A phase 2 trial exploring the significance of homologous recombination status in patients with platinum sensitive or platinum resistant relapsed ovarian cancer receiving combination cediranib and olaparib.

OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.

Combined aromatase, CDK4/6 and PI3K blockade using letrozole/abemaciclib/LY3023414 in endometrial cancer.

Several lines of preclinical evidence indicate that combining PI3K and CDK4/6 inhibitors may further enhance the efficacy of hormonal therapy by overcoming de novo and acquired resistance to PI3K and CDK4/6 blockade. We evaluated the combination of abemaciclib, letrozole and LY3023414 (an orally available, selective inhibitor of the class I PI3K isoforms and mTORC1/2) in recurrent endometrial cancer (EC). This study was terminated prematurely after 5 patients initiated protocol therapy due to discontinuation of further development of LY3023414. We report our findings from these patients, including one with recurrent endometrioid EC with AKT1, CTNNB1 and ESR1 hotspot mutations who had previously progressed through letrozole/everolimus and achieved a partial response to letrozole/abemaciclib/LY3023414.

Centralized Interactive Phenomics Resource: an integrated online phenomics knowledgebase for health data users.

OBJECTIVE: Development of clinical phenotypes from electronic health records (EHRs) can be resource intensive. Several phenotype libraries have been created to facilitate reuse of definitions. However, these platforms vary in target audience and utility. We describe the development of the Centralized Interactive Phenomics Resource (CIPHER) knowledgebase, a comprehensive public-facing phenotype library, which aims to facilitate clinical and health services research. MATERIALS AND METHODS: The platform was designed to collect and catalog EHR-based computable phenotype algorithms from any healthcare system, scale metadata management, facilitate phenotype discovery, and allow for integration of tools and user workflows. Phenomics experts were engaged in the development and testing of the site. RESULTS: The knowledgebase stores phenotype metadata using the CIPHER standard, and definitions are accessible through complex searching. Phenotypes are contributed to the knowledgebase via webform, allowing metadata validation. Data visualization tools linking to the knowledgebase enhance user interaction with content and accelerate phenotype development. DISCUSSION: The CIPHER knowledgebase was developed in the largest healthcare system in the United States and piloted with external partners. The design of the CIPHER website supports a variety of front-end tools and features to facilitate phenotype development and reuse. Health data users are encouraged to contribute their algorithms to the knowledgebase for wider dissemination to the research community, and to use the platform as a springboard for phenotyping. CONCLUSION: CIPHER is a public resource for all health data users available at https://phenomics.va.ornl.gov/ which facilitates phenotype reuse, development, and dissemination of phenotyping knowledge.

Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses.

PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.