药物反应预测因子（DRP®）与在 II 期试验中每日两次接受 2X-121/司替尼帕利（stenoparib）治疗的晚期、复发性卵巢癌患者总生存期的提高相关（NCT03878849）

2X-121 (stenoparib) inhibits PARP1/2 (1nM ~IC50) and Tankyrase 1/2 (IC50 ~50nM) limiting DNA repair while inhibiting WNT/ß-catenin oncogenic signaling. A 2X-121- specific Drug Response Predictor (DRP®) comprised of 414 genes was developed and highlights the gene expression profiles correlated with 2X-121 sensitivity, many of which are involved in the WNT/ ß-catenin pathway. In a ph1 clinical study, 2X-121 treatment showed clinical response by RECISTv1.1, notably in ovarian cancer patients. Blinded, retrospective analysis revealed that the 2X-121 DRP® identified the patients most likely to benefit from 2X-121. A follow-on, open label phase 2 trial in 3L+ ovarian cancer patients (DRP score > 50) began in May 2023 with 2X-121 dosed BID for the first time. 15 heavily pre-treated patients were enrolled independent of BRCA or Homologous DNA Repair status. Prior treatment included PARP inhibitors, mirvetuxumab, bevacizumab and immunotherapy. 14 of these patients were platinum resistant, 1 was primary platinum refractory. Collectively, the data show durable clinical benefit in patients with varied genetic and treatment backgrounds. Two patients (one BRCA mut , one BRCA WT ) remain on therapy > 26 mos. An additional patient (prior PARP inhibitor treatment) showed a complete, confirmed response and stayed on treatment > 10 mos. The patient with primary platinum refractory disease was on therapy > 10 mos and remains alive beyond 2 years. Kaplan-Meier analyses show that the median Overall Survival (OS) is now > 25 mos, having not been reached with >23 mos median time to follow-up. We assessed whether the DRP score from pre-treatment biopsies might be related to enhanced OS. Indeed, patients with higher DRP scores reliably showed the greatest OS. In a continuous cox proportional hazard analysis, a 50-point difference in DRP score was associated with a hazard ratio of 0.03 (95% CI, 0.0-1.4). Applying a fixed DRP cutoff of 80 yielded a hazard ratio of 0.13 (95% CI, 0.02-0.9). To address whether the DRP was prognostic vs predictive, we assessed RNA expression data from biopsies in the public TCGA dataset of 481 high grade serous ovarian cancer samples from patients treated with platinum/ taxane. The DRP scores ranged from 0 to 100 in this cohort. The 2X-121 DRP® did not correlate with better OS (continuous cox HR=0.76 (95% CI, 0.54-1.1)). Among the 90 samples from patients with platinum resistant disease, the hazard ratio was 0.96 (95% CI, 0.39-2.3). These results indicate that the 2X-121 DRP may be a predictive- rather than prognostic- biomarker, highlighting extended OS in patients treated twice daily with 2X-121. A new ph2 clinical trial protocol is currently enrolling platinum-resistant Ovarian Cancer patients to further explore and delineate the relationship between 2X-121 DRP® score and clinical benefit.