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Testing for homologous recombination deficiency – does it provide new insights for the use of veliparib?

      In the last decade treatment of ovarian cancer has shifted from a ‘one size fits all’ approach to biologically determined treatment options. This has been driven by an understanding of the importance of BRCA mutations to predict the benefit of PARP inhibitor treatment. Mutations in the BRCA gene, whether germline or somatic are found in about 20–25% of women with high grade ovarian cancers. During the early PARP inhibitor studies with olaparib, it became clear that non-BRCA-related mechanisms may also be responsible for defects in the DNA homologous recombination repair pathway which are key to successful PARP inhibitor activity. An improvement in progression-free survival (PFS) after a recurrence was also seen in women with BRCA wild-type tumours when maintenance therapy with PARP inhibitors was used following a response to platinum-based therapy [
      • Ledermann J.
      • Harter P.
      • Gourley C.
      • Friedlander M.
      • Vergote I.
      • Rustin G.
      • et al.
      Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
      ]. The hallmark of activity is HR deficiency (HRD) and is present in approximately 50% patients with high grade serous cancers [
      • Konstantinopoulos P.A.
      • Ceccaldi R.
      • Shapiro G.I.
      • D'Andrea A.D.
      Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer.
      ]. However, in recurrent ovarian cancer HRD has been a less useful discriminant of PARP inhibitor benefit than a response to platinum-based therapy [
      • Coleman R.L.
      • Oza A.M.
      • Lorusso D.
      • Aghajanian C.
      • Oaknin A.
      • Dean A.
      • et al.
      Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Mirza M.R.
      • Monk B.J.
      • Herrstedt J.
      • Oza A.M.
      • Mahner S.
      • Redondo A.
      • et al.
      Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
      ]. Consequently, PARP inhibitors are licensed for maintenance treatment in recurrent ovarian cancer after a response to platinum-based therapy, irrespective of BRCA status [
      • Mirza M.R.
      • Pignata S.
      • Ledermann J.A.
      Latest clinical evidence and further development of PARP inhibitors in ovarian cancer.
      ]. Ovarian cancer research has now shifted to explore PARP inhibitor maintenance therapy in the first-line setting.
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