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Background: This systematic review and network meta-analysis aimed to assess the comparative effectiveness and safety profiles of current combination therapies based on androgen deprivation therapy (ADT) for the heterogeneous population of individuals with metastatic castration-sensitive prostate cancer (mCSPC)., Methods: We retrieved pertinent literature from PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov, and international conference databases. The study was registered in the Prospective Register of Systematic Reviews (CRD42023453853) for transparency., Results: Our analysis included 20 RCTs involving 14,995 patients, evaluating 15 ADT-based combinations, including systemic therapies, radiotherapy and surgery. In the overall population, the darolutamide triplet (DARO + docetaxel + ADT) demonstrated comparable overall survival (OS) benefits to prostatectomy/radical local therapy (RLT) plus ADT (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.43-1.57). Additionally, the enzalutamide (ENZ) triplet (ENZ + DOC + ADT) appeared to confer the best progression-free survival (HR, 0.34; 95% CI: 0.27-0.43). Subgroup analysis based on metastatic burden indicated that RLT plus ADT had the best OS performance in patients with low burden, while the DARO triplet was associated with the best OS in patients with high burden. Regarding adverse events (AEs), the addition of certain androgen receptor pathway inhibitor (ARPI) agents to ADT led to an increased incidence of severe AEs, while the addition of DOC to the ARPI doublet did not appear to elevate the exposure-adjusted incidence rates., Conclusions: Our findings suggest that combined treatments result in better survival outcomes than does ADT alone. In the current landscape of systemic therapy, the significance of local therapy should not be underestimated, and therapeutic decisions should be tailored with meticulous consideration of clinical heterogeneity among patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC., Experimental Approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC., Key Results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells., Conclusion and Implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer., Design: Randomised, multicentre, open label, phase 3 trial., Setting: 7 cancer centres in China between 3 January 2016 and 17 July 2023., Participants: Female patients aged 18-70 years with early triple negative breast cancer after definitive surgery., Interventions: After risk stratification using the integrated signature, patients at high risk were randomised (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (arm A; n=166) or a standard treatment of four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (arm B; n=170). Patients at low risk received the same adjuvant chemotherapy as arm B (arm C; n=168)., Main Outcome Measures: The primary endpoint was disease-free survival in the intention-to-treat analysis for arm A versus arm B. Secondary endpoints included disease-free survival for arm C versus arm B, recurrence-free survival, overall survival, and safety., Results: Among the 504 enrolled patients, 498 received study treatment. At a median follow-up of 45.1 months, the three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03). The three year recurrence-free survival rate was 92.6% in arm A and 83.2% in arm B (hazard ratio 0.50, 95% CI 0.25 to 0.98; P=0.04). The three year overall survival rate was 98.2% in arm A and 91.3% in arm B (hazard ratio 0.58, 95% CI 0.22 to 1.54; P=0.27). The rates of disease-free survival (three year disease-free survival 90.1% v 80.6%; hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04), recurrence-free survival (three year recurrence-free survival 94.5% v 83.2%; 0.42, 0.22 to 0.81; P=0.007), and overall survival (three year overall survival 100% v 91.3%; 0.14, 0.03 to 0.61; P=0.002) were significantly higher in patients in arm C than in those in arm B with the same chemotherapy regimen. The incidence of grade 3-4 treatment related adverse events were 64% (105/163), 51% (86/169), and 54% (90/166) for arms A, B, and C, respectively. No treatment related deaths occurred., Conclusions: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable triple negative breast cancer. Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity., Trial Registration: ClinicalTrials.gov NCT02641847., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the National Key Research and Development Project of China, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Shanghai Key Laboratory of Breast Cancer, SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals, and CSPC Pharmaceutical Co Ltd, Shijiazhuang, China, for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting., Methods: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation., Results: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups., Conclusions: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms., (© 2024. The Author(s).)

Rationale: The incidence of pregnancy-associated breast cancer (PABC) is relatively low, but it has been increasing in recent years. The onset of PABC causes serious harm to the fetus and the mother due to the unique physiological characteristics of pregnancy, which poses a particular challenge to clinicians. This article reports a case of pregnancy-associated triple-negative breast cancer and describes the patient characteristics and systematic treatment of this type of breast cancer., Patient Concerns: A 33-year-old woman was admitted to hospital with a left breast mass that had appeared more than a year earlier. She was a second-time pregnant woman with a single live intrauterine fetus at 23 + 4 weeks of gestation. During the examination of the left breast, a 6 by 8 cm sized mass can be observed on the upper outer quadrant., Diagnosis: Pregnancy-associated triple-negative breast cancer., Intervention: The patient underwent a breast ultrasound which showed a left breast mass and the diagnosis was confirmed by a puncture biopsy of the left breast mass. The pregnancy was terminated after multidisciplinary discussion, taking into account the wishes of the patient and her family. After termination of the pregnancy, all treatments were given according to the standard triple-negative breast cancer (TNBC) treatment protocol. The patient was treated with neoadjuvant chemotherapy with epirubicin in combination with docetaxel (TE) in cycles of 21 days. After 3 cycles of TE, a modified radical mastectomy for left breast cancer was performed, and the appropriate radiotherapy and chemotherapy treatments were carried out in sequence., Outcomes: After the surgery, the disease-free survival for the patient was 3 months until local metastases were diagnosed. Thus the radiotherapy and chemotherapy were carried out, and then the patient was in good general condition with no recurrence or metastases., Lessons: Clinicians need more research into the diagnosis, treatment and prognosis of PABC. Improving the rate of early diagnosis and using standardized and individualized comprehensive treatment plans will minimize fetal damage and improve survival and quality of life for patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Anlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC., Methods: Locally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common., Conclusions: Anlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted., (© 2024. The Author(s).)

