A phase II study of the efficacy of olaparib maintenance monotherapy for patients with HRD-positive, newly diagnosed, advanced, high-grade ovarian cancer, evaluated by whole-exome sequencing (MSBM-OL)

BackgroundCurrently, olaparib maintenance monotherapy can be used only for patients with tumor BRCA1/2 mutations (tBRCAm). We originally evaluated HRD, called MSBM (Mutational Signature based BioMarker), by mutational signature 3, CCNE1 amplification, and BRCA1/2 status from whole-exome sequencing. The aim of this phase 2 study (MSBM-OL: jRCT 2080223978) was to evaluate the efficacy of olaparib maintenance monotherapy in patients with HRD-positive, advanced ovarian cancer, regardless of BRCA status.MethodsHRD was found in 66.8% (127 of 190 tumors) of stage IIIC-IV, high-grade ovarian carcinomas with visible residual disease after primary surgery, with 19.5% of tBRCAm (n=37). Patients with response to first-line platinum-doublet chemotherapy without bevacizumab were enrolled. The patients (n=32) were initially randomly assigned, in a 2:1 ratio, to receive either olaparib (ola, 300 mg bid) or placebo (pbo). However, randomization became ethically difficult after approval of ola for germline BRCA mutated patients in a first-line setting in 2019, we switched to a single-arm study and enrolled additional 26 patients for ola. The primary endpoint was PFS. Full analysis set was 45 patients treated with ola (21 by randomization and 24 as a single arm). Secondary endpoints included overall survival (OS), and adverse events.ResultstBRCAm was positive in 9 (4 germline, 5 somatic) in ola (20%). At the data cutoff (Jan. 31, 2024), median follow-up time was 29.1 months. Median PFS in ola was 22.3 months (95%CI: 16.4-33.3), which rejected the null hypothesis of the one-sample log-rank test (p<0.001, [HR], 0.35; 95% CI, 0.24 to 0.50). The median PFS of non-BRCA HRD and tBRCAm subgroup in ola was 20.7m and not reached, respectively. OS in ola at 24 months was 78.6% (95%CI: 62.8-88.3). The median PFS in pbo (n=11) was 16.7 months. Grade ≥3 AEs in ola included anemia at 25.5%, neutropenia at 12.8%, and infection at 8.5% (49% and 4.3% of G3/4 AEs without myelodysplasia).ConclusionsOlaparib monotherapy alone may be effective as first-line maintenance in patients with advanced ovarian cancer with HRD, and might be an alternative option for those unsuitable for bevacizumab combination.Clinical trial identificationjRCT 2080223978.Legal entity responsible for the studyEthics Review Board at the University of Tokyo Hospital.FundingAstraZeneca, plc (ESR-16-11943-R2).DisclosureK. Oda: Financial Interests, Institutional, Funding, Pruduct Samples: AstraZeneca plc; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca plc, Konica Minolta, Co. Ltd, Chugai Pharmaceutical Co. Ltd; Financial Interests, Personal, Research Funding: Konica Minolta, Co. Ltd. N. Matsumura: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca plc, Takeda Pharmaceutical Co. Ltd, MSD Co. Ltd, Eisai Pharmaceutical Co. Ltd. K. Kato: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca plc. K. Yoshihara: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceuticals. J. Hamanishi: Financial Interests, Personal, Invited Speaker: MSD, Eizai, Chugai, AstraZeneca, Horogic, Sanofi, Takeda; Financial Interests, Personal and Institutional, Research Grant: Chugai, Sumitomo Pharma, Kinopharma, Ono, Ono. T. Aoki: Financial Interests, Personal, Full or part-time Employment: Xcoo, Inc. K. Nishimura: Financial Interests, Personal, Full or part-time Employment: Xcoo, Inc. K. Hasegawa: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Takeda, Chugai, Genmab, Kaken, Eisai, Sanofi; Financial Interests, Personal, Advisory Board: GSK, Daiichi Sankyo, Terumo; Financial Interests, Institutional, Funding, contracted research: MSD, Ono, Daiichi Sankyo, Eisai, Takeda. All other authors have declared no conflicts of interest.