BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines.
METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed.
RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest.
CONCLUSIONS: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

Cancer-associated thromboembolism (CAT), including venous thromboembolism (VTE) and arterial thromboembolism (ATE), is a frequent complication of advanced pancreatic cancer. However, reports on its incidence and clinical outcomes, especially on ATE, are limited. The present study aimed to investigate the incidence of CAT and its effects on overall survival in patients with metastatic pancreatic cancer. As part of the Tokushukai REAl-world data project in Japan, 846 eligible patients with metastatic pancreatic cancer treated with first-line chemotherapy were identified between April 2010 and March 2020. Using diagnosis procedure combination data from these patients, the present study investigated the incidence of VTE, ATE and cerebral and gastrointestinal bleeding requiring hospitalization. Blood laboratory data were collected within 14 days of the start of first-line treatment, and Khorana scores were calculated. The associations between CAT complications and comorbidities, concomitant medications and prognosis were examined. Among the 846 patients, 21 (2.5) and 70 (8.3%) had VTE and ATE, respectively (including five with overlapping VTE and ATE). CAT-positive patients had a significantly higher rate of gastrointestinal bleeding events compared with CAT-negative patients [13 of 86 (15.2%) vs. 46 of 760 (6.1%); P=0.01]. CAT-positive patients had a poorer prognosis [hazard ratio (HR), 1.28; 95% confidence interval (CI), 1.01-1.62] compared with CAT-negative patients, even after adjusting for background factors (HR, 1.20; 95% CI, 0.95-1.52). Cox regression analyses showed that higher Khorana scores were associated with significantly worse prognosis. This real-world data demonstrated that the incidence rate of CAT in patients with metastatic pancreatic cancer was 10.2%, and no statistically significant differences were observed, although there was a trend toward an adverse prognosis. The Khorana score may also be useful for predicting prognosis, even in the absence of CAT. This study was registered in the UMIN Clinical Trial Registry (http://www.umin.ac.jp/ctr/index.htm; clinical trial no. UMIN000050590).

OBJECTIVE: To assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy.
METHODS: Patients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients\' clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits.
RESULTS: Between February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival.
CONCLUSIONS: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits.
BACKGROUND: https://www.chictr.org.cn/showproj.html?proj=130211 , identifier: ChiCTR2100049799, date of registration: 2021-08-09.

UNASSIGNED: To develop and validate a nomogram for predicting the overall survival of patients with metastatic pancreatic cancer.
UNASSIGNED: This retrospective study included 236 patients with metastatic pancreatic cancer treated at Guangxi Medical University Cancer Hospital between October 2013 and October 2022. Patients were grouped according to hepatitis B virus (HBV) infection status. Cox proportional hazard regression was used to identify the prognostic factors independently associated with overall survival. Results were used to build a nomogram, which was assessed through internal validation using bootstrap resampling.
UNASSIGNED: Patients in the HBV-positive group (N = 37) showed significantly better overall survival than those in the HBV-negative group (N=199; P = 0.014). Overall survival was independently associated with the following factors: HBV infection status, sex, chemotherapy, metastatic sites, a combined index of hemoglobin, albumin, lymphocytes, and platelets, neutrophil-albumin ratio, as well as levels of CA125. The nomogram showed good predictive power, with an area under the curve of 0.808 for the time-dependent receiver operating characteristic. Calibration and decision curve analyses indicated good calibration and clinical usefulness of the nomogram for predicting the overall survival of patients with metastatic pancreatic cancer.
UNASSIGNED: A nomogram based on the HBV infection status and inflammatory nutritional markers may help predict the overall survival of patients with metastatic pancreatic cancer and guide personalized clinical treatment.

OBJECTIVE: The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy.
METHODS: This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut-off value. The Kaplan-Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA).
RESULTS: The best cut-off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional-hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms\' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA.
CONCLUSIONS: We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.

The long-term follow-up findings of the phase I trial evaluating the efficacy of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy in metastatic pancreatic cancer (mPC) seem very promising. The study employed a replication-competent Adenovector in combination with chemotherapy in a dose-escalation format. The trial demonstrated a clinically meaningful median overall survival (OS) benefit, with patients in the highest dose cohort exhibiting an impressive median OS of 18.4 months. This contrasts starkly with patients receiving lower doses who experienced a median OS of 4.8 and 3.5 months, respectively. Remarkably, subject number 10, who received the highest dose, demonstrated an extraordinary survival of 59.1 months, presenting a compelling case for further exploration. Additionally, this patient displayed complete responses in lung and liver metastases, a rare occurrence in mPC treatment. Statistical analyses supported the observed survival benefit. The unprecedented OS results emphasize the potential of this treatment strategy and pave the way for future investigations into this promising gene therapy approach.

