Ahmet Dirican, Professor of Medical Oncology at Medicana International İzmir Hospital, shared a post on X:
“Are DDR mutations really actionable?
The OLAPCO trial suggests the answer may often be no. Three strategies were evaluated:
- Olaparib monotherapy.
- Olaparib + ATR inhibitor (ceralasertib).
- Olaparib + AKT inhibitor (capivasertib)
Key notes for precision oncology:
- PARP inhibitors do not work across all tumors, even when DDR mutations are present.
- The tumor-agnostic strategy failed to deliver meaningful responses.
- Olaparib + ATR inhibitor (ceralasertib) showed signals of activity and may help overcome PARP resistance.
- Particularly interesting activity was observed in PARP-resistant BRCA-mutated ovarian cancer.
- Some ATM-mutated tumors showed remarkably durable responses with the olaparib + ceralasertib combination.
- With olaparib monotherapy, responses were seen in ATM-mutant prostate cancer and IDH1-mutant chondrosarcoma.
A key lesson: Genomic mutation ≠ functional DNA repair vulnerability.”
Title: Targeted therapy for DNA damage response and homologous recombination repair defects: The Olaparib Combinations trial
Authors: Deborah B. Doroshow, Geoffrey I. Shapiro, Khanh Do, Vicki L. Keedy, Haider Mahdi, Davendra P. S. Sohal, Navid Hafez, Patricia M. LoRusso, Michael Cecchini, Jeffrey Sklar, Peter Mortimer, Colin Glover, Jacqueline Moses, Juliane M. Jürgensmeier, Joseph P. Eder
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