PARPInhibitors：UsurpingDNArepairtotargetcancer.ppt

Gem/Carbo (n = 59) BSI-201 + Gem/Carbo (n = 57) Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Nausea, n (%) 10 (16.9%) 2 (3.4%) 0 (0.0%) 7 (12.3%) 0 (0.0%) 0 (0.0%) Vomiting, n (%) 9 (15.3%) 0 (0.0%) 0 (0.0%) 4 (7.0%) 1 (1.8%) 0 (0.0%) Fatigue, n (%) 10 (16.9%) 6 (10.2%) 0 (0.0%) 10 (17.5%) 1 (1.8%) 0 (0.0%) Neuropathy, n (%) 2 (3.4%) 0 (0.0%) 0 (0.0%) 1 (1.8%) 0 (0.0%) 0 (0.0%) Diarrhea, n (%) 6 (10.2%) 1 (1.7%) 0 (0.0%) 1 (1.8%) 1 (1.8%) 0 (0.0%) Safety – Non-Hematologic ToxicityPhase II Gem Carbo +/- Iniparib O’Shaughnessy J, et al. NEJM 2011 Final Results:Phase II: Gem Carbo +/- Iniparib in TNBC O’Shaughnessy J et.al. NEJM 2011 Final Results:Phase II Gem Carbo +/- Iniparib in TNBC O’Shaughnessy J, et.al. NEJM 2011 Phase I: Olaparib + Paclitaxel in 1st and 2nd line MBC BKG: Olaparib single agent activity in BRCA 1/2 mutated MBC Olaparib + paclitaxel, N=19, 70% 1st line, unselected for BRCA mutations 33-40% RR; no CRs Median PFS: 5.2-6.3 months Hematologic toxicity high, requires G-CSF Dose reductions common Unclear whether combination be taken forward Resistance to PARP Inhibitors: Reversion of BRCA2 mutations Partial function of BRCA2 is restored and cells become competent for homologous recombination repair Edwards SL et al. Nature 2008; 451:1111-1115 The Future of PARP inhibitors: Many Unanswered Questions Can we use these agents more broadly? To treat other tumors with specific DNA repair defects, i.e. sporadic loss of BRCA 1/2, tumors with PTEN mutations Challenge is to identify them Timing of PARP inhibitor in relation to cytotoxic agent (before it, with it, how long to continue it?) Conclusions Targeting DNA repair mechanisms in tumor cells is a rational target PARP is an integral enzyme in DNA repair Multiple PARP inhibitors are available Preliminary results show activity in BRCA mutated cancers (Breast and Ovarian) Preliminary results show activity of iniparib with chemotherapy in TNBC Phase III results forthcoming *