The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN- status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0-2.9, P = 0.034), ypN+ (HR 1.9, 95% CI 1.1-3.6, P = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0-2.9, P = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL)., Methods: In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m 2 intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes., Results: Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12)., Conclusions: Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC., Competing Interests: Declaration of competing interest David M. Waterhouse received consulting fees from Bristol Myers Squibb (BMS), Amgen, Janssen, Merck, Fresenius Kabi, and Novartis; received honoraria from BMS, AstraZeneca, Amgen, Janssen, EMD Serono, Fresenius Kabi, and Sanofi; received support to attend meetings and/or travel from BMS and Amgen; and participated on a data safety monitoring board or advisory board for BMS, AstraZeneca, AbbVie, Amgen, Janssen, Eisai, EMD Serono, Merck, Pfizer, Fresenius Kabi, Sanofi, Astellas, Gilead, Takeda, Daiichi, and Bayer. Sacha Rothschild received grants or research support from AstraZeneca, Merck Serono, Roche Pharma, and Amgen; received consulting fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck KG, MSD, Novartis, Otsuka, Pfizer, PharmaMar, Roche Pharma, Roche Diagnostics, Sanofi Aventis, and Takeda; received honoraria from Roche Pharma, BMS, AstraZeneca, Amgen, MSD Oncology, Novartis, Roche Diagnostics, and Takeda; received payment for expert testimony from Roche, AstraZeneca, and BMS; received support for attending meetings and/or travel from Roche Pharma, Eli Lilly, BMS, Amgen, AstraZeneca, and MSD; participated on a data safety monitoring board or advisory board for Roche Pharma; and is the vice president of the Swiss Group for Clinical Cancer Research (SAKK) and elected member of the Swiss Federal Drug Commission (Federal Health Office). Christophe Dooms has nothing to disclose. Bertrand Mennecier received honoraria from Amgen, Roche, AstraZeneca, Pharma Mar, Eli Lilly, BMS, MSD, Sanofi, Takeda, and Pfizer; and received support for attending meetings and/or travel from MSD, Roche, BMS, AstraZeneca, and Takeda. Farastuk Bozorgmehr received grant/research support from Roche and AstraZeneca; received honoraria from Novocure, Daiichi Sankyo, GSK, and AstraZeneca, received support for attending meetings and/or travel from Janssen; and participated in a data safety monitoring board or advisory board for Amgen, AstraZeneca, Daiichi Sankyo, and Janssen. Margarita Majem received consulting fees from AstraZeneca, Roche, MSD, Janssen, and Sanofi; received honoraria from MSD, Roche, AstraZeneca, Casen Recordati, Takeda, and Helsinn; received support for attending meetings and/or travel from MSD, Pfizer, Roche, and AstraZeneca, and is the vice president of ICAPEM and a board member of AEC Barcelona. Michel M. van den Heuvel participated on a data safety monitoring board or advisory board for Amgen. Helena Linardou received payment or honoraria for lectures and/or speakers bureaus from Roche, AstraZeneca, Pfizer, BMS, MSD, Novartis, Amgen, and GSK; received support for attending meetings and/or travel from Pfizer and Roche; participated on a data safety monitoring board or advisory board for Roche, AstraZeneca, MSD, BMS, Novartis, Pfizer, and Amgen; and held unpaid positions in non-profit organizations, including president of a scientific committee in the Hellenic Cooperative Oncology Group and board member for Hellenic Foundation of Cancer Research, FairLife Lung Cancer, and W4O-Hellas. Byoung Chul Cho received grant/research support from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridge Biotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS BIO, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG. Rachel Roberts-Thomson received royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; received consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, MedPacto, Blueprint Medicines, RaND Bio, and Hanmi; received honoraria from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer; participated on a scientific advisory board for Kanaph Therapeutics, Bridge Biotherapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, and Amgen; was a board member for J INTS BIO; owned stock in TheraCanVac Inc, Gencurix Inc, Bridge Biotherapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., and J INTS BIO; was employed by Yonsei University Health System and is a founder of DAAN Biotherapeutics. Kentaro Tanaka received consulting fees from Pfizer and received honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Takeda Pharmaceutical, Novartis, Ono Pharmaceutical, Daiichi Sankyo, Merck, MSD, and BMS. Normand Blais received consulting and speakership fees from Amgen. Gustavo Schvartsman received consulting fees from AstraZeneca, BMS, Merck, Sharp & Dome, and Daiichi Sankyo; received honoraria from Roche, Amgen, Adiu, and Pfizer; and received support for attending meetings and/or travel from Merck, Sharp & Dome and Daiichi Sankyo. Karin Holmskov Hansen participated in clinical trial safety meetings for MSD and Incyte (not paid) and was head of the Danish Oncology Group until February 2023 (not paid) and a member of the Expert Committee under the Danish Medicines Council (not paid). Izabela Chmielewska received consulting honoraria from Amgen; and received speakership fees from Amgen, BMS, Takeda, Roche, and MSD. Martin D. Forster received grant/research support from Cancer Research UK Early Detection Committee Program Grant, Bristol Myers Squibb Research Grant, NIHR RfPB Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, Merck Educational Grant, MSD Educational Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, MRC BMC:DPFS Grant Award, and Boehringer Ingelheim Educational Grant and received consulting fees from Amgen and participated in an Advisory Board for Amgen. Christina Giannopoulou is an employee of Amgen Europe GmbH and holds stock in Amgen. Björn Stollenwerk is an employee of Amgen Europe GmbH and holds stock in Amgen. Cynthia C. Obiozor is an employee of and holds stock in Amgen. Yang Wang is an employee of and holds stock in Amgen.Silvia Novello received honoraria from AstraZeneca, Amgen, Thermo Fisher, MSD, Novartis, Sanofi, Roche, Pfizer, Takeda, and Janssen and participated on a data safety monitoring board or advisory board from Pfizer, AstraZeneca, Sanofi, Jannsen, and Daiichi., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lutetium-177 [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 improves survival and quality of life in patients with metastatic castration-resistant prostate cancer, but whether it confers a benefit in hormone-sensitive disease is unknown. We aimed to evaluate [ 177 Lu]Lu-PSMA-617 before docetaxel treatment in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer., Methods: UpFrontPSMA was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 11 Australian hospitals. Eligible patients had prostate adenocarcinoma without clinically significant neuroendocrine differentiation or small-cell histology, were aged 18 years or older, had less than 4 weeks on androgen deprivation therapy, had an Eastern Cooperative Oncology Group performance status of 0-2, and had high-volume PSMA-avid disease on [ 68 Ga]Ga-PSMA-11 PET-CT with no major discordance on 2-[ 18 F] fluorodeoxyglucose-PET-CT. Patients were randomly assigned (1:1) to the experimental treatment ([ 177 Lu]Lu-PSMA-617 followed 6 weeks later by docetaxel) or standard-of-care treatment (docetaxel alone) using computer-based block randomisation with random block sizes, stratified by disease volume by conventional imaging and duration of androgen deprivation therapy at the time of registration. Neither patients nor investigators were masked to treatment assignment. Patients in the experimental group received two cycles of [ 177 Lu]Lu-PSMA-617 7·5 GBq every 6 weeks intravenously, followed 6 weeks later by six cycles of docetaxel 75 mg/m 2 every 3 weeks intravenously, whereas patients in the standard-of-care treatment group received six cycles of docetaxel 75 mg/m 2 every 3 weeks intravenously. All patients received continuous androgen deprivation therapy. The primary endpoint was undetectable prostate-specific antigen (≤0·2 ng/mL) at 48 weeks, assessed using a modified intention-to-treat analysis. The trial is registered with ClinicalTrials.gov, NCT04343885., Findings: Between May 5, 2020, and April 18, 2023, 130 patients were randomly assigned, 63 (48%) to [ 177 Lu]Lu-PSMA-617 plus docetaxel and 67 (52%) to docetaxel alone. All patients were male and no race or ethnicity data were collected. Median follow-up was 2·5 years (IQR 1·8-3·0). Four patients in the docetaxel alone group withdrew consent after randomisation and no data beyond screening were collected. An additional four patients were not evaluable for the primary endpoint at 48 weeks (two in each group). 25 (41%) of 61 patients (95% CI 30-54) in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group had undetectable PSA at 48 weeks compared with ten (16%) of 61 patients (9-28) in the docetaxel alone group (OR 3·88, 95% CI 1·61-9·38; p=0·0020). The most common grade 3 or 4 treatment-related adverse events were febrile neutropenia (seven [11%] of 63 patients in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group vs six [10%] of 63 patients in the docetaxel alone group) and diarrhoea (four [6%] of 63 patients vs none). Serious adverse events occurred in 16 (25%) patients in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group (none were definitely related to [ 177 Lu]Lu-PSMA-617) and 16 (25%) patients in the docetaxel alone group. No treatment-related deaths occurred., Interpretation: [ 177 Lu]Lu-PSMA-617 followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects. Our data potentially support a role for [ 177 Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer., Funding: Prostate Cancer Research Alliance (Movember Foundation and Australian Government Medical Research Future Fund), US Department of Defence Impact Award-Clinical Trials, Endocyte/Advanced Accelerator Applications (a Novartis company), Australian Nuclear Science and Technology Organization, Victorian Cancer Agency, University of Melbourne, and Peter MacCallum Cancer Foundation., Competing Interests: Declaration of interests AAA reports grants from Aptevo Therapeutics (institutional), Astellas (investigator), Astellas (institutional), AstraZeneca (institutional), AstraZeneca (investigator), Bionomics (institutional), Bristol Myers Squibb (institutional), Eli Lilly (institutional), Exelixis (institutional), Gilead Sciences (institutional), GlaxoSmithKline (institutional), Hinova (institutional), Ipsen (institutional), Janssen (institutional), MedImmune (institutional), Merck Serono (investigator), Merck Serono (institutional), Merck Sharpe & Dohme (institutional), Novartis (institutional), Pfizer (institutional), Sanofi Aventis (institutional), and SYNthorx (institutional); consulting fees from Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck, Bayer, Ipsen, Merck Serono, Amgen, and Noxopharm; honoraria from Janssen, Astellas, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharma, Bristol Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm, Daiichi Sankyo, and Arvinas; speakers' bureau fees from Astellas, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol Myers Squibb, and Merck Serono; support for attending meetings from Amgen, Astellas, Bayer, Hinova, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; participation on data safety monitoring or advisory boards for Arvinas, Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck Sharpe & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm, and Daiichi Sankyo. MV reports personal fees from AstraZeneca and Merck Sharpe & Dohme and grants (to their institution) from AstraZeneca, Merck Sharpe & Dohme, Alpine Immune Sciences, Virocure, Hinova, Atridia/Hengrui, Antengene, and Biogene. AJW declares grants to their institution from Merck Sharpe & Dohme; consulting fees from Merck Sharpe & Dohme, Bayer, Bristol Myers Squibb, Pfizer, Ipsen, and Astellas; honoraria from Astellas and Bristol Myers Squibb; and support for attending meetings from Bayer. AG reports grants from Sun Pharma; consulting fees from Regeneron and Bayer; support to attend meetings from Sun Pharma and Bristol Myers Squibb; and participation in a data safety monitoring or advisory board for Regeneron and Bayer. RJF reports committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). LE reports research grant support (to their institution) from Novartis and Clarity Pharma; consulting fees for lectures or advisory boards from Astellas, Janssen, AstraZeneca, Clarity, Novartis, and Telix in the past 5 years; and philanthropic grant support from the Prostate Cancer Foundation, St Vincent's Clinic Research Foundation, and the Curran Foundation. DGM has received reimbursement for advisory board or speaker bureau activity from the following companies (in the past 36 months): Janssen, Astellas, Bayer, AstraZeneca, Mundipharma, Novartis, and Ipsen. AR has received reimbursement for advisory board or speaker bureau activity from the following companies: AstraZeneca, Daiichi Sankyo, Lily, Pfizer, Merck Sharpe & Dohme, Roche, and Novartis. DAP reports personal fees from Eisai. MSH reports grants and receipt of equipment, materials, drugs, medical writing, gifts, or other services from the Prostate Cancer Foundation, NHRMC, Movember, US Department of Defense, Medical Research Future Fund, Bayer, Peter MacCallum Foundation, Isotopia, and the Australian Nuclear Science and Technology Organisation; consulting fees from Merck Sharp & Dohme and Novartis; honoraria from Janssen, Novartis, and AstraZeneca; and support for meetings from Merck Sharp & Dohme, Novartis, Janssen, AstraZeneca, and Astellas. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations., Methods: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m 2 on day 1 and either plinabulin (30 mg/m 2 ) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed., Findings: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group., Interpretation: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population., Funding: BeyondSpring Pharmaceuticals., Competing Interests: Declaration of interests TF received research funding from BeyondSpring Pharmaceuticals to conduct this trial and is a speaker for Sanofi and Sobi. CH received research funding from BeyondSpring Pharmaceuticals to conduct this trial. GHK is President of Kentucky Society of Oncology and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from BMS, Genentech, AstraZeneca, Regeneron, Guardant, EMD Serono, and Novartis; consulting fees from BMS, Genentech, AstraZeneca, Regeneron, and Guardant; and payment for participation on a data safety monitoring board or advisory board from BMS, Genentech, AstraZeneca, and Regeneron. LB has received research support from Beyondspring and consulting fees from Sanofi, Gilead, Pfizer, Boehringer Ingelheim, Neuvogen, Bayer, BioAtla, Daichi, Summit, Anheart, Merck, Abbvie, Regeneron, Janssen, Genentech, Novocure, InterVenn, Elevation Oncology, Turning Point, and Novartis; and has participated on data safety monitoring board or advisory boards for ORIC Pharmaceuticals. JZ, ZJ, BH, FY, ZL, YSu, and JS have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from MSD, BeiGene, Roche, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Programmed cell death-1 (PD-1) blockade improves survival in patients with advanced esophageal squamous cell carcinoma (ESCC). However, the efficacy of taxanes after exposure to PD-1 blockade remains unclear in patients with advanced ESCC., Methods: We retrospectively analyzed the clinical outcomes of advanced ESCC patients treated with taxanes (paclitaxel or docetaxel) with/without prior exposure to PD-1 blockade (Exposed /Naïve group) at National Cancer Center Hospital from June 2016 to December 2020., Results: Ninety-nine patients (Exposed group, n = 32; Naïve group, n = 67) were included. The objective response rate (ORR) of the Exposed group was significantly higher than that of the Naïve group (37.5% vs. 13.4%, p = 0.009). The median progression-free survival was similar between the Exposed and Naïve groups (3.8 vs. 2.8 months, HR 1.12, 95% CI 0.65-1.86, p = 0.66). PD-1 blockade exposure independently predicated higher ORR to taxanes in multivariate analysis. Grade ≥ 3 adverse events were comparable between the Exposed and Naïve groups (45.8% vs. 40.3%, p = 0.64)., Conclusions: Taxanes following PD-1 blockade in advanced ESCC showed a higher ORR but similar PFS compared to taxanes without prior PD-1 exposure., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear., Methods: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI)., Results: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts., Conclusions: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC., Competing Interests: Disclosure Loana Valenca received consulting fees from Janssen and travel grants from Janssen, Astellas, and Bayer. The other authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: To evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ZRC-3277 (pertuzumab biosimilar) with Perjeta® (pertuzumab) in previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)., Patients and Methods: This phase III, multicenter, double-blind study across 38 sites in India randomized (1:1) patients with HER2-positive MBC in either the ZRC-3277 or Perjeta® group. Both groups also received trastuzumab and docetaxel. Of 268 enrolled patients, mITT population had 243 patients (119 and 124 in the ZRC-3277 and Perjeta® groups, respectively). The primary objective was to compare the between-group objective response rate (ORR) after 6 cycles of treatment. ORR was determined by evaluating scans of computed tomography or magnetic resonance imaging following Response Evaluation Criteria in Solid Tumor (RECIST 1.1). Two-sided 95% confidence interval (95% CI) for the difference in ORR was determined to evaluate the noninferiority of ZRC-3277 to Perjeta®. The secondary outcomes included the assessment of PK, immunogenicity, and safety between the 2 groups., Results: In the mITT population, 104 (87.39%) and 114 (91.94%) participants achieved the ORR in the ZRC-3277 and Perjeta® groups, respectively. For predefined -15% noninferiority margin, obtained 2-sided 95% CIs (-12.19%, 3.11%) for the difference in ORR (-4.55%) between the 2 groups demonstrated the noninferiority of ZRC-3277 to Perjeta®. PK, immunogenicity, and safety were not significantly different between the 2 groups., Conclusion: Efficacy, PK, immunogenicity, and safety profiles of ZRC-3277 was found to be similar to those of Perjeta®., Competing Interests: Disclosure Deven Parmar is an employee of Zydus Therapeutics Inc, USA, whereas Maulik Doshi and Rahul Shrivastava are employees of Zydus Lifesciences Ltd. All other authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown., Methods: We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital., Results: Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0-NA] and 10.0 months (95% CI 6.3-15.6), respectively. Median OS [not reached (95% CI 31.5-NA) vs. 21.4 months (95% CI 13.5-33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4-NA) vs. 7.4 months (95% CI 6.0-12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%)., Discussion: The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival., (© 2024. The Author(s).)

