Abstract A030: 2X-121, a novel, dual inhibitor of PARP and tankyrase, shows promising clinical benefit in a phase 2 trial in advanced, recurrent ovarian cancer patients (NCT#03878849)

Abstract 2X-121 (stenoparib/ E7499) inhibits PARP1/2 (1nM ∼IC50) and Tankyrase 1/2 (IC50 ∼50nm). As such, 2X-121 impairs DNA repair while simultaneously inhibiting the WNT/ß-catenin oncogenic signaling pathway. A Drug Response Predictor (DRP®) specific for 2X-121 has been developed from the in vitro sensitivity of cell lines in monolayer culture and highlights the gene expression profiles correlated with sensitivity to 2X-121. This DRP® signature is comprised of 414 genes, many of which reflect WNT/ ß-catenin pathway activity. In a phase 1 dose escalation clinical study, 2X-121 showed clinical responses, especially in ovarian cancer patients. The 2X-121 DRP® retrospectively was able to identify patients who were most likely to benefit from 2X-121. A follow-on, open label phase 2 trial in 3L+ ovarian cancer patients with a DRP score > 50 started May 2023 with 2X-121 dosed BID for the first time. A total of fifteen (15) patients were enrolled independent of BRCA or Homologous DNA Repair status. Most patients were heavily pre-treated. Prior treatment included PARP inhibitors, mirvetuximab soravtansine and immunotherapy. Fourteen patients had platinum resistant disease, one had primary platinum refractory disease. The data show durable clinical benefit in patients with varied genetic and treatment backgrounds. 8 of 15 patients remained on study drug at least 16 weeks. 4 of these continued for more than 20 weeks and two patients remain on therapy now for more than 22 months – one being BRCA mutated, one BRCAwt/ HRP. The patient with primary platinum refractory ovarian cancer remained on study drug for nearly 50 weeks. In addition, one patient showed a complete, confirmed RECIST-based response and stayed on study drug for more than 30 weeks. Importantly, 2X-121 was well tolerated and did not show the myelotoxicity typical of earlier PARP inhibitors. These data prompted the development of a refined clinical trial protocol that has recently opened to enrollment. In this new protocol, eligible patients are either platinum resistant or ineligible and have had no more than 1 additional line of chemotherapy after the designation of platinum resistance, other than ADCs. Patients will be randomized to receive 600mg or 800 mg total daily dose given BID. DRP will be assessed retrospectively. In addition to safety, this study will assess Clinical Benefit Rate, RECIST v1.1 based response, and PFS. Collectively, the safety profile and clinical benefit coupled to the unique dual mechanism of action suggest that 2X-121 may be a promising new therapy for advanced ovarian cancer patients. Citation Format: Fernanda Musa, Steen Knudsen, Thomas Jensen, Annette Nielsen, Peter Gimsing, Anker Hansen, Mogens Winkel Madsen, Jose Iglesias, Jeremy Graff, Kathleen Moore. 2X-121, a novel, dual inhibitor of PARP and tankyrase, shows promising clinical benefit in a phase 2 trial in advanced, recurrent ovarian cancer patients (NCT#03878849) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A030.