bluuebunny/crossref_metadata_2025 huggingface dataset:
The use of healthcare systems data for RCTs
Authors: Toader Alice-Maria , Gamble Carrol L. , Dodd Susanna , Williamson Paula R.
Published: January 2024

Background

Healthcare systems data (HSD) has the potential to optimise the efficiency of randomised controlled trials (RCTs), by decreasing trial-specific data demands. Therefore, the use of HSD in trials is expected to increase. In 2019, it was estimated that 47% of NIHR-funded trials were planning to use HSD. We aim to understand the extent and nature of its current use and its evolution over time.

Methods

We identified a cohort of RCTs within the NIHR Journals Library that commenced after 2019 and were described as being in progress on 6 June 2022. Details on the source and use of HSD were extracted from eligible RCTs. The use of HSD was categorised according to whether it was used as the sole data source for outcomes and whether the outcomes were primary or secondary. HSD is often insufficient for patient-reported outcomes (PROs). We aimed to determine methods used by trialists for collecting PRO data alongside HSD.

Results

Of the 84 eligible studies, 52 (62%) planned to use HSD and 79 (94%) planned to collect PROs. The number of RCTs planning to use HSD for at least one outcome was 28 (54%) with 24 of these planning to use HSD as the sole data source for at least one outcome.

The number of studies planning to use HSD for primary and secondary outcomes was 10 (20%) and 21 (40%) respectively. The sources of HSD were National Health Service (NHS) Digital (n = 37, 79%), patient registries (n = 7, 29%), primary care (n = 5, 21%), The Office for National Statistics (ONS) (n = 3, 13%) and other (n = 2, 8%).

PROs were collected for 92% of the trials planning to use HSD. Methods for collection of PROs included in-person (n = 26, 54%), online (n = 22, 46%), postal (n = 18, 38%), phone (n = 14, 29%) and app (n = 2, 4%).

Conclusions

HSD is being used in around two thirds of the studies but cannot yet be used to support PRO data collection within the cohort we examined. Comparison with an earlier cohort demonstrates an increase in the number of RCTs planning to use HSD.
Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage
Authors: Toader Alice-Maria , Campbell Marion K. , Quint Jennifer K. , Robling Michael , Sydes Matthew R , Thorn Joanna , Wright-Hughes Alexandra , Yu Ly-Mee , Abbott Tom. E. F. , Bond Simon , Caskey Fergus J. , Clout Madeleine , Collinson Michelle , Copsey Bethan , Davies Gwyneth , Driscoll Timothy , Gamble Carrol , Griffin Xavier L. , Hamborg Thomas , Harris Jessica , Harrison David A. , Harji Deena , Henderson Emily J. , Logan Pip , Love Sharon B. , Magee Laura A. , O’Brien Alastair , Pufulete Maria , Ramnarayan Padmanabhan , Saratzis Athanasios , Smith Jo , Solis-Trapala Ivonne , Stubbs Clive , Farrin Amanda , Williamson Paula
Published: January 2024

Background

Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community.

Methods

The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups.

Results

Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving.

Conclusions

We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.
Development and validation of a nomogram for predicting in-hospital mortality of patients with cervical spine fractures without spinal cord injury
Authors: Xing Zhibin , Cai Lingli , Wu Yuxuan , Shen Pengfei , Fu Xiaochen , Xu Yiwen , Wang Jing
Published: January 2024

Background

The incidence of cervical spine fractures is increasing every day, causing a huge burden on society. This study aimed to develop and verify a nomogram to predict the in-hospital mortality of patients with cervical spine fractures without spinal cord injury. This could help clinicians understand the clinical outcome of such patients at an early stage and make appropriate decisions to improve their prognosis.

Methods

This study included 394 patients with cervical spine fractures from the Medical Information Mart for Intensive Care III database, and 40 clinical indicators of each patient on the first day of admission to the intensive care unit were collected. The independent risk factors were screened using the Least Absolute Shrinkage and Selection Operator regression analysis method, a multi-factor logistic regression model was established, nomograms were developed, and internal validation was performed. A receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the discrimination of the model. Moreover, the consistency between the actual probability and predicted probability was reflected using the calibration curve and Hosmer–Lemeshow (HL) test. A decision curve analysis (DCA) was performed, and the nomogram was compared with the scoring system commonly used in clinical practice to evaluate the clinical net benefit.

Results

The nomogram indicators included the systolic blood pressure, oxygen saturation, respiratory rate, bicarbonate, and simplified acute physiology score (SAPS) II. The results showed that our model had satisfactory predictive ability, with an AUC of 0.907 (95% confidence interval [CI] = 0.853–0.961) and 0.856 (95% CI = 0.746–0.967) in the training set and validation set, respectively. Compared with the SAPS-II system, the NRI values of the training and validation sets of our model were 0.543 (95% CI = 0.147–0.940) and 0.784 (95% CI = 0.282–1.286), respectively. The IDI values of the training and validation sets were 0.064 (95% CI = 0.004–0.123; P = 0.037) and 0.103 (95% CI = 0.002–0.203; P = 0.046), respectively. The calibration plot and HL test results confirmed that our model prediction results showed good agreement with the actual results, where the HL test values of the training and validation sets were P = 0.8 and P = 0.95, respectively. The DCA curve revealed that our model had better clinical net benefit than the SAPS-II system.