Objective: Radical cystectomy (RC) is the standard of care (SOC) in BCG-unresponsive NMIBC and is associated with a significant health-related quality-of-life burden. Recently, promising results have been published on Gemcitabine/Docetaxel, Pembrolizumab, and Hyperthermic Intravesical Chemotherapy (HIVEC) as salvage therapy options trying to increase the rate of bladder preservation. Here, we performed a Cost-Effectiveness-Analysis of those treatment modalities., Patients and Methods: We developed a Markov model from a payer's perspective drawing on clinical data of single-arm trials testing intravesical gemcitabine/docetaxel and pembrolizumab in BCG-unresponsive NMIBC, as well as clinical data from patients receiving hyperthermic intravesical chemotherapy HIVEC (n = 29) as intravesical salvage chemotherapy at our uro-oncological centre in Cologne. Costs were simulated utilising a non-commercial diagnosis-related groups grouper, utilities were derived from comparable cost-effectiveness studies. We used a Monte Carlo simulation to identify the optimal treatment, comparing the incremental cost effectiveness ratios (ICERs) at a willingness-to-pay threshold of €50 000 (euro)/quality-adjusted life year (QALY)., Results: Over a horizon of 10 years, gemcitabine/docetaxel, HIVEC, and pembrolizumab were associated with costs of €48 353, €64 438, and €204 580, as well as a gain of QALYs of 6.16, 6.48, and 6.00, resulting in an ICER of €26 482, €42 567, and €184 533 respectively, in comparison to RC with total costs of €21 871 and a gain of QALYs of 5.01. Monte Carlo simulation identified HIVEC as the treatment of choice under assumption of a WTP of <€50 000., Conclusion: Considering a WTP of <€50 000/QALY, gemcitabine/docetaxel and HIVEC are highly cost-effective therapeutic options in BCG-refractory NMIBC, while RC remains the cheapest option. At its current price, pembrolizumab would only be cost-effective assuming a price reduction of at least 70%., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive cancer-related disease with a dismal clinical course. The patient in this report was a 43-year-old man with metastatic salivary duct carcinoma arising from the parotid gland. Combined androgen blockade therapy was administered started as first-line treatment, but failed after 5 months, followed by docetaxel plus carboplatin therapy as second-line treatment, which failed after 3 months. Genomic profiling revealed a BRAF V600E mutation, and combined BRAF and MEK inhibitor therapy was started as third-line treatment. The cancer remained stable during the first 10 months of third-line treatment, but treatment was subsequently discontinued due to the onset of symptoms of fatigue, myalgia and arthritis. Twenty days after the onset of these symptoms and interruption of third-line treatment, the patient was urgently admitted to hospital with respiratory distress and severe thrombocytopenia. CT images at the time of admission led our radiologist to the possibility of PTTM, but the patient died the day after admission and autopsy findings indicated that PTTM was the cause of death. This report describes a very informative case of PTTM with sequential imaging and detailed autopsy findings were available and provides a literature review., Competing Interests: Declaration of competing interest Three of the authors (Yoshitaka Honma, Ken Kato, Masahiko Kusumoto) declare the following financial interests/personal relationships which may be considered as potential competing interests: 1) Yoshitaka Honma has received compensation as a member of the advisory role of Janssen, Eisai, and Rakuten Medical Japan; received honoraria from Novartis, Chugai pharma, MSD, Ono pharmaceutical, Bristol Myers Squibb, Merck Biopharma, Eisai, Eli Lilly, Nutri, Teijin pharma, Bayer, and Taiho pharmaceutical; and received research funding from Taiho pharmaceutical, Chugai pharma, MSD, GlaxoSmithKline, Janssen, Adlai Nortye Biopharma, Maruho, Merck Biopharma, Genmab, Astellas pharma, Rakuten Medical Japan, and AstraZeneca. 2) Ken Kato reports funding to the institution from Merck Sharp & Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai. 3) Masahiko Kusumoto received honoraria for lecture fees from Daiichi-Sankyo Co.,Ltd. Masahiko Kusumoto received a research grant from Canon medical systems corporation., (Copyright © 2024. Published by Elsevier B.V.)

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Proton pump inhibitors (PPIs) are widely used due to their affordability and minimal severe side effects. However, their influence on the efficacy of cancer treatments, particularly androgen receptor signaling inhibitors (ARSIs), remains unclear. This study investigates the impact of PPI usage on the treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: A total of 117 mCRPC patients were retrospectively analyzed and divided into two groups based on the concomitant use of PPI at the initiation of ARSI treatment: PPI+ (n = 38) and PPI- (n = 79). Patient characteristics, including age at ARSI treatment administered, prostate-specific antigen (PSA) value at ARSI treatment administered, International Society of Urological Pathology grade group at prostate biopsy, metastatic site at ARSI treatment administered, prior docetaxel (DTX) treatment, and type of ARSI (abiraterone acetate or enzalutamide) were recorded. Progression-free survival (PFS), overall survival (OS), and PSA response rates were compared between the two groups. Patients were further stratified by clinical background to compare PFS and OS between the two groups., Results: The PPI- group exhibited significantly extended PFS and a trend toward improved OS. For PSA response (reduction of 50% or more from baseline), the rates were 62.3% and 45.9% in the PPI- group and the PPI+ group, respectively. For deep PSA response (reductions of 90% or more from baseline), the rates were 36.4% and 24.3% in the PPI- group and the PPI+ group, respectively. The effects were consistent across subgroups divided by prior DTX treatment and type of ARSI administered., Conclusions: The administration of PPIs appears to diminish the therapeutic efficacy of ARSIs in mCRPC patients. Further prospective studies are needed to confirm these findings and explore the biological mechanisms involved., (© 2024 Wiley Periodicals LLC.)

Background and Objective: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes., Methods: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses., Key Findings and Limitations: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups., Conclusions and Clinical Implications: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data., Methods: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr., Results: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors., Conclusion: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Docetaxel is commonly used for treatment of castration-resistant prostate cancer. Unfortunately, many prostate cancer patients develop resistance to docetaxel. Clinical markers less invasive than biopsies, such as blood samples, would be ideal for monitoring and predicting patient treatment outcomes to docetaxel. Lipid alterations are often associated with the progression of many cancers, including prostate cancer. This study investigated the use of lipids from whole blood as clinical markers for docetaxel resistance in a small cohort of patients with prostate cancer. Qualitative lipidomics was performed by liquid chromatography-tandem mass spectrometry to assess the lipid composition of prostate cancer cells exposed to docetaxel as well as whole blood from prostate cancer patients before, during and after docetaxel treatment. Three patients had castration resistant prostate cancer, three had castration sensitive prostate cancer, and four had de novo prostate cancer during the extent of the study. Mean decrease accuracy and classical univariate receiving operating characteristic curve analyses were performed to identify potential biomarkers. In total, 245 and 221 altered lipids were identified from a second stage of mass spectrometry analysis of prostate cancer cells and clinical blood samples, respectively. Both models indicated that docetaxel treatment altered ether-linked phosphatidylcholines, lysophosphatidylcholine, diacylglycerols, ceramides, hexosylceramides, and sphingomyelins. The results also indicated several lipid changes were associated with sphingolipid signaling and metabolism, and glycerophospholipid metabolism. Collectively, these data suggest the potential usage of identified lipid species as indicators of docetaxel resistance in prostate cancer., (© 2024. The Author(s).)

Docetaxel is a commonly used taxane chemotherapeutic agent in the treatment of a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer. Docetaxel exerts its anti-cancer effects through inhibition of the cell cycle and induction of proapoptotic activity. However, docetaxel also impacts rapidly proliferating normal cells in the scalp hair follicles (HFs), rendering the HFs vulnerable to docetaxel-induced cell death and leading to chemotherapy-induced alopecia (CIA). In severe cases, docetaxel causes persistent or permanent CIA (pCIA) when hair does not grow back completely six months after chemotherapy cessation. Hair loss has severe negative impacts on patients' quality of life and may even compromise their compliance with treatment. This review discusses the notable prevalence of docetaxel-induced CIA and pCIA, as well as their prevention and management. At this moment, scalp cooling is the standard of care to prevent CIA. Treatment options to promote hair regrowth include but are not limited to minoxidil, photobiomodulation (PBMT), and platelet-rich plasma (PRP). In addition, a handful of current clinical trials are exploring additional agents to treat or prevent CIA. Research models of CIA, particularly ex vivo human scalp HF organ culture and in vivo mouse models with human scalp xenografts, will help expedite the translation of bench findings of CIA prevention and/or amelioration to the clinic.

