Apatinib combined with pegylated liposomal doxorubicin (PLD) versus PLD for platinum-resistant recurrent ovarian cancer (APPROVE): a multicenter, randomized, controlled, open-label, phase II trial

Objectives: Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Methods: Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Conclusions: Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD. Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD.