Laurence Gladieff

PURPOSE: Previously reported results from the placebo-controlled double-blind randomized phase III ATALANTE/ENGOT-ov29 trial (ClinicalTrials.gov identifier: NCT02891824 ) showed that progression-free survival improvement with the addition of atezolizumab to standard bevacizumab and platinum-based chemotherapy for late-relapsing recurrent ovarian cancer did not reach statistical significance in the intention-to-treat (ITT; hazard ratio [HR] 0.83 [95% CI, 0.69 to 0.99]; two-sided P = .041) or PD-L1–positive populations (dual primary end points). Here we report the final analysis, including overall survival (OS). PATIENTS AND METHODS: Patients with recurrent epithelial ovarian cancer, one or two prior chemotherapy lines, and platinum-free interval (PFI) >6 months were randomly assigned 2:1 to atezolizumab or placebo for up to 24 months, combined with bevacizumab and six cycles of investigator-selected platinum-based chemotherapy, stratified by PFI, PD-L1 status, and chemotherapy regimen. OS was a secondary end point. RESULTS: At 5 years' median follow-up, the median OS was 35.8 months with atezolizumab-containing therapy (n = 410) and 30.6 months with standard therapy (n = 204) in the ITT population (HR, 0.83 [95% CI, 0.69 to 0.98]); 5-year OS rates were 27% versus 17%, respectively. Time to second subsequent therapy showed consistent results favoring atezolizumab. There was no evidence of an enhanced treatment effect in the PD-L1–positive population. CONCLUSION: At the final analysis, a clinically meaningful 5-month improvement in median OS was observed with atezolizumab added to bevacizumab and a platinum doublet.

Figure S5. Association between maximal circulating fraction and DNA extraction yield.

Figure S3. Technical control: association between the amount of DNA processed in bisulfite and ddPCR and the number of ALB copies detected.

Purpose:ctDNA may offer a noninvasive means to evaluate tumor response and anticipate disease dynamics before radiologic changes in advanced endometrial carcinoma.Experimental Design:This ancillary analysis included patients from the multicenter, randomized, phase II GINECO-UTerin OLAparib (UTOLA) trial (NCT03745950) evaluating olaparib/placebo as maintenance after first-line platinum-based chemotherapy. Plasma samples were collected at screening after chemotherapy (baseline), 3 months (M3), and progression. ctDNA detection was assessed by a validated methylation-based Droplet Digital PCR (MethddPCR) assay targeting DNA positions universally methylated in endometrial carcinoma.Results:Among 130 evaluable patients, ctDNA was detected in 25 of 129 (19%, 1 technical fail) at baseline, 15 of 80 (19%) at M3, and 33 of 52 (63%) at progression. Baseline ctDNA positivity was independently associated with poorer progression-free survival (PFS) [median 1.81 vs. 7.39 months; adjusted HR = 5.33 (3.17–8.97)] and overall survival (OS) [10.3 vs. 24.7 months; adjusted HR = 3.98 (2.28–6.91); adjusted for age, stage IV at diagnosis, p53abn subgroup, and residual measurable lesions after chemotherapy]. Patients with baseline ctDNA had median OS of 9.36 months under olaparib versus 19.6 months under placebo (log-rank P = 0.05). Patients with increasing ctDNA at M3 had median PFS of 1.67 months, versus 9.64 months without, and median OS of 18.8 versus 25.8 months. ctDNA rising was predictive of poor postprogression OS under olaparib but not under placebo (interaction test, P < 0.001).Conclusions:MethddPCR-ctDNA is an independent prognostic biomarker for OS in advanced/metastatic endometrial carcinoma. MethddPCR-ctDNA may identify patients unlikely to benefit from PARP inhibition, guide therapeutic decisions, and should be further evaluated as a new stratification parameter in future endometrial carcinoma trials.

Figure S6. Association between ctDNA levels and sample timing. Lines highlight paired samples.

Figure S1. Flow overview. ctDNA: circulating tumor DNA. C1-C6 : figure cycle 1 to cycle 6 of first line chemotherapy.