For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ethnopharmacological Relevance: Traditional Chinese Medicines (TCMs) have emerged as a promising complementary therapy in the management of prostate cancer (PCa), particularly in addressing resistance to Docetaxel (DTX) chemotherapy., Aim of the Review: This review aims to elucidate the mechanisms underlying the development of resistance to DTX in PCa and explore the innovative approach of integrating TCMs in PCa treatment to overcome this resistance. Key areas of investigation include alterations in microtubule proteins, androgen receptor and androgen receptor splice variant 7, ERG rearrangement, drug efflux mechanisms, cancer stem cells, centrosome clustering, upregulation of the PI3K/AKT signaling pathway, enhanced DNA damage repair capability, and the involvement of neurotrophin receptor 1/protein kinase C., Materials and Methods: With "Prostate cancer", "Docetaxel", "Docetaxel resistance", "Natural compounds", "Traditional Chinese medicine", "Traditional Chinese medicine compound", "Medicinal plants" as the main keywords, PubMed, Web of Science and other online search engines were used for literature retrieval., Results: Our findings underscore the intricate interplay of molecular alterations that collectively contribute to the resistance of PCa cells to DTX. Moreover, we highlight the potential of TCMs as a promising complementary therapy, showcasing their ability to counteract DTX resistance and enhance therapeutic efficacy., Conclusion: The integration of TCMs in PCa treatment emerges as an innovative approach with significant potential to overcome DTX resistance. This review not only provides insights into the mechanisms of resistance but also presents new prospects for improving the clinical outcomes of patients with PCa undergoing DTX therapy. The comprehensive understanding of these mechanisms lays the foundation for future research and the development of more effective therapeutic interventions., Competing Interests: Declaration of competing interest We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. All authors have approved the manuscript and agree with submission to your esteemed journal., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD., Methods: In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period., Results: All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated., Conclusion: The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073)., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study., Results: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X 2  = 9.14, p < 0.05) and those below the age of 18 (X 2  = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models., Conclusion: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: The high costs of cancer care can cause significant harm to patients and society. Prostate cancer, the leading nonskin malignancy in men, is responsible for the second-highest out-of-pocket (OOP) payments among all malignancies. Multiple first-line treatment options exist for metastatic castration-resistant prostate cancer (mCRPC); although their costs vary substantially, comparative effectiveness data are limited. There is little evidence of how gross payments made by insurers and OOP payments made by patients differ by treatment and health plan type and how these payment differences relate to utilization., Study Design: Retrospective cohort study., Methods: We used IBM MarketScan databases from 2013-2019 to identify men with prostate cancer who initiated treatment with 1 of 6 drugs approved for first-line treatment of mCRPC. We calculated and compared gross and OOP payments and drug utilization across drug and insurance plan types., Results: We identified 4298 patients who met our inclusion criteria. Insurer payments varied substantially by first-line therapy but were similar across different health plan types, except for docetaxel. OOP payments for a given first-line therapy, in contrast, varied by health plan type. Utilization of first-line therapies varied by plan type in unadjusted analyses, but not after adjusting for patient characteristics., Conclusions: The extent to which patient OOP payments for drugs reflect differences in gross payments made by insurers varies across health insurance plan types. However, even though OOP payments for the same treatment differ across plan types, treatment choice is not significantly different across type of health insurance after controlling for patient characteristics.

Primary ovarian sarcoma is a rare malignancy, with primary ovarian leiomyosarcoma being even rarer because of the lack of smooth muscle in the ovaries. We herein report a case of primary ovarian leiomyosarcoma in a woman in her late 50s who presented with a 6-month history of abdominal pain. Imaging revealed a pelvic mass. The patient underwent surgery and was diagnosed with ovarian leiomyosarcoma. One month postoperatively, she began gemcitabine and docetaxel chemotherapy and continued this treatment for 6 months. Eight months postoperatively, however, recurrence was detected in the pelvic cavity. This case is reported with the aim of raising awareness about this rare disease., Competing Interests: Declaration of conflicting interestThe authors declare that they have no conflict of interest regarding the publication of this research.

Background: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer., Materials and Methods: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab)., Results: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups., Conclusion: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

Background: Guidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce., Methods: A secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method., Results: Median follow-up (f/u) for all patients was 23 months (IQR 13-34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months)., Conclusions: Gem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results., Competing Interests: Declaration of competing interest I affirm that none of the authors have a conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: ARASENS was a randomized, double-blind, phase 3 trial comparing darolutamide + docetaxel + androgen deprivation therapy (ADT) with placebo + docetaxel + ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC)., Objective: To use clinical trial data from ARASENS to understand whether the addition of darolutamide to docetaxel + ADT leads to increased hospitalizations and to estimate the budget impact on the US health care system., Methods: We used mixed-effects negative binomial regression to estimate hospitalization and intensive care unit (ICU) admission rates and length of hospital stay (LoHS) counts. Hospitalization rates were estimated per treatment arm for the period during and after administration of docetaxel. Based on these estimates, a budget impact analysis evaluated the hospitalization costs (including ICU admissions) and standalone ICU hospitalization costs for the totality of the US population over a 5-year time horizon. The analysis compared a scenario without darolutamide vs one with darolutamide included in the US payer formulary. Hospitalization estimates were varied in a one-way sensitivity analysis., Results: The first 4 months of treatment (when patients were receiving docetaxel) were associated with increased hospitalizations across both arms. The addition of darolutamide was associated with a numerical reduction in the rate of hospitalization (per year) due to any reason both during docetaxel treatment (1.01 visits per year [95% CI = 0.82-1.20] vs 1.18 visits per year [95% CI = 0.96-1.41]) and after docetaxel treatment (0.28 visits per year [95% CI = 0.23-0.34] vs 0.33 visits per year [95% CI = 0.27-0.40]). Darolutamide was associated with a marginally longer LoHS per hospitalization compared with placebo (+1.90 days per year) both during and after docetaxel treatment. ICU admissions were low in the ARASENS data; admission rates were assumed to be the same during and after docetaxel treatment. ICU admission rate estimates were equivalent across arms (0.02 visits per year [95% CI = 0.01-0.03]). The budget impact per treated member per month represents a cost-neutral option after Year 5 with a cumulative budget impact of -$9.71., Conclusions: The addition of darolutamide to docetaxel + ADT was associated with a numerically lower rate of hospitalization but marginally longer LoHS compared with docetaxel + ADT alone. Darolutamide represents a cost-neutral alternative per treated member per month compared with docetaxel + ADT with regard to hospitalizations at the end of a 5-year time horizon.

Purpose: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC., Methods: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR)., Results: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients., Conclusion: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence., (© 2024. The Author(s).)

Background/aim: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification., Patients and Methods: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated., Results: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of castration-resistance was also long and significantly longer in the undetectable PSA group than that in the detectable PSA group (median: 124 vs. 17 months, HR=0.20, 95% CI=0.12-0.34, p<0.001)., Conclusion: Patients with low-risk and/or low-volume mCSPC showed long-term survival when undetectable PSA was achieved during conventional ADT. In these patients, skipping upfront treatment intensification does not seem to negatively impact survival., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The aim of this study was to observe the therapeutic effect of sintilimab combined with a modified docetaxel + cisplatin + fluorouracil (DCF) regimen on advanced gastric cancer and its effect on Th1/Th2 immune balance. Ninety-eight cases of advanced gastric cancer patients who visited our hospital from April 2020 to May 2022 were selected and divided into 48 cases each in the conventional group and the research group by random number table method; the DCF regimen was adopted in the conventional group, and sintilimab combined with modified DCF regimen was adopted in the research group, and the therapeutic effects of the patients in the two groups and the changes of Th1/Th2 immune indexes were compared. CEA, CA199, CA242, CD168 AQ3, and IL-4 in the study group were lower than those in the conventional group at the end of three cycles of treatment, and the difference was statistically significant ( P  < 0.001). The levels of IFN-γ and IL-4 in the study group at the end of three cycles of treatment were higher than those in the conventional group ( P  < 0.001). The incidence of adverse reactions during treatment in the study group was lower than that in the conventional group ( P  < 0.001), and the grading of adverse reactions in the study group was milder than that in the conventional group. Sintilimab combined with a modified DCF regimen in the treatment of advanced gastric cancer not only improves the therapeutic effect but also positively affects the Th1/Th2 immune balance, which provides better immune regulation for patients with advanced gastric cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults., Methods: We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed., Results: Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3)., Conclusions: Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy., (© 2024 The Author(s). Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI., Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan-Meier method., Results: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel ( p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively., Conclusions: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC.

