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The medians and ranges for all analytes at baseline.

Purpose:GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses.Experimental Design:Plasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell–derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates.Results:Baseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo.Conclusions:The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

Association between outcomes (PFS and OS) and baseline covariates (age, stage/debulking status, and performance status).

Quartile analysis of IL6. Median survival times are given in months, and HR's represent treatment hazard ratios.

Relationship between covariates and IL6.

Legends

3-way interaction analyses between outcome, treatment, and markers.

Flow diagram of patients through the study.

Background: Over 50% of patients with ovarian cancer (OVCA) succumb to their disease within five years from diagnosis, highlighting the need for new approaches to identify therapeutic options. The PARIS® test is a CLIA certified organoid based high throughput drug sensitivity assay that can be used by oncologists to select personalized treatments. In this study our objectives were to: 1) demonstrate the feasibility of organoid based drug testing in the clinical setting; 2) highlight the clinical utility and the predictive value of the PARIS® test; and 3) identify new therapeutic options for OVCA patients. Methods: 93 patients, with a median age at diagnosis of 55 years (range 25-82) were selected as eligible for the PARIS® test at the discretion of the oncologists. The cohort included 74.1% high grade serous tumors, 6.9% low grade serous tumors, 6.0% clear cell carcinomas, 3.4% granulosa cell tumors, 2.5% Mullerian tumors, 1.7% carcinosarcomas and 2.5% fallopian tumors. 16.1% of patients were treatment naïve and 83.9% received one or more previous lines of treatment. 116 patient derived tumor organoids (PDTOs) were derived from surgical excisions, biopsies, or body fluids and subjected to functional testing with a panel of chemo- and targeted therapies that are FDA-approved or in clinical development. Drug responses were evaluated using a proprietary score ranking drugs from exceptional responses to no response. The median turnaround time from biopsy to report delivery was 19 days. Results: The success rate for deriving OVCA organoids was 92%; 81.0% of samples demonstrated exceptional/good response to at least one drug. PDTO drug sensitivities were highly concordant with both retrospective and prospective clinical response. Drugs that frequently showed exceptional/good responses included WEE1 inhibitors (28.4%), HDAC inhibitors (25.0%), and Pan-DNMT inhibitors (11.2%). Further, 12.9% of cases showed responses to the BTK/EGFR inhibitor ibrutinib and 23.3% to HER2 inhibitors lapatinib and neratinib. Two patients with advanced stage, recurrent low grade serous ovarian cancer showed exceptional and durable clinical responses to PARIS® guided treatments, ibrutinib and lapatinib, respectively. Conclusions: This study demonstrates the utility of organoid based drug testing to identify potentially effective drugs and to guide treatment choice for patients with ovarian cancer. Tumor organoid based personalized treatments lead to extraordinary responses in several patients, including a patient in hospice care who responded to ibrutinib monotherapy and is still alive after 27 months. Citation Format: Amanda M. Prechtl, Marwah Al-Aloosi, Payel Chatterjee, Rachele Rosati, Samantha Velazquez, Lauren Appleyard, Grace Durenberger, Cristina Cordero, Robert Diaz, Hallie Swan, Brady Bernard, Siddhartha Mukherjee, Barbara Goff, Elizabeth Swisher, Heidi Gray, Kalyan Banda, Christopher Kemp, Carla Grandori. Tumor organoid based drug sensitivity testing in ovarian cancer identifies exceptional responders to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3399.