Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Ovarian microcystic stromal tumor: Radiologic-pathologic correlation

Ovarian microcystic stromal tumor (MST) is characterized by microcysts, solid cellular regions with lobulated growth, and collagenous or fibrous stroma forming hyaline plaques. While several reports have evaluated the unique pathologic and immunohistochemical profile of these tumors, there has been limited description of the radiologic findings of ovarian microcystic stromal tumor in the literature. We present a case of a 66 year old female who presented for evaluation of a new cystic pelvic mass found to have ovarian microcystic stromal tumor. To our knowledge, this is one of the first reports to evaluate the radiologic features associated with this tumor. An enhanced understanding of the correlation between imaging appearance and specific histopathologic findings may aid in the early recognition of this rare neoplasm. Keywords: Ovarian microcystic stromal tumor, Ovarian neoplasm, Radiolog

Heavy metal contamination and health risk assessment in the vicinity of the abandoned Songcheon Au–Ag mine in Korea

The objective of this study is, firstly, to investigate the contamination levels and dispersion patterns of As and heavy metals, secondly, to estimate the bioaccessible fraction of the metals in soil and crop plant and, finally, to assess the risk of health effects on the residence in the vicinity of the abandoned Songcheon Au–Ag mine, Korea. Samples of tailing, soil, crop plant and water were collected around the mine site. After appropriate preparation, all samples were analyzed for As, Cd, Cu, Pb and Zn by ICP-AES and ICP-MS. Elevated levels of As and heavy metals were found in tailing. Mean concentrations of As in agricultural soil were higher than the permissible level. Especially, maximum levels of As and Hg in farmland soil were up to 626 mg/kg and 4.9 mg/kg, respectively. The highest levels in crop plant were 33 mg As/kg and 3.8 mg Pb/kg (in green onion root), 0.87 mg Cd/kg and 226 mg Zn/kg (in lettuce root), 16.3 mg Cu/kg (in sesame leaves). The concentration of heavy metals in leaves is much higher than those in grains and stalk. Vegetables grown on the contaminated soil were rich in As and heavy metals. Concentrations of As, Cd, and Zn in most stream waters which are used for drinking water around the mine area were higher than the permissible levels regulated in Korea. Maximum levels of As, Cd and Zn in stream waters were 0.71 mg/L, 0.19 mg/L and 5.4 mg/L, respectively. These results indicate that mine tailings can be the main contamination sources of As and heavy metals in the soil–water system of the mine site. The average of estimated human-bioaccessible fraction in soil in simulated stomach was 3% As, 40% Cd, 15% Cu, 31% Pb and 21% Zn, and that in simulated small intestine 12% As, 2.2% Cd, 5.6% Cu, 0.5% Pb and 1.2% Zn. The highest value of human-bioaccessible fraction of metal in farmland soil was 85% for Cd. The estimated human-bioaccessible fraction of plant was up to 97% for Cd in simulated stomach, and to 51% for Pb in simulated small intestine. The highest human-bioaccessible fractions were found in Chinese cabbage (in stomach) and potato leaves (in small intestine). The average human-bioaccessible fraction in plants were 47% As, 70% Cd, 62% Cu, 0% Pb and 62% Zn in simulated stomach and 22% As, 7% Cd, 27% Cu, 9% Pb and 23% Zn in simulated small intestine. The HQ (hazard quotient) value of the mine site was 16, and especially, the HI (hazard index) value of only As was 15. The carcinogenic risk of the mine site was 2.7E−03. This value means the probable possibility that about 3 cancer patients among 1000 people happen. Carcinogenic risk exceeded in the generally accepted range of E−04 to E−06.This work was supported by the grant (M10324060002-03B3106-00210) from the Korea Ministry of Science and Technology

Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers

Abstract Background Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers. Methods Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated. Results Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles. Conclusions Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle. Trial registration ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010)

Whole genome survey of big cats (Genus: Panthera) identifies novel microsatellites of utility in conservation genetic study

Big cats (Genus: Panthera) are among the most threatened mammal groups of the world, owing to hunting, habitat loss, and illegal transnational trade. Conservation genetic studies and effective curbs on poaching are important for the conservation of these charismatic apex predators. A limited number of microsatellite markers exists for Panthera species and researchers often cross-amplify domestic cat microsatellites to study these species. We conducted data mining of seven Panthera genome sequences to discover microsatellites for conservation genetic studies of four threatened big cat species. A total of 32 polymorphic microsatellite loci were identified in silico and tested with 152 big cats, and were found polymorphic in most of the tested species. We propose a set of 12 novel microsatellite markers for use in conservation genetics and wildlife forensic investigations of big cat species. Cumulatively, these markers have a high discriminatory power of one in a million for unrelated individuals and one in a thousand for siblings. Similar PCR conditions of these markers increase the prospects of achieving efficient multiplex PCR assays. This study is a pioneering attempt to synthesise genome wide microsatellite markers for big cats

#523 Initial efficacy and safety results from ENGOT-Ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC)

peer reviewe

MOONSTONE/GOG-3032: Interim analysis of a phase 2 study of niraparib + dostarlimab in patients (pts) with platinum-resistant ovarian cancer (PROC)

5573 Background: PROC is poorly responsive to anticancer therapy. PARP inhibitors such as niraparib may increase neoantigen load and synergize with anti-PD-1 agents. TOPACIO reported a preliminary objective response rate (ORR: 18%) and disease control rate (DCR: 65%) to niraparib + pembrolizumab in pts with OC of any BRCA status. MOONSTONE sought to determine efficacy in pts without BRCA mutation ( BRCAm). Methods: In this phase 2 open-label, single-arm study, eligible pts received 1–3 prior lines of therapy including platinum, taxane, and bevacizumab, had RECIST v1.1 radiographic progression within 6 mo of last platinum line and had no known germline BRCAm. Pts were treated with niraparib 300/200 mg PO daily (based on weight/platelets) and 500 mg dostarlimab IV Q3W (cycles 1–4) followed by 1000 mg Q6W until disease progression, toxicity or consent withdrawal. Programmed death-ligand 1 (PD-L1) positive status was determined by Ventana SP263 assay using visually-estimated combined positive score ≥5%. The primary endpoint was investigator-assessed ORR per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), DCR, and safety. Futility was prespecified as ≤5 responses in the first 40 pts. Results: At interim analysis (data cutoff Oct 6, 2021), 41 pts were enrolled; median age was 65.0 y (range 35–77). At baseline, 8 (20%)/22 (54%)/11 (27%) pts had received 1/2/3 prior lines of therapy, respectively; 26 (63%) pts had primary resistance to platinum therapy and 15 (37%) were sensitive to first platinum treatment. Overall, tumors were PD-L1+/PD-L1–/unknown in 13 (32%)/25 (61%)/3 (7%), respectively. Efficacy results are shown in the Table. Treatment-related adverse events were reported in 95% of pts, most commonly nausea (56%), fatigue (34%), vomiting (32%), and anemia (29%). Conclusions: PROC remains difficult to treat; the ORR observed with niraparib + dostarlimab did not reach the threshold for 2nd-stage accrual in this cohort of pts with PROC, no known BRCAm, and prior bevacizumab treatment. PD-L1 status did not predict response; HRD testing is in process. Although DCR was 29%, futility was declared based on low ORR. The safety of the combination was similar to the safety profile of each monotherapy. Clinical trial information: NCT03955471. [Table: see text