The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC 50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26 , that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

Purpose: The open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non-small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti-PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported., Methods: Patients were randomly assigned 1:1 (stratified by histology, best response to last anti-PD-(L)1-containing regimen, and AGA treatment received or not) to SG (one 10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (one 75 mg/m 2 intravenous infusion on day 1) in 21-day cycles. Primary end point was overall survival (OS). Key secondary end points were investigator-assessed progression-free survival (PFS), objective response rate, patient-reported symptom assessment, and safety., Results: In the intention-to-treat population (SG, n = 299; docetaxel, n = 304), 55.4% had one previous line of therapy. Median follow-up was 12.7 months (range, 6.0-24.0). The primary end point was not met. There was a numerical OS improvement for SG versus docetaxel (median, 11.1 v 9.8 months; hazard ratio [HR], 0.84 [95% CI, 0.68 to 1.04]; one-sided P = .0534), consistent across squamous and nonsquamous histologies. Median PFS was 4.1 versus 3.9 months (HR, 0.92 [95% CI, 0.77 to 1.11]). An OS benefit was observed for SG (n = 192) versus docetaxel (n = 191) in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen (3.5-month median OS increase; HR, 0.75 [95% CI, 0.58 to 0.97]); this was consistent across histologies. Among patients receiving SG and docetaxel, 6.8% and 14.2% discontinued because of treatment-related adverse events (TRAEs), respectively; 1.4% and 1.0%, respectively, had TRAEs leading to death., Conclusion: Although statistical significance was not met, OS numerically improved with SG versus docetaxel, which was consistent across histologies. Clinically meaningful improvement in OS was noted in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen. SG was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals.

The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Anthracycline-taxane is the standard chemotherapy strategy for treating high-risk early breast cancer despite the potentially life-threatening adverse events caused by anthracyclines. Commonly, the combination of docetaxel and cyclophosphamide (TC) is considered an alternative option. However, the efficacy of TC compared to anthracycline-taxane chemotherapy is unclear. This study compares disease-free survival (DFS), overall survival (OS) and cardiotoxicity between adjuvant TC and anthracycline-taxane for stages I-III, HER2-negative breast cancer., Methods: A systematic search on MEDLINE, Embase and Cochrane CENTRAL for randomized-controlled trials published until 11 March 2024, yielded 203 studies with 11,803 patients, and seven trials were included., Results: TC results in little to no difference in DFS (HR 1.09, 95% CI 0.98-1.20; moderate-certainty of evidence); OS (1.02, 95% CI 0.89-1.16; high-certainty of evidence); and cardiotoxicity (RR 0.54, 95% CI 0.16-1.76; high-certainty of evidence), compared to anthracycline-taxane. In the subgroup analysis, patients with ≥4 lymph nodes had improved DFS from anthracycline-taxane over TC., Conclusions: Overall, there was no difference between TC and anthracycline-taxane in DFS, OS and cardiotoxicity. In women with ≥4 nodes, anthracycline-taxane was associated with a substantial reduction in relapse events, compared to TC. Our study supports the current standard of practice, which is to use anthracycline-taxane and TC chemotherapy as a reasonable option in select cases.

Importance: The standard adjuvant treatment for patients with ERRB2-positive breast cancer is chemotherapy plus 1 year of trastuzumab. Shorter durations of trastuzumab administration improve cardiac safety, but more information is needed about their effect on survival., Objective: To compare survival outcomes after 9-week vs 1-year administration of trastuzumab with the same adjuvant chemotherapy., Design, Setting, and Participants: This post hoc secondary analysis of an open-label, multicenter, noninferiority-design randomized clinical trial included women aged 18 years or older with early ERBB2-positive, axillary node-negative or axillary node-positive breast cancer who were enrolled from January 3, 2008, to December 16, 2014, at 65 centers in 7 European countries. The current exploratory analysis was conducted after achieving the maximum attainable follow-up data when the last patient enrolled had completed the last scheduled visit in December 2022., Intervention: Chemotherapy consisted of 3 cycles of docetaxel administered at 3-week intervals followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide at 3-week intervals. Trastuzumab was administered in both groups for 9 weeks concomitantly with docetaxel. In the 9-week group, no further trastuzumab was administered after chemotherapy, whereas in the 1-year group, trastuzumab was continued after chemotherapy to complete 1 year of administration., Main Outcomes and Measures: The primary objective was disease-free survival (DFS). Distant DFS and OS were secondary objectives. Survival between groups was compared using the Kaplan-Meier method and log-rank test or univariable Cox proportional hazards regression., Results: Among the 2174 women analyzed, median age was 56 years (IQR, 48-64 years). The median follow-up time was 8.1 years (IQR, 8.0-8.9 years); 357 DFS events and 176 deaths occurred. Trastuzumab for 9 weeks was associated with shorter DFS compared with trastuzumab for 1 year (hazard ratio [HR], 1.36; 90% CI, 1.14-1.62); 10-year DFS was 80.3% in the 1-year group vs 78.6% in the 9-week group. The 5-year and 10-year OS rates were comparable between the 9-week and 1-year groups (95.0% vs 95.9% and 89.1% vs 88.2%, respectively; HR for all time points, 1.20; 90% CI, 0.94-1.54). In multivariable analyses, 9-week treatment was associated with shorter DFS compared with 1-year treatment (HR for recurrence or death, 1.36; 95% CI, 1.10-1.68; P = .005), but there was no between-group difference in OS (HR, 1.22; 95% CI, 0.90-1.64; P = .20). Only 4 patients (0.2%) died of a cardiac cause., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, 1-year vs 9-week adjuvant trastuzumab was associated with improved DFS among patients with ERRB2-positive breast cancer receiving chemotherapy, but there was no significant difference in OS between the groups., Trial Registration: ClinicalTrials.gov Identifier: NCT00593697.

