Neoadjuvant combination treatment of olaparib and pembrolizumab for patients with HRD-positive advanced ovarian cancer.
Authors: Harano Kenichi , Nakao Takehiro , Nishio Shin , Katsuta Takahiro , Tasaki Kazuto , Takehara Kazuhiro , Yokoyama Takanori , Furuya Hideki , Hongo Kyoko , Asano Masatoshi , Ikeno Takashi , Wakabayashi Masashi , Sato Akihiro , Odajima Suguru , Tanabe Hiroshi , Taki Tetsuro , Watanabe Reiko , Ishii Genichiro , Mukohara Toru 
Published: June 2024

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Background: Olaparib, a PARP inhibitor, is effective as maintenance therapy for newly diagnosed BRCA-mutated or homologous recombination deficiency (HRD)-positive advanced ovarian cancer and maintenance therapy in platinum-sensitive recurrent ovarian cancer. Preclinical studies suggest synergy between PARP inhibitors and immune checkpoint inhibitors, with demonstrated efficacy in recurrent ovarian cancer patients. However, the efficacy and safety of this combination therapy in neoadjuvant therapy remain uncertain. Methods: This open-label, multicenter pilot study evaluated the efficacy and safety of olaparib in combination with pembrolizumab as neoadjuvant therapy in patients with newly diagnosed HRD-positive stage III-IV high-grade serous or endometrioid ovarian, fallopian, or primary peritoneal cancer (NCT04417192). HRD status was determined by myChoice HRD plus assay. Patients received olaparib 300 mg orally twice daily for 6 weeks and pembrolizumab 200 mg intravenously every 3 weeks for 2 cycles. Debulking surgery was performed after study treatment. Adjuvant chemotherapy was administered post-surgery. If the gynecologic oncologist deemed debulking surgery unfeasible following the study treatment, standard preoperative chemotherapy was administered, followed by a reevaluation of the surgery. The primary endpoint was the objective response rate (ORR) assessed using RECIST version 1.1. Key secondary endpoints included adverse event (AE) evaluated using CTCAE ver. 5.0, pathological response based on the chemotherapy response score (CRS) in patients with serous carcinoma with metastatic disease of the omentum, and progression-free survival (PFS). Results: Twenty patients were enrolled. The median age was 62 (range, 45-85), and all patients had high-grade serous carcinoma histology. Among them, 11 had stage IIIC, 1 had stage IVA, and 8 had stage IVB disease. BRCA 1/2 mutations were present in 13 patients (65%). All patients completed the study treatment. ORR was 70% (95% CI, 45.7-88.1). BRCA1/2 mutations tended to be associated with tumor response [ p=0.066, Odds ratio 7.33 (95% CI, 0.88 - 61.33)]. After the study treatment, 17 patients underwent tumor-debulking surgery. Two patients underwent immediate surgery after the study treatment, while 15 received preoperative chemotherapy. In 13 patients with evaluable CRS, the pathological response rate was 84.6% (95% CI, 54.6 - 98.1). Pathological complete response (no residual tumor in the surgical specimen) was achieved in 6 patients (30%). The 12-month PFS rate was 91.7% (95%CI, 53.9-98.8). The proportion of grade 3 or higher AEs was 35%. Common AEs included nausea (50%), anemia (45%), vomiting (30%), and diarrhea (20%). Conclusions: Neoadjuvant combination treatment of olaparib and pembrolizumab showed promising efficacy and safety in patients with HRD-positive advanced ovarian cancer. Clinical trial information: NCT04417192 .