A Phase II Trial to Evaluate the Efficacy of Bortezomib and Liposomal Doxorubicin in Patients With BRCA Wild-type Platinum-resistant Recurrent Ovarian Cancer (KGOG 3044/EBLIN).

BACKGROUND/AIM: The majority of targeted therapies are focused on BRCA mutations, homologous recombination repair deficiency, and BRCA wild-type platinum-sensitive recurrent ovarian cancer. There is a growing need for platinum-resistant patients without BRCA mutations. Herein, we conducted a phase II multicenter study evaluated the efficacy and safety of bortezomib plus pegylated liposomal doxorubicin (PLD) in patients with BRCA wild-type platinum-resistant recurrent ovarian cancer (NCT03509246).

PATIENTS AND

METHODS

Ovarian cancer patients with wild-type BRCA who experienced platinum-resistant recurrence after three or less prior treatment cycles from three Institutions were included. All patients received bortezomib, 1.3 mg/m2 subcutaneously (days 1, 4, 8, and 11), and PLD, 40 mg/m2 intravenously (day 4), every 4 weeks. The primary endpoint was best objective response rate (ORR), and secondary endpoints included disease control rate, progression-free survival (PFS), overall survival, and safety. Targeted sequencing was performed to evaluate biomarkers and their potential association with response to treatment.

RESULTS

The trial was terminated after 23 patients were recruited because of slow accrual. The median follow-up was 29.5 months. The overall ORR was 8.7% (2/23); partial response was observed in two patients. The median duration of response was 10.5 months, and median PFS was 2.9 months. Treatment-related adverse events (TRAEs) of grade 3/4 were reported in 43.5% of patients. One patient who exhibited TRAEs discontinued treatment. However, grade 4/5 TRAEs were not observed. Mutations in TP53 and CDK12 were detected in 67% (14/21) and 24% (12/21) of patients, respectively. Two patients with partial response harbored mutations in genes related to homologous recombination repair deficiency, including BRCA2, ATM, and CDK12.

CONCLUSION

The combination of bortezomib and PLD was well tolerated; however, antitumor activity was not sufficient to warrant further investigation in ovarian cancer.