High-dose intravenous vitamin C (HDIVC) administered to produce pharmacologic concentrations shows promise in preclinical models and small clinical trials, but larger prospective randomized trials are lacking. We evaluated the clinical benefit of combining HDIVC with docetaxel in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). In this double-blind, placebo-controlled phase II trial, 47 patients were randomized 2:1 to receive docetaxel (75 mg/m2 i.v.) with either HDIVC (1 g/kg) or placebo. Coprimary endpoints were PSA50 response and adverse event rates. Secondary endpoints included overall survival, radiographic progression-free survival, and quality of life measured using the Functional Assessment of Cancer Therapy-Prostate instrument. Correlative analyses included pharmacokinetics and oxidative stress markers. Eighty-nine percent of patients previously had three or more lines of therapy. The PSA50 response rate was 41% in the HDIVC group and 33% in the placebo group (P = 0.44), with comparable adverse event rates in both groups. There were no significant differences in Functional Assessment of Cancer Therapy-Prostate scores. The median radiographic progression-free survival was not significantly different between the HDIVC and placebo groups, with durations of 10.1 and 10.0 months (HR, 1.35; 95% confidence interval, 0.66-2.75; P = 0.40), respectively. The median overall survival was 15.2 months in the HDIVC group and 29.5 months in the placebo group (HR, 1.98; 95% confidence interval, 0.85-4.58; P = 0.11). HDIVC did not decrease F2-isoprostanes, indicators of oxidative stress. The study was suspended after prespecified interim analysis indicated futility in achieving primary endpoints. In this patient population, combining HDIVC with docetaxel did not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. Findings do not support the routine use of HDIVC in mCRPC treatment outside of clinical trials., Significance: This is the first randomized, placebo-controlled, double-blind trial to evaluate HDIVC in cancer treatment. The addition of HDIVC to docetaxel in patients with mCRPC does not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. The routine use of HDIVC in mCRPC treatment is not supported outside of clinical trials., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background and Objective: There has been a shift toward systemic treatment intensification for men with metastatic hormone-sensitive prostate cancer (mHSPC). Recent trials have demonstrated the efficacy of triplet therapy with an androgen receptor signalling inhibitor (ARSI), docetaxel, and androgen deprivation therapy (ADT). However, ARSI treatment is expensive. The objective was to determine the cost effectiveness of current treatments strategies for men with mHSPC., Methods: We developed a Markov state-transition model to simulate outcomes for men with newly diagnosed mHSPC. For the simulation, patients were entered in the model in the mHSPC disease state before progressing to castration-resistant disease and finally dying from prostate cancer. Costs were calculated from a USA health sector perspective in 2022 US dollars. Deterministic and probabilistic sensitivity analyses were conducted to account for uncertainty in the parameter estimates. We also performed scenario analyses for costs in the UK and Australian health sectors., Key Findings and Limitations: Treatment intensification with doublet and triplet therapy resulted in an improvement in quality-adjusted survival for all strategies in comparison to ADT monotherapy. However, only docetaxel doublet therapy was cost effective at standard thresholds, with an incremental cost-effectiveness ratio of $13 647. The cost of ARSIs needed to be discounted by 47-70% before they were cost effective. Only medication costs impacted the model results. If the generic price for abiraterone acetate is used, then triplet therapy with abiraterone is the best-value option. Similar results were obtained for analyses for the UK and Australian health sectors., Conclusions and Clinical Implications: Treatment intensification with ARSIs in men with mHSPC results in better quality-adjusted survival but is not cost effective according to standard thresholds. The costs of these medications would need to be heavily discounted before they are cost effective. The cost of generic ARSIs, once available, would render these strategies cost effective., Patient Summary: This report examines whether increasing the number of systemic drugs used to treat a patient's metastatic hormone-sensitive prostate cancer is cost effective for the health care system. We found that the additional cost of triplet therapy does not justify the increase in patient benefit., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Pyrotinib, a new irreversible dual pan-human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase inhibitor blocking EGFR and HER2, has achieved a promising efficacy for advanced HER2-positive (HER2 + ) breast cancer. This study intended to further investigate the efficacy and safety of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2 + breast cancer treatment. Methods: Thirty-eight HER2 + breast cancer patients who received neoadjuvant pyrotinib and trastuzumab plus chemotherapy (docetaxel and carboplatin) were retrospectively reviewed. Clinical response by Response Evaluation Criteria in Solid Tumors (RECIST), pathological complete response (pCR), and adverse events data was retrieved. Results: According to the RECIST, the complete response rate was 0.0%, 10.5%, and 15.8% after second-cycle, fourth-cycle, and sixth-cycle therapy, respectively; whereas the objective response rate was 76.3%, 92.1%, and 100.0%, accordingly. The total pCR (tpCR) rate was 52.6%, the pCR rate of the breast was also 52.6%, and the pCR rate of lymph nodes was 86.8%. The tpCR rate was lower in patients with HER2 immunohistochemistry (IHC)++ and amplification by fluorescent in situ hybridization (FISH) than in those with HER2 IHC+++ (14.3% vs. 61.3%, p  = 0.024), which was also lower in patients with Ki-67 expression ≥30% than in those with Ki-67 expression <30% (40.0% vs. 76.9%, p  = 0.031). The common adverse events included diarrhea (84.2%), anemia (73.7%), nausea and vomiting (63.2%), fatigue (50.0%), hypomagnesemia (44.7%), leukopenia (42.1%), thrombocytopenia (39.5%), elevated transaminase (36.8%), and pruritus (31.6%). Conclusions: Pyrotinib and trastuzumab plus chemotherapy serve as an acceptable neoadjuvant regimen exhibiting good efficacy and tolerance in HER2 + breast cancer patients, while further large-scale validation is warranted.

Purpose: The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens., Methods: A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA. Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000)., Results: Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue., Conclusion: Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: This study sought to investigate the affordable price of sotorasib among patients with previously treated advanced KRASG12C-mutant non-small cell lung cancer (NSCLC) through a cost-effectiveness analysis from the perspectives of both the Chinese healthcare system and the patients., Methods: We developed a Markov model spanning a 20-year time horizon with a cycle length of 21 days. Our data were derived from the CodeBreaK 200 clinical trial, supplemented with published literature, publicly available national databases, and local hospitals. The primary outcomes were the affordable prices of sotorasib which would result in the incremental cost-effectiveness ratios (ICERs) of sotorasib relative to docetaxel below the preset willing-to-pay (WTP) threshold. Sensitivity analyses were performed to evaluate the model's robustness., Results: At the national level, from the perspective of the Chinese healthcare system and patients, the price of sotorasib should be lower than US$0.04673 and $0.03231, respectively, to make it affordable, which is equivalent to $1346 and $931 per box (120 mg × 240 pieces). At the provincial level, the price ceiling of sotorasib/mg fluctuated between $0.04084 to $0.08061 from the Chinese healthcare system's perspective and between $0.02642 to $0.06620 from the patients' perspective. Probabilistic sensitivity analyses revealed that, as the price of sotorasib decreased, its likelihood of being cost-effective increased., Conclusion: Sotorasib might be a cost-effective therapy in China. The pharmaco-economic evidence generated from this study has significant implications not only for guiding the drug pricing of the upcoming sotorasib but also for determining the reimbursement ratio for its potential inclusion in the National Reimbursement Drugs List in the future., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)