ECOG=EasternCooperative Oncology Group; FIGO=Fédération Internationale de Gynécologie et d’Obstétrique; tBRCA=tumour BRCA; tBRCAm=tumour BRCA mutation

PAOLA-1 pre-specified exploratory subgroup analysis: Lynparza + bevacizumab achieved a median PFS >3 years for HRD-positive women (including tBRCAm)2

Adapted from:Ray-Coquard I, et al. 2019

Note: Please interpret data around this exploratory endpoint with caution; this is not statistically significant.
Of the 48% of PAOLA-1 patients who were HRD-positive, 29% had a tBRCAm
*< 50% of events had occurred in the Lynparza + bevacizumab arm (data maturity 34%), therefore the median is currently unstable and is likely to increase with further follow-up2
HRD subgroups analysis should be regarded with caution and some potential statistical biases (selection bias, given that only 82% of the ITT population of PAOLA-1 had a conclusive HRD test; and imbalance bias, due to the randomisation not being stratified according to HRD status) should be taken into account. Although the BRCAm status was a stratification factor in the study, HRD status was not randomised. HRD analysis was a prespecified exploratory analysis and was not controlled for Type 1 error. HRD-positive is either tumour BRCA mutation and/or genomic instability score =42.
 
BRCAm = BRCA1/2-mutated; HRD =homologous recombination deficiency; tBRCAm = tumour BRCA1/2-mutated
 
  • Among the ~50% of patients in PAOLA-1 whose tumours were HRD-positive, as defined by the presence of a tBRCAm or high genomic instability, Lynparza + bevacizumab showed a median PFS of 37.2 months vs 17.7 months for placebo + bevacizumab; data maturity, 34%; HR=0.33 95% CI: 0.25, 0.452
    • There was a 67% reduction in risk of disease progression or death, with 66% of patients free of progression or death at 2 years in the Lynparza + bevacizumab arm vs. 29% for the placebo + bevacizumab arm2

PAOLA-1 pre-specified exploratory subgroup analysis: Lynparza + bevacizumab achieved a median PFS of 28.1 months in HRD-positive women without a tBRCAm (vs. 16.6 months for placebo)2

Adapted from:Ray-Coquard I, et al. 2019

Note: Please interpret data around this exploratory endpoint with caution; this is not statistically significant.
*<50% of events had occurred in the Lynparza + bevacizumab arm (data maturity 44%), therefore the median is currently unstable and is likely to increase with further follow-up
HRD subgroups analysis should be regarded with caution and some potential statistical biases (selection bias, given that only 82% of the ITT population of PAOLA-1 had a conclusive HRD test; and imbalance bias, due to the randomisation not being stratified according to HRD status) should be taken into account. Although the BRCAm status was a stratification factor in the study, HRD status was not randomised. HRD analysis was a prespecified exploratory analysis and was not controlled for Type 1 error. HRD-positive is either tumour BRCA mutation and/or genomic instability score ≥42.
 
BRCAm = BRCA1/2-mutated; HRD = homologous recombination deficiency; PFS=progression-free survival; tBRCAm = tumour BRCA1/2-mutated
 
  • Within the HRD-positive (excluding tBRCAm) subgroup, Lynparza + bevacizumab showed a median PFS of 28.1 months, vs 16.6 months for placebo + bevacizumab (data maturity, 44%; HR=0.43 95% CI: 0.28, 0.66)2
    • There was a 47% reduction in risk of disease progression or death, with 52% of patients free of progression or death at 2 years in the Lynparza + bevacizumab arm vs. 26% for the placebo + bevacizumab arm2

PAOLA-1 pre-specified exploratory subgroup analysis: Lynparza + bevacizumab achieved a median PFS >3 years in women with a tBRCAm2

Adapted from:Ray-Coquard I, et al. 2019

Note: Please interpret data around this exploratory endpoint with caution; this is not statistically significant.
*<50% of events had occurred in the Lynparza + bevacizumab arm (data maturity 26%), therefore the median is currently unstable and is likely to increase with further follow-up
HRD subgroups analysis should be regarded with caution and some potential statistical biases (selection bias, given that only 82% of the ITT population of PAOLA-1 had a conclusive HRD test; and imbalance bias, due to the randomisation not being stratified according to HRD status) should be taken into account. Although the BRCAm status was a stratification factor in the study, HRD status was not randomised. HRD analysis was a prespecified exploratory analysis and was not controlled for Type 1 error. HRD-positive is either tumour BRCA mutation and/or genomic instability score ≥42.
 
BRCAm = BRCA1/2-mutated; HRD = homologous recombination deficiency; PFS=progression-free survival; tBRCAm = tumour BRCA1/2-mutated
 
  • Within the tBRCAm subgroup, Lynparza + bevacizumab showed 94% and 74% of patients being progression-free at one and two years respectively.2
    • Median PFS in women with a tBRCAm was 37.2 months in the Lynparza + bevacizumab treatment group vs. 21.7 months for placebo + bevacizumab (data maturity, 26%; HR=0.31 95% CI: 0.20, 0.47)2
    • It should be noted that medium PFS of 37.2 months in the Lynparza + bevacizumab arm may be underestimated due to the low number of events (26% maturity)

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PAOLA-1: ~60% of women remained on the full recommended starting dose of Lynparza2

AE=adverse event

  • The majority of adverse events were managed by Lynparza dose modifications, rather than discontinuation2

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