Effectiveness and safety of niraparib as neoadjuvant therapy in advanced ovarian cancer with homologous recombination deficiency: NANT study protocol for a prospective, multicenter, exploratory, phase 2, single-arm study (041)

Abstract

Objectives: Neoadjuvant chemotherapy followed by interval debulking surgery did not achieve survival benefits compared to primary debulking surgery in advanced ovarian cancer. Niraparib is the only approved poly (ADP-ribose) polymerase inhibitor by the FDA to treat homologous recombination deficiency (HRD)-positive ovarian cancer patients with platinum-sensitive relapse after ≥ 3 lines of chemotherapy hitherto. We aimed to assess the efficacy and safety of neoadjuvant niraparib monotherapy in BRCAmut/HRD-positive patients with advanced unresectable ovarian cancer. Methods: This multi-center phase II single-arm study followed Simon’s two-stage design. We planned to recruit 53 patients (aged 18-75 years) with newly diagnosed BRCAmut/HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography score ≥ 3), FIGO stage III-IV high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Enrolled patients received two cycles (four weeks per cycle) of individualized starting dose of neoadjuvant niraparib (200mg or 300mg per day), interval debulking surgery, and at least four cycles of platinum-based chemotherapy. Maintenance therapy of niraparib was dosed (200mg or 300mg per day) within 12 weeks up to three years or disease progression or patient withdrawal. The dual primary objectives were objective response rate (ORR) and R0 resection rate. Both progression-free survival and overall survival were secondary objectives. The data manager will record adverse events (AEs). If more than five patients achieved OR in the first stage, the study would enter the second stage. Results: Since February 2021, 16 patients have been enrolled. By September 20, 2021, six patients had completed neoadjuvant niraparib monotherapy, and four had completed interval debulking surgery. Their baseline characteristics are shown in Table 1. The ORR was 100% (CR n=0; PR n=6) and R0 reduction rate was 75% (R0, n=3; R1, n=1). CA-125 began to decline since day-14 after the first dose of niraparib, significantly decreased after the first cycle of neoadjuvant niraparib (median decrease, 70.8% [min, 23.8%; max, 97.4%] of baseline concentration), and continued to decline thereafter. Treatment-emergent adverse events (TEAEs) could be analyzed in nine patients, and the most common TEAEs were hematological AEs, including any grade leukopenia (66.7%), anemia (66.7%), and thrombocytopenia (55.6%). No treatment-related death was recorded. The grade ≥3 TEAEs were anemia (n=1) and thrombocytopenia (n=5). Thrombocytopenia mainly occurred after the first cycle of neoadjuvant niraparib, which synchronized with the decline of CA-125. Objectives: Neoadjuvant chemotherapy followed by interval debulking surgery did not achieve survival benefits compared to primary debulking surgery in advanced ovarian cancer. Niraparib is the only approved poly (ADP-ribose) polymerase inhibitor by the FDA to treat homologous recombination deficiency (HRD)-positive ovarian cancer patients with platinum-sensitive relapse after ≥ 3 lines of chemotherapy hitherto. We aimed to assess the efficacy and safety of neoadjuvant niraparib monotherapy in BRCAmut/HRD-positive patients with advanced unresectable ovarian cancer. Methods: This multi-center phase II single-arm study followed Simon’s two-stage design. We planned to recruit 53 patients (aged 18-75 years) with newly diagnosed BRCAmut/HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography score ≥ 3), FIGO stage III-IV high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Enrolled patients received two cycles (four weeks per cycle) of individualized starting dose of neoadjuvant niraparib (200mg or 300mg per day), interval debulking surgery, and at least four cycles of platinum-based chemotherapy. Maintenance therapy of niraparib was dosed (200mg or 300mg per day) within 12 weeks up to three years or disease progression or patient withdrawal. The dual primary objectives were objective response rate (ORR) and R0 resection rate. Both progression-free survival and overall survival were secondary objectives. The data manager will record adverse events (AEs). If more than five patients achieved OR in the first stage, the study would enter the second stage. Results: Since February 2021, 16 patients have been enrolled. By September 20, 2021, six patients had completed neoadjuvant niraparib monotherapy, and four had completed interval debulking surgery. Their baseline characteristics are shown in Table 1. The ORR was 100% (CR n=0; PR n=6) and R0 reduction rate was 75% (R0, n=3; R1, n=1). CA-125 began to decline since day-14 after the first dose of niraparib, significantly decreased after the first cycle of neoadjuvant niraparib (median decrease, 70.8% [min, 23.8%; max, 97.4%] of baseline concentration), and continued to decline thereafter. Treatment-emergent adverse events (TEAEs) could be analyzed in nine patients, and the most common TEAEs were hematological AEs, including any grade leukopenia (66.7%), anemia (66.7%), and thrombocytopenia (55.6%). No treatment-related death was recorded. The grade ≥3 TEAEs were anemia (n=1) and thrombocytopenia (n=5). Thrombocytopenia mainly occurred after the first cycle of neoadjuvant niraparib, which synchronized with the decline of CA-125.