Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer
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Saeed Rafii1, Charlie Gourley2, Rajiv Kumar1, Elena Geuna1, Joo Ern Ang1, Tzyvia Rye2, Lee-May Chen3, Ronnie Shapira-Frommer4, Michael Friedlander5, Ursula Matulonis6, Jacques De Greve7, Amit M. Oza8, Susana Banerjee9, L. Rhoda Molife1, Martin E. Gore9, Stan B. Kaye1 and Timothy A. Yap1
1Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK
2University of Edinburgh Cancer Research UK Centre, Edinburgh, UK
3University of California San Francisco, San Francisco, CA, USA
4Sheba Medical Centre, Ramat Gan, Israel
5Prince of Wales Cancer Centre, Randwick, Australia
6Dana-Farber Cancer Institute, Boston, MA, USA
7Oncologisch Centrum UZ Brussel, Brussels, Belgium
8Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
9Gynae-Oncology Unit, Royal Marsden Hospital, London, UK
Timothy A. Yap, email: firstname.lastname@example.org
Keywords: PARP inhibitor, olaparib, BRCA, ovarian cancer, predictive biomarkers
Received: October 25, 2016 Accepted: February 22, 2017 Published: April 10, 2017
Background: The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib.
Results: 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib.
Methods: We conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib.
Conclusion: PTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity.
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