UNASSIGNED: There is a controversy about whether surgery should proceed among metastatic pancreatic cancer (mPC) patients. A survival benefit was observed in mPC patients who underwent primary tumor resection; however, determining which patients would benefit from surgery is complex. For this purpose, we created a model to identify mPC patients who may benefit from primary tumor excision.
UNASSIGNED: Patients with mPC were extracted from the Surveillance, Epidemiology, and End Results database, and separated into surgery and nonsurgery groups based on whether the primary tumor was resected. Propensity score matching (PSM) was applied to balance confounding factors between the two groups. A nomogram was developed using multivariable logistic regression to estimate surgical benefit. Our model is evaluated using multiple methods.
UNASSIGNED: About 662 of 14,183 mPC patients had primary tumor surgery. Kaplan-Meier analyses showed that the surgery group had a better prognosis. After PSM, a survival benefit was still observed in the surgery group. Among the surgery cohort, 202 patients survived longer than 4 months (surgery-beneficial group). The nomogram discriminated better in training and validation sets under the receiver operating characteristic (ROC) curve (AUC), and calibration curves were consistent. Decision curve analysis (DCA) revealed that it was clinically valuable. This model is better at identifying candidates for primary tumor excision.
UNASSIGNED: A helpful prediction model was developed and validated to identify ideal candidates who may benefit from primary tumor resection in mPC.

UNASSIGNED: The regimen with nanoliposomal irinotecan plus 5-fluorouracil and L-leucovorin (nal-IRI/FL) is used for metastatic pancreatic cancer. A clinical study has indicated that the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 polymorphism is associated with neutropenia during nal-IRI/FL treatment; however, no studies have reported risk factors for the occurrence of adverse events in the clinical setting. This study aimed to explore the risk factors for adverse events of nal-IRI/FL.
UNASSIGNED: This study included patients with metastatic pancreatic cancer who started nal-IRI/FL treatment. Patient information, including laboratory data before nal-IRI/FL initiation and adverse events during nal-IRI/FL treatment, was retrospectively obtained from medical records.
UNASSIGNED: This study consisted of 36 patients, including 16, 16, and 4 with UGT1A1*6 or *28 wild-type (-/-), heterozygous (+/-), and homozygous (+/+), respectively. Patients with UGT1A1*6 or *28 (+/+) exhibited significantly lower nadir counts of white blood cells (p=0.033) and neutrophils (p=0.043). Multiple regression analyses revealed that the decreased white blood cell count was significantly associated with the genotype of UGT1A1*6 or *28 (+/+) (p=0.009), high aspartate aminotransferase (AST) value before the therapy (p=0.019), and pancreatic head cancer (p=0.030). Also, the decreased neutrophil count was significantly related to the genotype of UGT1A1*6 or *28 (+/+) (p=0.017).
UNASSIGNED: Patients with UGT1A1*6 or *28 (+/+) should be especially concerned about neutropenia and leukopenia during nal-IRI/FL treatment. Additionally, high AST value and pancreatic head cancer may be risk factors for leukopenia during nal-IRI/FL treatment.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a notably poor prognosis. A large number of patients with PDAC develop metastases before they are diagnosed with metastatic pancreatic cancer (mPDAC). For mPDAC, FOLFIRINOX or gemcitabine plus nab-paclitaxel are the current first-line treatments. It is important to note, however, that many patients will fail chemotherapy because of drug resistance. ​Heterogeneous tumors and complex tumor microenvironments are key factors. As a result, clinical researchers are exploring a variety of alternative treatment modalities. Current understanding of the molecular signature and immune landscape of PDAC has motivated the emergence of different targeted and immune-based therapeutic approaches, some of which have shown promising results. The purpose of this review is to discuss the new targets and new drugs for mPDAC in terms of specific pathogenic factors such as metabolic vulnerability, DNA damage repair system, tumor microenvironment and immune system, in order to identify potential vulnerabilities in mPDAC patients and hopefully improve the prognosis of mPDAC patients.