Conclusion

We explored the in-hospital mortality of patients with cervical spine fractures without spinal cord injury and constructed a nomogram to predict their prognosis. This could help doctors assess the patient’s status and implement interventions to improve prognosis accordingly.
The Multidimensional Assessment of Interoceptive Awareness, version 2 (MAIA-2): psychometric properties in a Dutch non-clinical sample
Authors: Scheffers Mia , Coenen Jaisey , Moeijes Janet , de Haan Albertine , van Busschbach Jooske , Bellemans Tina
Published: January 2024

Background

Interoceptive awareness is a multidimensional construct that refers to the sensation, interpretation, and integration of signals within the body. There is increasing evidence that problems with interoceptive awareness form an important component of mental health problems. The Multidimensional Assessment of Interoceptive Awareness 2 (MAIA-2) is presently the most used self-report questionnaire to measure interoceptive awareness. The aim of the present study is to psychometrically evaluate the Dutch version of the MAIA-2.

Method

The psychometric properties of the MAIA-2-NL were examined in a non-clinical sample of 1054 participants aged between 18 and 83. Internal consistency and test-retest reliability were investigated. Factor structure was examined by exploratory factor analysis (EFA), followed by confirmatory factor analysis (CFA).

Results

Internal consistency was good, with McDonald’s omega (ω) ranging from 0.67 to 0.89. Test-retest reliability was moderate to good, with intraclass correlation coefficients (ICC) ranging from 0.67 to 0.79. Factor analyses suggested a six-factor structure, combining the original subscales Noticing with Emotional awareness and Self-regulation with Body listening. However, a CFA based on the original eight factors showed a somewhat better fit than the CFA based on six factors.

Conclusion

The MAIA-2-NL is a reliable and valid instrument to measure interoceptive awareness in healthy Dutch adults. We recommend to maintain the original 37 items.
Association between body weight perception and actual body mass index among adult women in Erbil city, Iraq
Authors: Shabu Sherzad A. , Saka Mariwan H. , Boya Manhal N. , Ahmed Hamdia M. , Zaki Sahar M. , Hettinga Florentina , Shabila Nazar P.
Published: January 2024

Background

The misperception of body weight can significantly affect individuals' health behaviors, such as physical activity, diet, and weight management. This study aimed to examine the association between body weight perception and actual body mass index (BMI) among adult women and explore the factors influencing this relationship.

Methods

Five hundred forty female individuals aged 18–65 participated in this cross-sectional study. The validated Global Physical Activity Questionnaire was used for data collection. The BMI of the participants was calculated from measured body weight and height. Body weight perception was assessed using a single questionnaire item. The association of BMI and body weight perception was assessed, and the result was categorized as underestimation, consistency, and overestimation. The Chi-square test was used to assess the association between the consistency of BMI and body weight perception by different sociodemographic factors. The kappa test was used to analyze the consistency of BMI and body weight perception.

Results

Of the 540 participants, 13.3% underestimated their body weight status, 79.1% accurately perceived their body weight status, and 7.6% overestimated their body weight status. Unmarried women (11.7%) were more likely than ever married (4.3%) to overestimate their body weight (p = 0.005). On multiple logistic regression, being unmarried (OR = 1.68 (95%CI 1.01–2.80)) was significantly associated with body weight misperception. Body weight perception and BMI categories showed a significantly good consistency (kappa = 0.612, p < 0.001). Correct perception of body weight was highest among the overweight, followed by normal weight and underweight individuals (82.1%, 75.8%, and 72.2%, respectively).

Conclusion

Body weight perception was well associated with actual body weight status. Unmarried women are more likely to misperceive body weight, particularly overestimating it. Underestimation of body weight was relatively high and much higher than the overestimation, which might keep obese individuals from weight loss activities. Preventing obesity should include awareness about body weight misperceptions.
Marijuana use may be associated with reduced prevalence of prostate cancer: A cross-sectional study using the national survey on drug use and health database.
Authors: Mohammed Turab J , Yu James , Qiao Yong , Kim Youngchul , Swede Helen , Wu Zhao , Mortensen Eric , Zhang Jingsong
Published: January 2024

101

Background: Preclinical data from cell lines and animal xenograft models support the anti-tumor effects of cannabinoids in prostate cancer (PC). Methods: We performed a cross-sectional study to investigate this association using National Survey on Drug Use and Health (NSDUH) data consisting of 2503 participants accrued from 2002 to 2020. Key independent variable was defined as current, former, and never users of marijuana (MJ). Dependent variable was self-reported PC (yes, no). Other MJ-related variables evaluated: age at first use, number of days used in the past 30 days, use of medical MJ, legality of MJ use in state of residence. Demographic variables assessed as potential confounders or covariates were: age, sex, race/ethnicity, education, marital status, total family income, insurance status, sexual identity, residence status, served in armed forces, cigarette smoking, and alcohol consumption. Multivariate (MV) logistic regression was employed to calculate odds ratios (OR) and 95th percentile confidence intervals (CI) to quantify relationship with MJ use in relation to PC status. Results: Prevalence of PC was significantly lower among current MJ users (46/145, 31.7%), and former users (323/1021, 31.6%) in comparison to non-users (534/1337, 39.9%, p < 0.001). Older MJ users (≥ 65) had significantly lower prevalence of PC compared to nonusers (36.4% vs. 42.4%, p = 0.016). A similar significant reduction was documented among non-Hispanic white (NHW) MJ users when compared to nonusers (28.9% vs. 38.3%, p < 0.001). There were no significant differences in the prevalence of PC between MJ users and non-users among the young (50-64) or other race/ethnicity. In MV logistic regression analyses, former MJ use was associated with a lower prevalence of PC compared to never use (OR = 0.74, 95% CI 0.62 - 0.90, p=0.001). Current MJ use also was suggestive of reduced prevalence but did not reach statistical significance (OR=0.77, 95% CI 0.52 – 1.14, p=0.198) possibly due to low sample size. Conclusions: Our findings provide additional data to link MJ use with low prevalence of PC, particularly in NHW. Future prospective studies using regulatory approved medical MJ are warranted. [Table: see text]
The effect of radiotherapy on the course of disease in prostatic cancer with high metastatic burden.
Authors: Falick Tal , Blumenfeld Philip , Skripai Antoni , Wygoda Marc R.
Published: January 2024

112

Background: Many retrospective studies suggest that local RT for the prostate in the metastatic setting improves overall survival, however the question of whether metastatic burden is an independent factor influencing the results of localized treatment was not directly addressed. Moreover, results are conflicting with the outcomes from prospective trials on the subject. Thus overall, there is a limited, conflicting and insufficient data on the effect of radiotherapy on prostate cancer patients with a significant metastatic burden. Here we show that RT treatment in prostate cancer patients with a significant metastatic burden (four or more bone metastases with one or more outside the vertebral bodies or pelvis or a visceral metastases) is beneficial and extends overall survival while reducing symptoms. Methods: We conducted a retrospective study examining 100 high metastatic burden prostate cancer patients treated in Hadassah Ein Karem Medical Center between the years of 2004-2022. Data was collected from the medical records of the hospital. Variables that were recorded include basic demographics, time and durations of hospitalization, cancer staging, treatment course, RT course, imaging after RT, vital status, clinical symptoms and PSA levels. Tumors could be of any grade (Gleason score 6–10) and T or N stage (T1-T4; N0-N1; M1). Prostate RT included external EBRT to the prostate with/ without pelvis. Radiotherapy dosage between 30-60 gy using conventional fractionation. Results: Overall Survival was higher in the RT group when compared to NRT group (P < 0.046). Progression free survival (PFS) was not significantly higher in the RT group as compared to the NRT group (P < 0.153). However, a trend towards better PFS was noted. Biochemical progression free survival was higher in the RT group when compared to NRT group (P < 0.033). Time without symptom worsening as defined by time since treatment beginning until worsening of a symptom or appearance of a new symptom reported by the patient included urinary incontinence, urinary urgency, and increased frequency, need for catheter or urinary obstruction. Time without symptom worsening was higher in the RT group as compared to NRT group (P < 0.017). The amount of hospitalization wasn’t significantly higher in the RT group when compared to NRT group (P < 0.460). The duration of hospitalization was significantly higher in the NRT group when compared to the RT group (P < 0.038). Conclusions: Here we show for the first time an increase of overall survival specifically in the high metastatic burden group when adding the RT to a standard treatment of choice (ADT with or without chemotherapy). We also demonstrate an improvement in QOL of our patients.
Baseline characteristics of patients with PSMA-PET–positive and –negative disease with high-risk of biochemical recurrence (BCR) after radical prostatectomy (RP) in the ongoing phase 3 PRIMORDIUM study.
Authors: Hadaschik Boris A. , Mottet Nicolas , Ost Piet , De Nunzio Cosimo , Tunariu Nina , Zaucha Renata , Brasso Klaus , Osman-Garcia Ignacio , Tural Deniz , Lukac Martin , Stitou Hind , Pissart Geneviève , Efficace Michela , Fanti Stefano
Published: January 2024

119

Background: Positron emission tomography of radiolabeled prostate-specific membrane antigen (PSMA-PET) is more sensitive and specific than conventional imaging for the detection of lesions in patients with BCR prostate cancer. PRIMORDIUM (NCT04557059) includes standardized PSMA-PET imaging and enrolls PSMA-PET positive patients (≥1 locoregional lesion; interventional cohort) and PSMA-PET negative patients (no lesion; observational cohort); all patients are non-metastatic by conventional imaging at screening. Methods: We presented study methods at ESMO 2021 (Poster 649TiP). All patients enrolled in PRIMORDIUM have high-risk BCR (prostate specific antigen [PSA] doubling time ≤12 months or Gleason score ≥8) after RP. PSMA-PET-positive patients are randomized 1:1 to either the control arm (whole pelvic salvage radiotherapy [RT] + 6 months of luteinizing hormone-releasing hormone agonist [LHRHa]) or the interventional arm (RT + LHRHa + apalutamide 240 mg/day for 180 days); stereotactic body RT (SBRT) to ≤3 distant lesions is optional. PSMA-PET-negative patients are managed per routine clinical practice. Results: Key baseline characteristics of 198 enrolled patients at data cutoff (12-Jan-2023) are summarized in the table. Conclusions: The PRIMORDIUM study aims to evaluate the intensification of treatment with apalutamide for patients assessed with PSMA-PET. From 198 enrolled patients with high-risk BCR, positive PSMA-PET was documented in 44% of patients at a median of 39 months after RP and a median PSA of 0.51 ng/mL, while negative PSMA-PET was observed in 56% of patients at a median of 26 months after RP and a median PSA of 0.35 ng/mL. In this analysis, all PSMA-PET-positive patients had locoregional lesion(s) and 10% also had distant lesion(s) on PSMA-PET. Clinical trial information: NCT04557059 . [Table: see text]
Predictors of PSA response to Lu177-PSMA-617 in metastatic castration-resistant prostate cancer.
Authors: Hassoun Rebecca , Tann Mark , Sims Justin , Auxier Ashleigh , Althouse Sandra K. , Salous Tareq , King Jennifer , Adra Nabil
Published: January 2024

135

Background: Lu177-PSMA-617 (Lu177) therapy is effective in a subgroup of patients with metastatic castration resistant prostate cancer (mCRPC). We evaluated PSA responses in subgroups of pts with mCRPC. Methods: Pts with mCRPC who progressed after androgen receptor pathway inhibitor (ARPI) and taxane chemotherapy (or who have refused chemotherapy) were treated with Lu177. Baseline clinical/molecular characteristics and PSMA PET parameters were analyzed and association with PSA30 and PSA50 response was evaluated. Results: 97 pts were included. Median age was 73.4 (55.9, 90.2). At baseline PSMA PET: 78 pts had PSMA + disease in bone, 61 lymph nodes, 9 lungs, 5 liver, and 1 brain. 33 pts had 1 prior ARPI, 64 pts had ≥2 prior ARPI. 13 pts had no prior taxane regimen, 42 had 1 prior taxane, 31 had 2 prior taxanes and 11 had ≥3 taxane regimens. 17 pts had prior PARP inhibitor. With a median follow-up of 6.5 months (1.38-14.54) from starting Lu177 therapy, 56 (57.7%) pts achieved a PSA30 response, and 49 (50.5%) pts achieved a PSA50 response. 59 (60.8%) pts achieved any confirmed PSA response. Grade≥3 toxicity occurred in 9 pts. Differential PSA response by subgroups is listed in the Table. Conclusions: There is a trend with higher PSA30 and PSA50 response to Lu177 with higher SUVmean, higher SUVmax, and less prior taxane exposure. [Table: see text]
Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design.
Authors: Kyriakopoulos Christos , Chatta Gurkamal S. , Laccetti Andrew Leonard , Iannotti Nicholas , Sokolova Alexandra , Hotte Sebastien J. , Tutrone Ronald F. , Markowski Mark Christopher , Nordquist Luke T. , Pili Roberto , Saad Fred , Zhang Jingsong , Villaluna Karen , Younginger Brett , Le Moigne Ronan , Cesano Alessandra
Published: January 2024

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Background: EPI-7386 (masofaniten) is a next-generation aniten that inhibits androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription, irrespective of ligand-binding domain resistance mechanisms. Preclinically, the combination of masofaniten with Enz results in a deeper blockade of the AR pathway and greater antitumor activity than either agent alone. Methods: This is a Phase 1/2 multicenter clinical trial (NCT05075577) enrolling patients (pts) with mCRPC on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy in the metastatic hormone-sensitive setting allowed). P1 examines escalating doses of masofaniten + Enz at 120 or 160 mg QD. Primary and secondary endpoints of P1 evaluate the safety and pharmacokinetics (PK) of masofaniten + Enz when co-administered to establish the recommended P2 combination doses (RP2CDs). P2 is designed as a two arm, 2:1 randomized, open-label trial evaluating the antitumor activity of masofaniten in combination with Enz versus Enz alone; approximately 120 pts will be randomized with masofaniten 600 mg BID + Enz 160 mg QD (n=80) vs single agent Enz at 160 mg QD (n = 40). Results: P1 completed enrollment with 18 pts in 4 cohorts with 16 pts evaluable for efficacy as per protocol. The combination regimen was well tolerated with a safety profile consistent with Enz monotherapy. One grade 3 rash was observed in cohort 4 evaluating masofaniten 600 mg BID + Enz 160 mg QD. PK results demonstrated Enz exposure was not impacted by concomitant administration of masofaniten, allowing testing of the full dose of Enz (160 mg). By contrast, masofaniten exposure was consistently reduced by concomitant administration of Enz (CYP3A4 inducer that metabolizes masofaniten) but remained within the clinically relevant range with the highest exposures and Cmin observed using masofaniten BID dosing. Although efficacy data are still maturing, to date, response rates were PSA50 88% (14/16 pts), PSA90 69% (11/16 pts) and PSA <0.2 ng/mL 56% (9/16 pts) in evaluable pts, regardless of their previous chemotherapy status. Conclusions: The RP2CD for P2 was established at masofaniten 600 mg BID + Enz 160 mg QD. Updated results, including long term follow-up of the dose escalation patients, and P2 study design, will be presented. Clinical trial information: NCT05075577 .
Enzalutamide combination treatment (tx) suspension in men with high-risk biochemically recurrent (BCR) prostate cancer: Outcomes from EMBARK.
Authors: Freedland Stephen J. , Sieber Paul R. , Gleave Martin , De Giorgi Ugo , Mehlhaff Bryan Allyn , Danila Daniel Costin , Dunshee Curtis , Lallas Costas D. , Pliskin Marc , Tang Yiyun , Haas Gabriel P. , Rosales Matt , Tarazi Jamal Christo Christo , Zohren Fabian , Russell David , Shore Neal D.
Published: January 2024

156

Background: The 3-arm EMBARK trial found statistically superior and clinically meaningful improvements in metastasis-free survival (MFS) with enzalutamide + leuprolide acetate (enza combo) and enza monotherapy vs placebo + leuprolide (alone) in patients (pts) with high-risk BCR prostate cancer. Tx was suspended at week 37 in 321 (90.9%) pts in the enza combo arm and 240 (67.8%) in the leuprolide-alone arm based on prostate-specific antigen (PSA) response. Outcomes in the enza combo vs leuprolide-alone arms by tx suspension status are reported. Methods: The phase 3 EMBARK study enrolled pts with high-risk BCR, defined as PSA doubling time ≤9 months, and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomized 1:1 to enza 160 mg/day + leuprolide (22.5 mg every 12 weeks) or leuprolide alone. Tx was suspended at week 37 if serum PSA was <0.2 ng/mL at week 36 and restarted when PSA reached ≥2 ng/mL (primary RP) or ≥5 ng/mL (no primary RP). A secondary endpoint was the proportion of pts with undetectable PSA 2 years after suspension. MFS (per blinded independent central review) was analyzed descriptively between tx arms by suspension status. P-values were nominal. Results: The 3-year MFS rate (95% CI) in the suspension group was 94.4% (91.2–96.5%) with enza combo and 90.0% (85.3–93.2%) with leuprolide alone; in the no suspension group, 3-year MFS rates were 76.2% (33.2–93.5%) and 66.9% (55.4–76.1%), respectively. MFS in the suspension group was improved with enza combo vs leuprolide alone (HR 0.470, 95% CI 0.308–0.717; P=0.0003); no difference in MFS was observed in the no suspension group (HR 0.719, 95% CI 0.225–2.295; P=0.5763), although sample size was small for enza combo (n=9). Compared with no suspension, a higher proportion of pts in the suspension group received prior RP and a lower proportion received prior RT (Table). Two years after suspension, 16.8% (95% CI, 12.9–21.4%) of enza combo pts and 9.6% (95% CI, 6.2–14.0%) of leuprolide-alone pts had undetectable PSA ( P=0.0089). Conclusions: MFS was improved with enza combo vs leuprolide alone for pts with BCR who suspended tx. No difference in MFS was observed in the no suspension group, but firm conclusions were precluded by the limited number of pts who did not suspend tx with enza combo. Pts who suspended tx had higher rates of prior RP vs those who did not. Pts who had received enza combo prior to tx suspension were more likely to have undetectable PSA 2 years thereafter compared with those who received leuprolide alone. Clinical trial information: NCT02319837 . [Table: see text]
Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.
Authors: Shore Neal D. , Clarke Noel , Armstrong Andrew J. , Oya Mototsugu , Procopio Giuseppe , Guedes João Daniel Cardoso , Arslan Cagatay , Mehra Niven , Brown Emma , Schlürmann Friederike , Joung Jae Young , Sugimoto Mikio , Vianna Karina , Hosius Christian , Barnicle Alan , Liu Yu-Zhen , Harrington Elizabeth , McGuinness David , del Rosario Paula Michelle , Saad Fred
Published: January 2024

165

Background: PROpel (NCT03732820) met its primary endpoint and showed a significant investigator-assessed radiographic progression-free survival (rPFS) benefit with O + A vs P + A in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). At final prespecified analysis, median overall survival (OS) with O + A vs P + A was 42.1 vs 34.7 months (HR 0.81, 95% CI 0.67–1.00; P=0.0544). We report gene-by-gene efficacy of O + A vs P + A for pts from PROpel with a HRRm. Methods: PROpel was a Phase 3 randomized (1:1), double-blind trial. Pts were enrolled irrespective of biomarker status and received O (300 mg twice daily [bid]) or P, plus A (1000 mg once daily) and prednisone/prednisolone (5 mg bid). rPFS by investigator assessment was the primary endpoint (data cutoff [DCO]: 7/30/2021). OS was a key secondary endpoint (DCO: 10/12/2022). Following randomization and before primary analysis, HRRm status was assessed by tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests and is reported using aggregated results from both tests. Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. HR and CIs are not reported in subgroups with <5 events in either arm for both rPFS and OS. Results: 28.4% pts had an HRRm.For most pts with a single gene HRRm, there was a lower proportion of rPFS events and deaths in the O + A arm relative to the P + A arm (Table). The most prevalent gene mutations were BRCA2, ATM and CDK12; HRs for rPFS and OS numerically favored O + A (rPFS: BRCA2, HR 0.20, 95% CI 0.08–0.44; ATM, HR 0.55, 95% CI 0.20–1.38; CDK12, HR 0.51, 95% CI 0.20–1.18. OS: BRCA2, HR 0.20, 95% CI 0.07–0.48; ATM, HR 0.79, 95% CI 0.33–1.77; CDK12, HR 0.57, 95% CI 0.24–1.27). Conclusions: BRCA2, ATM and CDK12 were the most prevalent single gene mutations and clinical benefit was observed with O + A. Other single gene mutations were rare, limiting interpretation. The greatest treatment benefit was observed in pts with BRCA mutations. Clinical trial information: NCT03732820 . [Table: see text]
Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy.
Authors: Shore Neal D. , Tombal Bertrand F. , Hussain Maha H. A. , Saad Fred , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Fralich Todd , Li Rui , Smith Matthew Raymond
Published: January 2024

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Background: Darolutamide (DARO) + ADT + docetaxel (DOC) is approved for metastatic hormone-sensitive prostate cancer (mHSPC) based on the phase 3 ARASENS study (NCT02799602). To address the impact of informative intercurrent events (eg, use of subsequent therapy) in censored patients (pts), as defined by the European Medicines Agency, we performed a post hoc sensitivity analysis of OS. Methods: Pts with mHSPC were randomized 1:1 to oral DARO 600 mg twice daily or placebo (PBO) + ADT + DOC. The primary endpoint was OS using a log-rank test, with HR (95% CI) calculated by Cox model, stratified by extent of disease (EoD; nonregional lymph node vs bone ± lymph node vs visceral ± lymph node/bone metastases) and alkaline phosphatase (< vs ≥ upper limit of normal). Pts with no documented death were censored at last known alive or data cut-off date, whichever was earlier. The post hoc sensitivity analysis counted initiation of subsequent systemic antineoplastic therapy as an event in censored pts still alive at end of follow-up. In addition planned sensitivity analyses used an unstratified log-rank test/Cox model, a log-rank test/Cox model with stratification factors from electronic case report forms, and a log-rank test/Cox model with EoD stratification factors from central imaging review. Results: In the primary analysis DARO + ADT + DOC significantly improved OS ( P<0.0001; Table), despite a high percentage of pts who entered follow-up in the PBO group receiving subsequent life-prolonging systemic therapies (374/495, 76%). Time to first subsequent systemic antineoplastic therapy (a key secondary endpoint) was significantly longer with DARO + ADT + DOC vs PBO + ADT + DOC (HR 0.39, 95% CI 0.33–0.46, P<0.001). Findings from the post hoc sensitivity analysis counting initiation of subsequent systemic antineoplastic therapy as an event in censored pts (pts with events: DARO 300/651, 46.1%; PBO 476/654, 72.8%) and the planned sensitivity analyses were consistent and supported the primary OS analysis (Table). Treatment-emergent adverse events (TEAEs) were similar between groups. TEAEs led to DARO/PBO discontinuation in 13.5%/10.6% of pts. Conclusions: The results of the post hoc and planned sensitivity analyses were consistent with and supportive of the ARASENS primary OS analysis. These data reinforce DARO + ADT + DOC as an effective and well tolerated new standard of care for early treatment intensification in pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]
Optimal sequential therapy for metastatic castration-resistant prostate cancer after androgen receptor pathway inhibitors in the up-front era.
Authors: Naito Yushi , Nagayama Jun , Sano Yuta , Inoue Satoshi , Matsuo Kazuna , Sano Tomoyasu , Ishida Shohei , Matsukawa Yoshihisa , Kato Masashi , Akamatsu Shusuke
Published: January 2024

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Background: The optimal sequential therapy for metastatic castration-resistant prostate cancer (mCRPC) following the use of up-front androgen receptor pathway inhibitors (ARPIs) for metastatic hormone-sensitive prostate cancer (mHSPC) is still unclear. Methods: A total of 220 patients who received systemic therapy for de novo mHSPC at Nagoya University Hospital and its affiliated institutions between 2014 and 2022 were included in the study. Patients who received up-front therapy with ARPI as first-line therapy for mHSPC, followed by ARPI as primary therapy for mCRPC were defined as the AA group, followed by docetaxel (DOC) as primary therapy for mCRPC were defined as the AD group. On the other hand, the vAA group was defined as patients who received androgen deprivation therapy alone or combined androgen blockade as “vintage” first-line therapy for mHSPC, followed by two consecutive ARPIs as sequential therapy for mCRPC, and the vAD group was defined as patients who received ARPI followed by DOC as sequential therapy for mCRPC. Patient characteristics and progression-free survival (PFS) of the second agent after the first ARPI were compared in each group. Results: We identified 14 patients in the AA group, 16 in the AD group, 84 in the vAA group, and 59 in the vAD group. There were no differences in patient background such as initial PSA, Gleason score, and metastatic burden between the groups, while patient age was lower in the AD and vAD groups compared to the AA and vAA groups. The PFS of the second agent in the AA group was significantly shorter than that in the vAA group (median, 6.8 vs. 1.9 months; hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.25-0.87; p=0.017). In contrast, there was no significant difference in PFS of the second agent in the vAD and AD groups (median, 7.0 vs. 4.0 months; HR, 0.63; 95%CI, 0.29-1.34; p=0.235). Conclusions: The effect of each agent after ARPI therapy in the UP-FRONT era may be poorer than that in the VINTAGE era. In the setting after up-front ARPI, sequential therapy with DOC may be more appropriate than sequential therapy with ARPI.
A double-blinded, placebo-controlled, cross-over pilot trial in healthy men to study the effects of Angelica gigas herbal supplement on prostate cancer–relevant inflammatory cytokines.
Authors: Strong Anne-Laure , Karelia Deepkamal N. , Schell Todd D. , Hershock Diane , Fan Tongyao , Sun Dongxiao , Zhu Junjia , Proctor Elizabeth , Jiang Cheng , Joshi Monika , Lu Junxuan
Published: January 2024

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Background: The ethanol extract of the root of Angelica gigas Nakai (AGN) dose-dependently inhibits animal models of prostate cancer. Multi-omic analyses have implicated immune and anti-inflammatory responses in the anti-cancer action. In our single dose-PK study (NCT02114957) in healthy volunteers with AGN dietary supplement CognI.Q, we observed a near doubling of the natural killer (NK) mRNA signature in peripheral blood mononuclear cells (PBMC) at 24 h after dosing while the inflammatory cytokine IL-8 mRNA was decreased by one half over the pre-dose baseline. Given NK incapacitation and inflammation have been linked to prostate cancer, the current trial (NCT03630328) was designed to assess safety and to delineate CognI.Q-specific immune and anti-inflammation functions. Methods: We used a double-blinded, placebo-controlled and crossover trial design to monitor hepatic and renal safety metrics based on Comprehensive Metabolic Panel (CMP) and compare the immune cell and cytokine responses to CognI.Q and placebo. Supplement period of 3 weeks was followed with a 2-week washout period. We employed the Ella microfluidic multiplex immunoassay to evaluate select plasma cytokines. Results: Fourteen healthy men completed the trial protocol. Physical examination on study visit days did not reveal any adverse events. Blood CMP monitoring detected abnormal hepatic integrity values in three subjects, all in the second washout period and were attributed to use of anti-allergy medication, an herbal tea for tooth ache, and excessive alcohol, respectively. Analysis of plasma cytokines detected corresponding elevation of MIG, CCL4, CXCL10 and IL-8 with these hepatic damage events. With the exclusion of these subjects or time point, the plasma cytokine measurement did not reveal a significant response to CognI.Q supplement vs. placebo. Conclusions: CognI.Q supplement at the current recommended dose (400 mg, twice per day) did not impair hepatic integrity or renal function, nor did it modulate select plasma cytokines in healthy men. Phase I dose-escalation trials should be implemented to establish safety profile and assess immune and inflammation modulatory effects of AGN supplement beyond the current dose. Clinical trial information: NCT03630328 .
Primary sarcoma of prostate: A genomic landscape study.
Authors: Batayneh Osama , Jacob Joseph M , Bratslavsky Gennady , Spiess Philippe E. , Kamat Ashish M. , Grivas Petros , Necchi Andrea , Cheng Liang , Ross Jeffrey S. , Basnet Alina
Published: January 2024

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Background: Primary sarcoma of prostate is exceedingly rare and not well-studied. We sought to describe the genomic landscape of this rare entity and identify potential therapy targets. Methods: From 19,057 cases of prostate cancers, only 11 (<.01%) cases of primary sarcomas were identified and underwent comprehensive genomic profiling (CGP) using FDA-approved hybrid capture-based system to assess all classes of genomic alterations (GA). Genomic-based ancestry, genomic signature, gLOH, MSI and TMB status were determined by CGP. Germline status was predicted using a Somatic-Germline-Zygosity algorithm. PD-L1 expression was determined by IHC (Dako 22C3 TPC scoring). Results: The routine histology and IHC stains from all 11 cases were reviewed centrally. There were 9 stromal sarcomas, and 1 each leiomyosarcoma and rhabdomyosarcoma. All patients (median age 57) were clinically advanced stage at the time of CGP. The primary tumor site was used in 6 patients and metastatic sites (3 bone, 1 ureter and 1 lung metastasis) in 5 patients. The mean number of GA per case was 2.3 (1 to 4 GA/sample). The most frequent GA were in TP53 (36.4%), RB1 (27.3%), ATRX (18.2%). Potentially targetable GA were rare and included MTOR pathway inhibitors for GA in TSC2 and PTEN (1 case each) and PIK3CA inhibitors (GA in PIK3CA in 1 case). There were 3 cases with non “targetable” gene rearrangements including a STAT6- NAB2 fusion in a stromal sarcoma (possible solitary fibrous tumor of prostate), a BCOR- MAML3 fusion and a TMPRSS2- ERG fusion in a stromal sarcoma with an adjacent focus of Gleason 6 prostate adenocarcinoma. 1 case featured a predicted germline mutation of the FLCN gene. All cases were microsatellite stable. TMB ranged from 0 to 9.8 mutations/Mb with median of 3.4 mutations/Mb with no cases at ≥10 mutations/Mb. gLOH scores were low, ranging from 0% to 10.9% (median 2.6%). Genomic ancestry was European in 7 patients and Admixed American in 4 others. There were no specific genomic signatures identified. PD-L1 was tested in 4 cases (all negative). Conclusions: Prostate sarcoma is an exceedingly rare primary cancer of the prostate with limited opportunities for targeted therapy or immunotherapy strategies. These tumors do not appear to be driven by “targetable” gene fusions and individual “targetable” mutations are uncommon. [Table: see text]
Prognostic value of PSMA-extracellular vesicles in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy: A multi-center observational study.
Authors: Lucien Fabrice , Andrews Jack R. , Kim Yohan J , Horjeti Edlira , Arafa Ali , Sutera Philip , De Bruycker Aurélie , Mercier Carole , Phillips Ryan , Song Daniel , Kiess Ana Ponce , Ost Piet , Tran Phuoc T. , Childs Daniel S , Sartor A. Oliver , Orme Jacob , Park Sean Sunghun
Published: January 2024

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Background: Two randomized clinical trials have demonstrated that SABR can prolong time to progression in oligometastatic castration-sensitive prostate cancer (omCSPC) patients. However, there is a need for predictive tools to identify patients who will benefit from SABR alone or with systemic therapy. We investigated the prognostic value of PSMA-positive extracellular vesicles (PSMA+EVs) in a blinded observational study using blood samples from three independent patient cohorts. Methods: We obtained plasma samples from 157 omCSPC patients treated with SABR from the ORIOLE cohort (N=30, JHU) and STOMP-like cohorts (N=80, UGhent; N=47, Iridium Net). Baseline PSMA+EV levels (EV/ml) were measured by nanoscale flow cytometry. Primary clinical endpoints were biochemical progression (bPFS) and radiographic progression (rPFS). Optimal cutoffs for PSA (ng/ml) and PSMA+EV (EVs/ml) were defined as the point with the most significant log-rank test split. Kaplan-Meier curves and univariate Cox regression models were used to determine the association of PSMA+EV levels with clinical outcomes. Results: Twenty percent of patients (N=157 total) were diagnosed with bone scan, 79% with PET imaging, and 1% with other modalities. Ninety-four percent of patients presented with ≤3 metastases on imaging. In the pooled STOMP-like cohorts, median bPFS was 27.9 and 18.0 months for PSMA+EV low and high groups, respectively (p=0.039). Median rPFS was 36.0 versus 27.0 months (p=0.029). In the ORIOLE cohort, median bPFS was 24.3 and 5.9 months in PSMA+EV low and high, respectively (p=0.021). Median rPFS was 36.0 versus 11.1 months (p=0.019). High baseline PSMA+EV levels were associated with higher risk of both biochemical and radiographic progression (Table). Combination of baseline PSA low and PSMA+EV low outperformed either biomarker alone and better predicted risk of disease progression after SABR. Conclusions: While prospective biomarker-guided trials are warranted, a PSMA+EV blood test can aid patient selection by identifying omCSPC patients who may have durable responses to SABR without ADT. [Table: see text]
Genomic mutations and homologous recombination deficiency (HRD) score in Japanese patients with metastatic hormone-sensitive prostate cancer (mHSPC): The impact of intraductal carcinoma of the prostate (IDC-P).
Authors: Kato Masashi , Yamamoto Akiyuki , Kawanishi Hideji , Naito Yushi , Akamatsu Shusuke , Tsuzuki Toyonori
Published: January 2024

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Background: Intraductal carcinoma of the prostate (IDC-P) is a significant prognostic factor associated with adverse clinical outcomes. A recent study has revealed significant associations between IDC-P and germline homologous recombination repair gene mutations (HRRm) and alterations in tumor suppressor genes. However, no study has investigated the association between IDC-P and gene mutations in a Japanese population. We evaluated the association between IDC-P in prostate core needle biopsies and gene mutations in metastatic hormone-sensitive prostate cancer (mHSPC) in a Japanese population. Methods: This study enrolled 102 mHSPC patients, classified as LATITUDE high-risk, diagnosed between 2018 and 2021 in Nagoya University and affiliated hospitals, all within three years of diagnosis, and with informed consent. Initial screening identified 106 patients with gene mutation data; four were excluded due to inadequate metastatic lesions or insufficient biopsy number. A single genitourinary pathologist assessed all biopsy slides according to 2019 ISUP grading system. Furthermore, the genetic analysis involved the examination of 108 genes using the Myriad myChoice HRD plus assay, alongside HRD (Homologous recombination deficiency) score analysis. Results: Our study achieved a 91% success rate in genomic testing. In total, 20 (19.6%) and 73 patients (71.6%) exhibited HRRm and molecular alterations in pathway other than HRR (MAOT-HRR), respectively. Notably, common HRRm included BRCA (n = 10; BRCA 1:2, BRCA 2:8) and CDK12 (n = 6) mutations, whereas common MAOT-HRR included FOXA1 (n = 30) and TP53 (n = 18) mutations. MAOT-HRR were more common in IDC-P positive patients (75.6% vs. 50%, p=0.06). PTEN and TP53 mutations were notably enriched in IDC-P positive patients (PTEN: 5.8% vs. 0%, TP53: 20.9% vs. 0%, p=0.06). Patients with IDC-P exhibited higher HRD scores (21.3 ± 8.8 vs. 16.6 ± 8.6, p = 0.06) compared to those without IDC-P, with CDK12 and BRCA mutations being more common in this group (CDK12: 7.0% vs 0%, BRCA: 10.5% vs 6.3%). In addition, the frequency of HRRm was slightly higher in patients with IDC-P compared to those without IDC-P (21% vs. 12.5%, p = 0.73). Finally, the frequency of genetic alterations (HRRm or MAOT-HRR) was significantly higher in patients with IDC-P positive patients (82.6% vs. 50%, p=0.0082). Conclusions: Among Japanese mHSPC patients, IDC-P demonstrates significant associations with an elevated incidence of genetic alterations and increased HRD score, emphasizing its potential clinical significance.