A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer

Purpose: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (GþC) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. Patients and Methods: Patients received either GþC (guadecitabine 30 mg/m² s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). Results: Of 100 patients treated, 51 received GþC and 49 received TC, of which 27 crossed over to GþC. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the GþC and TC groups, respectively; P ¼ 0.07). However, the 6-month PFS rate was significantly higher in the GþC group (37% vs. 11% in TC group; P ¼ 0.003). The incidence of grade 3 or higher toxicity was similar in GþC and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the GþC group. Conclusions: Although this trial did not show superiority for PFS of GþC versus TC, the 6-month PFS increased in GþC treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.