bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonadherence to medications for chronic conditions and risk of nonadherence to androgen receptor signaling inhibitors (ARSIs) in patients with prostate cancer.
Authors: Lichtenstein Morgan RL , Raghunathan Rohit R. , Wei Alexander Z , Gershman Boris , Stein Mark N. , Hershman Dawn L. 
Published: January 2024

92 Background: While ARSIs have become a cornerstone in treatment for prostate cancer, nonadherence to these oral medications is common. We investigated the association between patterns of prior nonadherence to medications for chronic conditions with ARSI nonadherence. Methods: In this retrospective cohort study, the MarketScan database was searched for patients >18 years old with a prostate cancer claim between 1/1/2014 and 12/31/2019 and who filled >2 ARSI prescriptions between 9/1/2013 and 12/31/2020. Nonadherence to medications for 4 chronic conditions (hypertension, hyperlipidemia, diabetes, benign prostatic hypertrophy (BPH)) in the 12 months before diagnosis was defined as a medication possession ratio (MPR) <80%. Nonadherence to ARSIs was defined as an MPR <80% between the first and last ARSI prescription up to 1 year. We used logistic regression to examine the relationship between nonadherence to prior medications and nonadherence to ARSIs. Results: Among 4,898 patients, 967 (19.7%) were nonadherent to ARSIs. Regarding prior medication nonadherence, of the patients prescribed hypertension medications (n=2602), 15.4% (n=402) were nonadherent to hypertension medications, of those prescribed hyperlipidemia medications (n=2234), 18.8% (n=419) were nonadherent to hyperlipidemia medications, of those prescribed diabetes mediations (n=826), 19.1% (n=158) were nonadherent to diabetes mediations, and of those prescribed BPH medications (n=1827), 13.4% (n=245) were nonadherent to BPH medications. Among those without prior medications (n=1031 [21.1%]), 21.3% of patients were nonadherent to ARSIs. Compared to those without prior medications, those who used at least 1 medication prior to ARSI and were adherent to all of them (n=2919 [59.6%]) had a 17.2% nonadherence rate to ARSI treatment (OR: 0.77; 95% CI: 0.64, 0.91; p: 0.003). Those who used at least 1 medication prior to ARSI and were nonadherent to 1 of them (n=722 [14.7%]) had a 24.0% nonadherence rate to ARSI (OR: 1.16; 95% CI: 0.93,1.46; p: 0.195), while those who used at least 1 medication prior to ARSI and were nonadherent to >2 (n=226 [4.6%]) had a 30.5% nonadherence rate to ARSI (OR: 1.62; 95% CI: 1.18,2.23; p: 0.003). Conclusions: Nonadherence to medications for chronic conditions prior to ARSI treatment is common and associated with greater nonadherence to ARSIs in patients with prostate cancer. History of medication nonadherence could serve a marker to target a high-risk population for adherence interventions. [Table: see text]
A cost-effectiveness analysis assessing systemic treatments in metastatic castration-sensitive prostate cancer (mCSPC) by volume of disease.
