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Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial

Abstract

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III–IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32–0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997.

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Fig. 1: Trial profile.
Fig. 2: Progression-free survival by BICR in the ITT population.
Fig. 3: Progression-free survival in the subgroups of patients with and without BRCA1 and BRCA2 mutations.
Fig. 4: Progression-free survival by investigator review in the ITT population.

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Data availability

The study protocol is published with this manuscript as Supplementary Information. All extracted data, including deidentified individual information, trial-level data (analysis datasets) and other information (for example, clinical study reports and informed consent form) are available from the corresponding author upon request, provided the FLAMES trial is not part of an ongoing or planned regulatory submission. The corresponding author will also accept requests for clinical trial data for unlicensed products and indications.

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Acknowledgements

This study was funded by IMPACT Therapeutics (Shanghai) Inc. The sponsor had a role in the study design, data collection, data analysis, data interpretation and writing and approval of this manuscript for publication. The authors wish to acknowledge and thank the study patients and their families, the investigators and the study teams at each of the participating centers, as well as S.X. Cai, Y. Tian, H. Xia, B. Li and Y. Zhang of IMPACT Therapeutics (Shanghai) Inc. and the entire research team of the FLAMES trial. Writing and editorial assistance was provided by J. Kolston and M. Yu at Parexel and was funded by IMPACT Therapeutics (Shanghai) Inc.

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Contributions

X.Wu and J.L. were the cochief investigators for this trial and are co-first authors of the manuscript. X.Wu, J.L., J.W., L.W. and Z.Lin contributed to the trial design and were involved in project administration and supervision. All authors contributed to patient accrual, trial conduct, treatment, safety assessments and data acquisition. All authors had full access to and verified the data in this study. All authors interpreted the data, reviewed the draft and final versions of the manuscript and provided final approval to submit this article for publication.

Corresponding author

Correspondence to Xiaohua Wu.

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Competing interests

C.X. and C.-Y.H. are employees of IMPACT Therapeutics (Shanghai) Inc., Shanghai, China. The other authors declare no competing interests.

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Nature Medicine thanks Michael Friedlander and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1

Structures of senaparib, olaparib, niraparib, and rucaparib.

Extended Data Fig. 2 Chemotherapy-free interval, time to first subsequent therapy or death, and time to treatment discontinuation or death.

Kaplan–Meier estimates of chemotherapy-free interval (a), time to first subsequent therapy or death (b), and time to treatment discontinuation or death (c) in the ITT population. CFI, chemotherapy-free interval; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; n/N, number with disease progression or death/total number evaluable; NR, not reached; TDT, time to treatment discontinuation or death; TFST, time to first subsequent therapy or death.

Extended Data Table 1 Baseline characteristics in patients who had evaluable data for homologous-recombination status
Extended Data Table 2 Exploratory subgroup analysis of progression-free survival according to homologous-recombination status
Extended Data Table 3 Summary of adverse events in the safety analysis set
Extended Data Table 4 Serious treatment-emergent adverse events occurring in at least 1% of patients in either treatment arm
Extended Data Table 5 Sequencing of dose amendments to manage toxicity
Extended Data Table 6 Management of nonhematological and hematological toxicities
Extended Data Table 7 Study endpoints

Supplementary information

Supplementary Information

Supplementary Methods and Study Protocol.

Reporting Summary

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Wu, X., Liu, J., Wang, J. et al. Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial. Nat Med 30, 1612–1621 (2024). https://doi.org/10.1038/s41591-024-03003-9

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