FLAMES shows activity of maintenance senaparib in ovarian cancer patients

Introduction

Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapies that have shifted the treatment paradigm for patients with recurrent ovarian cancer (OC), specifically those with BReast CAncer gene (BRCA) mutations (BRCAm). Since 75% of OC patients present with advanced disease and 85% of OC patients eventually recur, to achieve remission and extend progression-free survival (PFS) and overall survival (OS) is a high unmet need. In 2023, Surveillance, Epidemiology, and End Results (SEER) estimates 19,719 new OC cases and 13,270 deaths in the United States (1).

Several trials have established the use of PARPi as standard of care for OC patients with germline and somatic mutations in BRCA or with homologous recombination deficiency (HRD). In 2018, SOLO-1 allowed for olaparib approval in the United States as the first PARPi for first-line maintenance therapy in patients with germline and somatic BRCAm (2). Subsequent phase III trials, including PRIMA, PAOLA-1, VELIA, ARIEL, and ATHENA-MONO assessed the use of first line PARPi in patients beyond BRCAm and using combination treatments with bevacizumab (3-6). PRIMA led to the 2020 Food and Drug Administration (FDA) approval of niraparib regardless of biomarker status. PAOLA-1 led to approval of olaparib and bevacizumab in patients with HRD-positive advanced OC, including patients with BRCAm (3,4). Of note, the results of ARIEL4 and SOLO3, which suggested a detrimental effect of PARPi monotherapy after multiple lines of chemotherapy, prompted the respective pharmaceutical companies to voluntarily withdraw the indication of rucaparib, olaparib, and niraparib for patients with recurrent, platinum-sensitive epithelial OC. The FDA agreed and major medical societies updated their guidelines accordingly (7). These trials with olaparib, niraparib, and rucaparib, respectively, have all shown that PARPi allow for the greatest benefit in the frontline setting for BRCA mutated OC (2,3,6).

Senaparib is a novel, high potency PARP 1/2 inhibitor. In this commentary, we discuss the results of the FLAMES phase 3 study, presented by Dr. Xiaohua Wu from Fudan University Shanghai Cancer Center at the 2023 European Society for Medical Oncology Congress. In their primary analysis, this late breaking abstract: “Efficacy and safety of senaparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer (FLAMES study): A randomized, double-blind, placebo-controlled, phase III trial” reported that senaparib has significant improved PFS over placebo (8).

Summary of FLAMES

The FLAMES trial (ClinicalTrials.gov; identifier: NCT04169997), is a Chinese phase 3 study that enrolled patients with newly diagnosed, stage III or IV, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients had either a complete or partial response (CR or PR) to frontline platinum-based chemotherapy, completed within 8 weeks of randomization. Patients were randomized 2:1 to receive either oral senaparib at 100 mg daily (n=271) or placebo (n=133) as maintenance. Treatment was given for up to 2 years.

One patient in the senaparib arm did not obtain treatment. Baseline demographics of participants were similar and balanced. The median age of patients was 55 years in the senaparib arm (n=271) versus with 54 years in the placebo arm (n=133). Other demographics included an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (60.9% vs. 57.9%), serous histology (99.8% vs. 100%), and negative BRCAm (65.3 vs. 66.9%). Duration of treatment was 18.7 months in the senaparib arm vs. 11.4 months in the placebo group at a median follow-up of 22.3 months. The senaparib arm had a significant improvement in PFS over the placebo group. The median PFS by blinded independent centralized review was not reached in the senaparib arm and was 13.6 months in the placebo arm [hazard ratio =0.43; 95% confidence interval (CI): 0.32–0.58; P<0.0001]. The 12-month PFS rate was 72.2% in the senaparib arm and 53.7% in the placebo. The 24-month PFS rate was 63.0% and 31.3%, respectively. These PFS benefits in the senaparib arm were present regardless of mutation status and across all other predetermined subgroups. This represents a 57% reduction in progression or death (8).

Adverse events of any grade in the senaparib included anemia (81%), neutropenia (76%), leukopenia (75%), and thrombocytopenia (70%). Grade 3 or higher treatment emergent adverse events (TEAEs) were noted in 66.3% of patients on senaparib and 20.3% in the placebo group, leading to treatment discontinuation in 4.4% of patients in the senaparib arm and zero patients in the placebo group. There were no fatal TEAEs (8). Senaparib demonstrated an overall tolerable safety profile.

Conclusions

The FLAMES phase 3 trial demonstrates a significant 57% reduction in progression or death and an improved PFS in all comers with advanced OC who have responded to frontline platinum-based chemotherapy. These benefits are seen in patients with and without genetic mutations in BRCA. The FLAMES trial supports senaparib as another therapeutic option with which to target OC. This is a straightforward trial with limited confounders, though crossover could contaminate the data, as some patients on the placebo arm may have received a PARPi later in the course of their therapy. Since this trial did not compare senaparib with another PARPi, we cannot engage in cross-trial comparisons and cannot speculate on the relative efficacy or toxicity compared with other agents.

Several factors limit the applied importance of this trial. Acquisition of resistance is a common problem with PARPi and this is likely to be no exception. Several molecular mechanisms have been proposed for PARPi resistance, highlighting another important area for future scientific investigation. In addition, the generalizability of the article is important, as this trial was conducted in a single country, so we need to ensure that these findings translate to other populations.

Whether yet another PARPi will be embraced by the community of treating oncologists remains to be seen. It seems that senaparib has activity in the maintenance setting for patients with OC and is a promising new agent that warrants further development.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-23/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-23/coif). J.B. reports consulting fees from AstraZeneca and GSK/Tesaro, participation on the advisory board of Verastem, and serving on the Society of Gynecologic Oncology Board of Directors. V.M. serves on the Society of Gynecologic Oncology Board of Directors. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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