Pamiparib plus surufatinib with ctDNA monitoring in platinum-resistant ovarian cancer after PARP inhibitor progression: A phase Ib/II trial (POST-PARPi)

Background PARP inhibitors (PARPi) are standard front-line maintenance therapy for advanced ovarian cancer, but the efficacy of PARPi retreatment in later lines remains unclear. This phase Ib/II study evaluated the combination of pamiparib (a PARPi) and surufatinib (a small-molecule tyrosine kinase inhibitor) in platinum-resistant ovarian cancer patients who have progressed on or after prior PARPi treatment. Methods Eligible patients with platinum-resistant ovarian cancer and progression on or after prior PARPi treatment were enrolled. In phase Ib, a 3 + 3 design determined the recommended phase 2 dose (RP2D) of surufatinib in combination with pamiparib (40 mg twice daily). Surufatinib was administered starting at 250 mg once daily, with dose de-escalation if needed. After determining the RP2D, phase II enrollment commenced to assess antitumor activity. The primary endpoints were to establish the RP2D of surufatinib (phase Ib) and the 6-month progression-free survival (PFS) rate (phase II). Tumor tissue sequencing, homologous recombination deficiency (HRD) testing, and dynamic circulating tumor DNA (ctDNA) analysis were also performed. Results A total of 29 patients were enrolled. The RP2D of surufatinib was established at 250 mg once daily, with no dose-limiting toxicities (DLTs). As of the data cut-off (June 20, 2024), the median follow-up was 7.3 (range, 1.0–18.1) months. Two patients remained on treatment, while 27 had discontinued. The 6-month PFS rate was 46.7% (95% CI: 24.4–66.2), and the median overall survival was 14.7 (95% CI: 9.9–NE) months. The objective response rate was 8% in the efficacy evaluable set. Grade 3/4 treatment-related adverse events occurred in 37.9%, with thrombocytopenia (20.7%), and anemia (17.2%) being the most common. No significant difference in PFS was found between BRCA-mutant and wild-type patients, or HRD-positive and HRD-negative tumors. At cycle 7, day 1 (C7D1), ctDNA concentrations were significantly higher in patients who progressed within 6 months (P = 0.05). Patients with ctDNA partial response (CPR) at C3D1 and C7D1 had significantly longer PFS (P = 0.05 and P = 0.01, respectively). Conclusions The combination of pamiparib and surufatinib demonstrated modest yet clinically meaningful antitumor activity with manageable toxicities in platinum-resistant ovarian cancer patients who had progressed on or after prior PARPi treatment. CtDNA may serve as a valuable biomarker for predicting treatment outcomes, warranting further validation in larger studies.