Adavosertib in combination with carboplatin in advanced TP53-mutated platinum-resistant ovarian cancer.

person Alaa Embaby Department of Clinical Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands info_outline Alaa Embaby, Jill Jacqueline Geenen, Joachim Kutzera, Dick Pluim, Marta I. Lopez-Yurda, Jos H. Beijnen, Alwin Huitema, Petronella Witteveen, Neeltje Steeghs, Gijs van Haaften, Marcel A.T.M. van Vugt, Jeroen de Ridder, Frans Opdam

Authors person Alaa Embaby Department of Clinical Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands info_outline Alaa Embaby, Jill Jacqueline Geenen, Joachim Kutzera, Dick Pluim, Marta I. Lopez-Yurda, Jos H. Beijnen, Alwin Huitema, Petronella Witteveen, Neeltje Steeghs, Gijs van Haaften, Marcel A.T.M. van Vugt, Jeroen de Ridder, Frans Opdam Organizations Department of Clinical Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany, Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, Biometrics Department, Netherlands Cancer Institute, Amsterdam, Netherlands, Department of Pharmacy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, Department of Medical Oncology, Cancer Center University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands, Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands, Department of Medical Oncology, University Medical Center Groningen, Groningen, Netherlands, Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, Netherlands Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Ovarian cancer is globally the second most common cause of death among women with gynecologic malignancies. Despite high initial response rates, the overall prognosis of this patient population remains poor. The majority of advanced ovarian cancers will become platinum resistant defined by recurrence within six months after completion of platinum therapy. In the first part of the current phase II study, the combination of carboplatin and the Wee1 inhibitor adavosertib (AZD1775), showed to be safe and effective in patients with TP53 mutated platinum resistant ovarian cancer. The aim of this additional cohort is to gain more information about the safety and efficacy of the combination and to explore predictive biomarkers for resistance and response to adavosertib. Methods: In this additional cohort 29 evaluable were treated with carboplatin AUC 5 mg/ ml·min and adavosertib 225 mg BID for 2.5 days in a 21-day cycle. The anti-tumor activity was assessed according to RECIST 1.1. Pre-, on- and post-treatment biopsies were obtained to explore genetic determinants of drug resistance and response to adavosertib. Results: A total of 32 patients with a median age of 62 years (39-77 years) were enrolled in this cohort. All patients had carboplatin/paclitaxel as first line therapy. Six patients received a second-line non-platinum containing regimen. Median platinum free interval was 5.8 months (range 1.7 – 11.9). Twenty-nine patients were evaluable for efficacy. Grade 1-2 bone marrow toxicity, nausea, vomiting and fatigue were the most common adverse events. Dose reductions of carboplatin and/or adavosertib were made in 15/29 evaluable patients (52%). Dose delays occurred in the majority of patients (76%), mostly due to neutropenia and thrombocytopenia. Twelve patients showed PR as best response, resulting in an ORR of 38% in the intention-to-treat population (95% CI 21%-56%). The median PFS was 5.6 months (range 1.1-32 months, 95% CI 4.2-7.0) and median duration of response was 5.3 months (95% CI 0.13-10.5). Conclusions: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 in a 21-day cycle could be safely combined and shows promising anti-tumor efficacy in patients with platinum resistant ovarian cancer. Bone marrow toxicity remains the most common reason for dose reductions and dose delays. Translational biomarker results (CCNE1 analysis as potential predictive marker for response and resistance and WGS) to better understand the anti-tumor activity of the combination are pending. Clinical trial information: NCT01164995.