Novel WEE1 Inhibitor Increases Chemotherapy Efficacy in Ovarian Cancer

Adding the WEE1 inhibitor AZD1775 to carboplatin offered enhanced response rates in women with TP53-mutated ovarian cancer that was refractory or resistant to first-line platinum-based therapy in a phase II study.

“Despite initial therapy consisting of cytoreductive surgery and platinum-based chemotherapy, the majority of patients with epithelial ovarian cancer will experience relapse at some point in time,” wrote study authors led by Jan H. M. Schellens, MD, PhD, of the Netherlands Cancer Institute in Amsterdam. Inhibition of WEE1 in p53-deficient tumor cells was shown to improve response to chemotherapy in preclinical models.

The new study followed a phase I trial of AZD1775 that found a maximum tolerated dose along with carboplatin. The phase II study included 23 patients with TP53-mutated epithelial ovarian cancer, who had proven refractory or resistant to first-line platinum-based chemotherapy. The results were published in the Journal of Clinical Oncology.

The antitumor activity of the combination was assessed in 21 patients, as one patient’s TP53 mutation status could not be confirmed and one patient did not receive at least 2 cycles of the study treatment. Five patients (24%) showed progressive disease on the first evaluation, while seven patients (33%) experienced stable disease as their best response.

Eight patients (38%) had a partial response, and one patient (5%) had a complete response to the carboplatin-AZD1775 combination. This yielded an overall response rate of 43%; the complete response and one partial response lasted for extended periods (42 and 31 months, respectively). The median progression-free survival was 5.3 months, and median overall survival was 12.6 months.

The most common adverse events included bone marrow toxicity, fatigue (87%), diarrhea (70%), nausea (78%), and vomiting (48%). Dose reductions due to grade 4 thrombocytopenia and/or grade 2 to 4 neutropenia were required in 11 patients. Grade 3 hypomagnesemia occurred in 9% of patients, as did grade 3 anemia.

“Our study provides clinical evidence that AZD1775 enhances the antitumor efficacy of carboplatin in patients with TP53-mutated ovarian cancer resistant to first-line therapy and suggests that AZD1775 plus carboplatin may outperform first-line platinum-based chemotherapy in these patients,” the authors concluded. “On the basis of these encouraging results, further development starting with a randomized phase II or III study is warranted in this particular patient group and in other p53-deficient tumors to substantiate the true value of AZD1775.”