High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy.
de Bono, JS
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Despite impressive clinical activity in patients with germlineBRCA1andBRCA2 (BRCA1/2)mutant cancers, antitumor responses to poly(ADP-Ribose) polymerase (PARP) inhibitors are variable. We set out to assess the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors, its correlation with patient outcomes, and the identification of factors associated with RDR. We retrospectively reviewed all patients with advanced cancers from five early phase PARP inhibitor monotherapy trials. 113 patients (ovarian cancers 57.5%; breast cancers 23.9%) were included in this retrospective study; 46 (40.7%) patients developed RDR on PARP inhibitor monotherapy. We identified two patterns of RDR: early RDR (1st or 2nd on-treatment scans) in 69.6% of patients, and late RDR (penultimate or final scans) in 30.4% of patients. Early RDR was associated with shorter time to progression (TTP) (225 vs 367 days, HR:0.59, 95%CI 0.36-0.98; p=0.04) and overall survival (OS) (499 vs 857 days; HR:0.47, 95%CI 0.27-0.82, p=0.006). Seventy-nine (69.9%) patients had known germlineBRCA1/2mutations; 49.4% of theseBRCA1/2mutation carriers developed RDR versus 20.6% of patients with unknown or wildtypeBRCA1/2status. Harboring germlineBRCA1/2mutations was independently predictive for RDR (RR:2.93, 95% CI 1.08-7.90, p=0.03). Patients with germlineBRCA1mutations had worse TTP and OS thanBRCA2mutation carriers (212 vs 406 days, HR:0.58, 95% CI 0.36-0.94, p=0.023 and 515 vs 937 days; HR:0.49, 95% CI 0.29-0.83; p=0.007). RDR with PARP inhibitors are frequent, particularly in germlineBRCA1/2mutation carriers. These findings have clinical implications for patient outcomes and may reflect underlying intrapatient genomic heterogeneity.
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BRCA1 and BRCA2 mutations
radiological differential responses
Medicine (de Bono Prostate)
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Oncotarget, 2017, 8 (61), pp. 104430 - 104443