Authors: Naqvi Syed Arsalan Ahmed , Faisal Kunwer Sufyan , Khan Muhammad Ali , Khakwani Kaneez Zahra Rubab , Van Houten Holly K. , Moriarty James P. , Borah Bijan J. , Singh Parminder , Childs Daniel S , Sharma Vidit , Boorjian Stephen A. , Humphreys Mitchell R. , Sartor Oliver , Cobran Ewan Kemar , Riaz Irbaz Bin , Bryce Alan Haruo 
Published: January 2024

93 Background: The treatment paradigm for mCSPC patients has rapidly evolved over the last few years with the emergence of triplet therapy and prognostication by volume of disease. However, the health economic implications of triplet therapy by disease volume remain unclear. Methods: A Markov model where patients transitioned between the progression-free, progression and death states was developed. State utilities were derived from the LATITUDE trial. Point probabilities for overall survival, progression-free survival, grade ≥ 3 and 5 toxicities were obtained from the eligible mCSPC phase III clinical trials. Medicare Advantage and commercial total paid amounts (2022 US$) of treatments were obtained from OptumLabs Data Warehouse. Costs and disutilities of adverse events were derived from published literature. Half-cycle corrected costs and utilities were accrued monthly over a 20-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to calculate incremental cost-effectiveness ratios (ICERs). A willingness-to-pay (WTP) threshold of US$100,000 was used. Results: In terms of Medicare Advantage payer’s perspective (Table), docetaxel (D)+ADT was observed to provide additional 0.068 QALYs compared to ADT at an ICER of US$16,544 per QALY in high volume disease. Compared to D+ADT, abiraterone (AAP) triplet provided additional 1.03 QALYs at US$56,641 per QALY. Compared to AAP triplet, apalutamide (APA)+ADT provided additional 0.048 QALYs at US$5,846,248 per QALY in high volume disease. In low volume disease, D+ADT provided 0.45 more QALYs at US$20,690 per QALY compared to ADT alone. Compared to D+ADT, AAP triplet provided an additional 1.51 QALYS at US$44,267 per QALY. In terms of total paid commercial costs, AAP triplet provided an additional 1.19 QALYs compared to ADT at US$91,952 per QALY in high volume disease. In low volume, D+ADT provided additional 0.38 QALYs at US$22,058 per QALY compared to ADT. Compared to D+ADT, AAP triplet provided a 0.97 QALY gain at US$105,958 per QALY. Compared to AAP triplet, darolutamide (DARO) triplet provided a 0.47 QALY at US$689,196 per QALY. Compared to DARO triplet, APA+ADT provided an additional 0.49 QALYs at an ICER of US$971,389 per QALY. All other treatments (not reported here) were dominated. Conclusions: At the selected WTP of US$100,000 per QALY, AAP triplet therapy was most likely the cost-effective strategy in overall mCSPC population particularly in patients with high volume disease. However, these results should be interpreted with careful accounting for timing of metastases. [Table: see text]
Impact of combined novel hormonal agents on testosterone levels of patients with prostate cancer undergoing treatment with leuprorelin.
Authors: Lages Dr. Paulo Sergio , Vargas Pivato de Almeida Daniel , Bergerot Paulo Gustavo , Barbosa Michelle , Lages Luciana , Morbeck Igor Alexandre Protzner , Zulli Guilherme Augusto 
Published: January 2024

95 Background: Novel hormonal agents (NHA) are part of the management of prostate cancer (PCa) since from the high-risk localized disease throughout the disease continuum, while sustained androgen deprivation therapy (ADT), through the utilization of gonadotropin-releasing hormone (GnRH) agonists or antagonists, stands as the cornerstone of this combined treatment regimen. Although deeper and earlier PSA response rates were demonstrated with these combinations, there is a lack of information on the testosterone levels during the treatment with this doublet. In this retrospective real-world study, we meticulously analyzed data on testosterone tests obtained from a prominent Brazilian institution to comprehensively assess the clinical efficacy of leuprorelin either in monotherapy or in combinations on the management of PCa. Methods: We conducted a retrospective analysis by gathering data from the medical records of pts diagnosed with PCa who were undergoing treatment with leuprorelin alone or in combination with a novel hormonal agent (NHA). Descriptive statistics was assessed by medians and comparison between groups was assessed by chi-square test. This data collection spanned a nine-year period from 2014 to 2023. Results: A total of 1,744 tests were collected from 240 individual pts. Median baseline testosterone level was 373.9 ng/mL among those treated with leuprorelin monotherapy and 368 ng/mL for those receiving leuprorelin + NHA. Testosterone levels < 50 ng/mL were achieved in 776/786 tests (98.7%) of pts receiving leuprorelin and 945/958 tests (98.6%) in pts receiving leuprorelin + NHA (p=0.9). Testosterone levels < 20 ng/mL were found in 633/786 tests (80.5%) of pts receiving leuprorelin and 842/958 tests (87.9%) in pts receiving leuprorelin + NHA (p < 0.0001). Conclusions: In this robust institutional database analysis, we demonstrated that leuprorelin demonstrated similar levels of testosterone suppression (< 50 ng/mL) both in monotherapy or combined with NHA. However, when analyzing deeper testosterone suppression levels, the addition of NHA was associated with statistically significant difference in the rate of patients with testosterone < 20 ng/mL. These results reinforce the importance of intense hormonal treatment in pts with PCa receiving leuprorelin.
Association of body-mass index (BMI) with age, PSA, and survival in metastatic prostate cancer.
Authors: Schoen Martin W. , Montgomery Robert Bruce , Khan Saira , Eaton Daniel B. , Fedele Nicholas , Sachdeva Ashwin , Hahn Andrew Warren , Etzioni Ruth Douglas 
Published: January 2024

96 Background: Increased body-mass index (BMI) is associated with increased prostate cancer incidence and death. However, an ‘obesity paradox’ exists where patients with BMI have longer survival once diagnosed with cancer. We investigated the influence of BMI on overall survival of veterans with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: Two cohorts were identified in the US Veterans Health Affairs. The mHSPC cohort included patients diagnosed with de-novo mHSPC from 2011-2021. The mCRPC cohort was treated with abiraterone or enzalutamide from May 2011 to June 2017. We determined BMI at time of treatment and weight loss during the one year prior. BMI was categorized as ≤20, >20-25, >25-30 or >30 kg/m2. We used Kruskal-Wallis testing for ordinal variables and Cox hazard models to assess the association between BMI, age, Charlson comorbidity index, PSA level at diagnosis, Black race, weight loss, and survival. Results: We identified 5019 veterans with mHSPC and 8159 with mCRPC. Mean BMI was 27.2 (SD 5.9) in mHSPC and 28.2 (SD 5.8) in mCRPC. Mean age was 75.7 years (SD 9.8) in mHSPC and mean age of 74.6 (SD 9.3) in mCRPC. Median overall survival was 25.6 months (95% CI 24.6-26.6) in mHSPC and 20.5 months (95% CI 19.9-21.1) in mCRPC. There were significant differences in age, Black race, and PSA at diagnosis across BMI strata with BMI>30 having the youngest age, lowest percentage of Black race, lowest PSA, and longest survival in mHSPC and mCRPC (see Table). In unadjusted analyses, veterans with BMI>30 had lowest risk of death with Hazard Ratio (HR) 0.66 (95% CI 0.60-0.71) in mHSPC and 0.60 (95% CI 0.56-0.64) in mCRPC compared to BMI>20-25. In adjusted analyses, veterans with BMI>30 had lowest risk of death with adjusted hazard ratio (HR) 0.89 (95% CI 0.81-0.97) in mHSPC and HR 0.77 (95% CI 0.72-0.83) in mCRPC compared to BMI>20-25. Conclusions: Increased BMI is associated with younger age at diagnosis, lower PSA, and longer survival in both mHSPC and mCRPC. Further studies between BMI and prostate cancer are warranted to understand these complex interactions. [Table: see text]
Measuring oncological value of exercise and statin: Can we improve the prognosis of patients with cancer and change the microenvironment in different tumor types with exercise and statins (MOVES study)?
Authors: Sormunen Jorma T.J , Hakulinen Annastiina , Kemppainen Jukka , Tiainen Leena , Staff Synnöve , Kankaanranta Krista , Murtola Teemu 
Published: January 2024

TPS234 Background: Hypoxia is an important mechanism in cancer cells, which protects them from body’s immune reactions. Exercise improves circulation thus reducing hypoxia. Therefore, we study the effect of exercise and statins on prognosis of cancer patients. Lipid metabolism is an important energy source during hypoxia. We expect to see that patients who participate in regular physical exercise and use lipid-lowering medicine atorvastatin have longer survival than patients without such intervention. Methods: The MOVES study is an open-label single-centre randomised controlled phase 3 pilot trial. A total of 240 adult patients with stage IV cancer (prostate, renal cell, breast or ovarian) and starting 1st line oncological treatment are randomised 1:1:1 into one of three groups: 1) Supervised exercise for 3 months; 2) Supervised exercise with 40 mg atorvastatin daily for 3 months; and 3) Control group. Patients are followed at 3-month intervals for up to two years. Choice of oncological treatment is up to the clinician’s discretion according to the patient’s clinical need. Radiological, clinical and/or biochemical progression, death, side effects of the treatments and interruptions of the cancer treatments are registered. The primary outcome is progression-free survival, measured as time to 2nd line oncological treatment or death. The secondary outcomes are overall survival, quality of life, levels of hypoxia markers and cancer metabolites in blood and urine and treatment tolerability. A substudy will implement EF5-PET and FDG-PET scans to evaluate tumor hypoxia and metabolic activity before and after the trial intervention. The Ethics Committee of Tampere University Hospital has approved the study protocol. Results will be published after completion of the study in international peer viewed journals. Clinical trial information: NCT05796973 .
A phase I, open-label, dose-finding study of fatty acid synthase (FASN) inhibitor TVB-2640 administered in combination with enzalutamide (Enza) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Nuzzo Pier Vitale , Ribeiro Caroline Fidalgo , Rodrigues Silvia , Fernandez Escarleth , Molina Ana M. , Nauseef Jones , Sternberg Cora N. , Tagawa Scott T. , Loda Massimo , Nanus David M. 
Published: January 2024

TPS248 Background: Recent studies have shown that targeting lipid synthesis is a novel therapeutic strategy to overcome androgen resistance in mCRPC. TVB-2640 is a first-in-class FASN inhibitor, a key enzyme in de novo lipogenesis that is overexpressed and androgen-regulated in CRPC. FASN promotes the synthesis of palmitate that can be elongated and desaturated to produce saturated fatty acids (SFAs) and monounsaturated FA (MUFAs) that can support membrane synthesis and energy production, protect against free radicals and chemotherapeutics, and regulate post-translational modifications of major oncogenic pathways. Our preliminary in vitro and in vivo data show that TVB-2640 co-administered with enza to CRPC cells significantly reduced cell growth, increased apoptosis, and promoted cell cycle arrest, as well as down-regulating full-length androgen receptor (AR) and its splice variant, AR-V7. Methods: This is an open-label, single-arm, Phase I dose-escalation study that enrolls pts with mCRPC who are candidates to receive enza. The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of TVB-2640 in combination with enza. Secondary objectives include safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Exploratory objectives include the effects of FASN inhibition on metabolites, genetics, and lipids in human blood and tumor tissue, to identify potential predictive and prognostic markers of response. Pts with a confirmed histological or cytological diagnosis of PC, evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan), serum testosterone <50 ng/dl, who had progressed on androgen-depletion therapy (ADT), with documented progressive metastatic castration-resistant prostate cancer (mCRPC) based on Prostate Cancer Working Group 3 (PCWG3) criteria a are eligible. Enrolled pts will receive enza at a daily dose of 160 mg for 36 days to reach a steady state, followed by the addition of oral TVB-2640 starting at 100 mg/daily. The dose escalation will follow the Bayesian optimal interval (BOIN) design with additional dose levels of 150 mg, 200 mg, 250 mg, and 300 mg daily. The maximum sample size for this study is 30 pts, with a target dose-limiting toxicity (DLT) rate of 25% or less and a maximum of 15 pts at any given dose level. This is the first clinical trial to evaluate the targeting of the AR pathway through inhibition of lipid synthesis as a new approach to treating mCRPC. Enrollment of Cohort 1 began in August 2023. Clinical trial information: NCT05743621 .
A phase Ib trial of enzalutamide with oral decitabine/cedazuridine in metastatic castration-resistant prostate cancer (CRPC).
Authors: Roy Arya Mariam , Gopalakrishnan Dharmesh , Jatwani Karan , Green Kelly , Farmer Bailey , Jaiswal Neha , Attwood Kristopher , Levine Ellis Glenn , Beltran Himisha , Goodrich David , Chatta Gurkamal S. 
Published: January 2024

TPS252 Background: Exposure to androgen receptor (AR)-pathway inhibitors like enzalutamide (Enza) is associated with the emergence of ARlow subclones that coexist with ARhigh subclones in CRPC. These ARlow cells, including those in neuroendocrine prostate cancer (NEPC), are not critically dependent on AR signaling for survival and proliferation. Alterations in RB1, TP53, and PTEN tend to co-occur in human ARlow CRPC and NEPC. These as well as tumors from triple knockout mouse models demonstrate altered expression of epigenetic reprogramming factors, including consistent upregulation of DNA methyltransferase 1 (DNMT1).1 DNA methylation in CpG islands is increased in human CRPC/NEPC as well as CRPC xenograft models indicating that elevated DNMT activity may correlate with resistance to AR-targeted therapies.2 Treatment with decitabine (Dec), a DNMT inhibitor, delays the development of ARlow NEPC and increases Enza sensitivity in murine models of prostate cancer.2 Cedazuridine (Ced), an inhibitor of cytidine deaminase which degrades Dec, increases its oral bioavailability. We hypothesize that the combination of Enza with oral Dec/Ced will reverse acquired therapeutic resistance in ARlow CRPC/NEPC tumors where DNMT activity is aberrantly elevated by RB1 and/or TP53 loss. Methods: This is a single-center, open-label, non-randomized, dose escalation/de-escalation phase Ib study of fixed drug combination (FDC) oral Dec/Ced [ASTX727, FDC 35mg/100mg] with Enza (160mg/day) in patients with Enza-refractory mCRPC. Three dose levels of ASTX727 will be evaluated using a 3+3 study design - FDC of ASTX727 will be administered on either 4 (cohort 1), 3 (cohort -1) or 5 (cohort 2) consecutive days of a 28-day cycle. The primary endpoint will be safety with determination of the maximum tolerated dose (MTD) and recommended phase II dosing (RP2D). We plan to include an expansion cohort of 10 patients at the MTD, eligibility for which will be restricted to patients with genomic alterations in RB1 and/or TP53. Correlative studies will be aimed at 1) Evaluation of DNMT1 levels and DNA methylation patterns, 2) Analysis of circulating tumor DNA to monitor changes in DNA methylation and emergence of ARlow CRPC/NEPC, 3) Evaluation for tissue markers of neuroendocrine lineage, RB1 loss and/or TP53 mutations to examine for treatment emergent ARlow CRPC/NEPC and its correlation with RB1 and/or TP53 loss. The study is currently open with 6 patients enrolled. 1) McCabe MT et al. Cancer Res. 2005;65(9):3624-32. 2) Ku SY et al. Science. 2017;355(6320):78-83. 3) Zorn CS et al. Clin Cancer Res. 2007;13(7):2136-43. Clinical trial information: NCT05037500 .
Safety, tolerability, and dosimetry of 177Lu-TLX591 with best standard of care in patients with PSMA-expressing metastatic castration-resistant prostate cancer (ProstAct-SELECT).
Authors: Lenzo Nat , O'Byrne Ken , Ngai Stanley , Meyrick Danielle , Patel Neel , Hayward Colin 
Published: January 2024

TPS253 Background: Prostate-specific membrane antigen (PSMA) has proven to be an ideal therapeutic target in prostate cancer (PC) as it is highly expressed by malignant prostate cells. Based on previous clinical evidence of its favorable safety profile and specificity for PC tumors, 177Lu-DOTA-HuJ591-CHO (hereafter referred to as 177Lu-TLX591) may be a potential radioimmunotherapy for the treatment of PC. ProstACT-SELECT (NCT04786847) is a phase 1 study designed to evaluate the safety, tolerability, biodistribution and dosimetry of 177Lu-TLX591 administered with standard of care (SoC) for patients with PSMA-expressing, metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug. We previously reported positive interim results, and primary analysis of safety and dosimetry data is currently underway and expected to be available in mid-October 2023. Methods: Approximately 30 participants were to be enrolled in 2 cohorts. Cohort 1: 5 patients received a single (27 mCi) intravenous infusion of 177Lu-TLX591. SPECT images and pharmacokinetic blood samples will be acquired at several time points until Day 13 after dosing. Dosimetry analysis and qualitative comparison of biodistribution of tracer level of 177Lu-TLX591, as demonstrated by SPECT, with 68Ga-PSMA-11 on PET imaging were performed to ensure equivalent (or improved) radiopharmaceutical tumour targeting. Patients were to receive a second administration of 177Lu-TLX591, at a full therapeutic dose of 76 mCi, 14 days following the initial dose after safety confirmed by independent review board. SoC was to continue according to standard practice. Cohort 2: Subsequent patients were to receive 2 administrations of 76 mCi 177Lu-TLX591, with SPECT dosimetry and pharmacokinetics as in cohort 1. The primary endpoints include the absorbed radiation dose of administered 177Lu-TLX591 to kidneys, liver, lungs, spleen, bone/red marrow, and salivary glands; tumour-to-healthy tissue ratios and residence times; and type, frequency, and severity of TEAEs. Clinical trial information: NCT04786847 .