Niraparib, Dostarlimab, and Bevacizumab as Combination Therapy in Pretreated, Advanced Platinum-Resistant Ovarian Cancer: Findings From Cohort A of the OPAL Phase II Trial.

Purpose: To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC).

Methods: Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks).

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors.

Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).

Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks.

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 = .044, which met the one-sided significance level of 0.

Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016.

Introduction: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC.

Methods: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens.

A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies.

Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers.

NRG-GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer.

Purpose: This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer.

Methods: This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2.

Incidence of venous thromboembolism in patients with advanced stage ovarian cancer undergoing neoadjuvant chemotherapy: Is it time for thromboprophylaxis?

Objectives: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment.

Methods: This retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution.

A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas.

Real-World Implementation of Best-Evidence Cancer Distress Management: Truly Comprehensive Cancer Care.

Background: Cancer distress management is an evidence-based component of comprehensive cancer care. Group-delivered cognitive behavioral therapy for cancer distress (CBT-C) is the first distress treatment associated with replicated survival advantages in randomized clinical trials. Despite research supporting patient satisfaction, improved outcomes, and reduced costs, CBT-C has not been tested sufficiently within billable clinical settings, profoundly reducing patient access to best-evidence care.

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl).

Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula.

The effect of older age on treatment outcomes in women with advanced ovarian cancer receiving chemotherapy: An NRG-Oncology/Gynecologic Oncology Group (GOG-0182-ICON5) ancillary study.

Objective: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction.

Methods: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included.

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study.

Purpose: In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.

Purpose: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients.

Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours.

Purpose: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study.

CHFR and Paclitaxel Sensitivity of Ovarian Cancer.

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease.

Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study.

Background: Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy.

Methods: Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial.

Characterization of a -silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

Acquired PARP inhibitor (PARPi) resistance in - or -mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment .

Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization.

Background: Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined.

An unusual case of aggressive malignant spread of epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm which typically originates from liver, lung, or bone. Due to the low incidence of disease, the most effective treatment is not easily studied and much of the information known about EHE has been learned through case reports and case series. In this case, we will present an uncommon form of primary soft tissue EHE with local recurrence, bone metastasis, and lymphangitic spread to the lungs leading to respiratory failure.

Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2).

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi.

Statistical analysis of comparative tumor growth repeated measures experiments in the ovarian cancer patient derived xenograft (PDX) setting.

Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained.