bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustained software development, not number of citations or journal choice, is indicative of accurate bioinformatic software
Authors: Gardner Paul P. , Paterson James M. , McGimpsey Stephanie , Ashari-Ghomi Fatemeh , Umu Sinan U. , Pawlik Aleksandra , Gavryushkin Alex , Black Michael A.
Published: February 2022

Background

Computational biology provides software tools for testing and making inferences about biological data. In the face of increasing volumes of data, heuristic methods that trade software speed for accuracy may be employed. We have studied these trade-offs using the results of a large number of independent software benchmarks, and evaluated whether external factors, including speed, author reputation, journal impact, recency and developer efforts, are indicative of accurate software.

Results

We find that software speed, author reputation, journal impact, number of citations and age are unreliable predictors of software accuracy. This is unfortunate because these are frequently cited reasons for selecting software tools. However, GitHub-derived statistics and high version numbers show that accurate bioinformatic software tools are generally the product of many improvements over time. We also find an excess of slow and inaccurate bioinformatic software tools, and this is consistent across many sub-disciplines. There are few tools that are middle-of-road in terms of accuracy and speed trade-offs.

Conclusions

Our findings indicate that accurate bioinformatic software is primarily the product of long-term commitments to software development. In addition, we hypothesise that bioinformatics software suffers from publication bias. Software that is intermediate in terms of both speed and accuracy may be difficult to publish—possibly due to author, editor and reviewer practises. This leaves an unfortunate hole in the literature, as ideal tools may fall into this gap. High accuracy tools are not always useful if they are slow, while high speed is not useful if the results are also inaccurate.
Electrical stimulation to prevent recurring pressure ulcers in individuals with a spinal cord injury compared to usual care: the Spinal Cord Injury PREssure VOLTage (SCI PREVOLT) study protocol
Authors: Wijker Boas J. , de Groot Sonja , van Dongen Johanna M. , van Nassau Femke , Adriaansen Jacinthe J. E. , Achterberg-Warmer Wendy J. , Anema Johan R. , Riedstra Andries T. , van Tulder Maurits W. , Janssen Thomas W. J.
Published: February 2022

Background

Pressure ulcers (PUs) on the buttocks are among the most common secondary complications in individuals with chronic spinal cord injury (SCI). PUs can result from sitting for extended periods, disuse atrophy, increased sitting pressure and reduced circulation. Compared with usual care, activation of paralysed muscles using electrical stimulation (ES) has been shown to markedly increase paralysed muscle mass, improve circulation of skin and muscle and improve sitting pressure distribution. ES might therefore be a useful method to reduce PU incidence.

Methods

A multicentre randomized controlled trial (SCI PREVOLT) will be conducted with an economic and process evaluation alongside. One hundred participants with a SCI in the chronic phase and a minimal incidence of 1 PU in the last 5 years will be recruited from rehabilitation centres across the Netherlands. Participants will be stratified by centre and age and randomized to the intervention or control group. The intervention group will use ES at least 1 h/day during at least 4 times a week for 1 year next to usual care. The control group will only receive usual care. The primary outcome is the incidence of PUs, measured by a blinded person assessing the presence or absence of a PU on the buttocks on a photo made by the participant or his/her caregiver. The incidence of a PU will be evaluated every 2 weeks. Secondary outcomes include interface pressure distribution, blood flow in the profunda femoris artery, muscle thickness of the hamstrings and gluteal muscles and questionnaires about different dimensions of life, e.g. participation and quality of life. Secondary outcomes will be measured at baseline and 3, 6, 9 and 12 months after randomization.

Discussion

This study will assess if electrical stimulation is a (cost-)effective method to prevent PUs and reduce the risk factors of getting PUs. If ES is effective and cost-effective compared with usual care, ES could be implemented in daily treatment of individuals with a SCI.

Trial registration

Netherlands Trials Register NTR NL9469. Registered on 26 May 2021.
Comparison of self-sampling blood collection for N-glycosylation analysis
Authors: Cvetko Ana , Tijardović Marko , Bilandžija-Kuš Iva , Gornik Olga
Published: February 2022

Objective

Self-sampling of capillary blood provides easier sample collection, handling, and shipping compared to more invasive blood sampling via venepuncture. Recently, other means of capillary blood collection were introduced to the market, such as Neoteryx sticks and Noviplex cards. We tested the comparability of these two self-sampling methods, alongside dried blood spots (DBS), with plasma acquired from venepunctured blood in N-glycoprofiling of total proteins. We have also tested the intra-day repeatability of the three mentioned self-sampling methods. Capillary blood collection with Neoteryx, Noviplex and DBS was done following the manufacturers’ instructions and N-glycoprofiling of released, fluorescently labelled N-glycans was performed with ultra-performance liquid chromatography.

Results

Comparability with plasma was assessed by calculating the relative deviance, which was 0.674 for DBS, 0.092 for Neoteryx sticks, and 0.069 for Noviplex cards. In repeatability testing, similar results were obtained, with Noviplex cards and Neoteryx sticks performing substantially better than DBS (CVs = 4.831% and 7.098%, compared to 14.305%, respectively). Our preliminary study on the use of Neoteryx and Noviplex self-sampling devices in glycoanalysis demonstrates their satisfactory performance in both the comparability and repeatability testing, however, they should be further tested in larger collaborations and cohorts.
Bone mineral density in men with de novo metastatic castration-sensitive prostate cancer treated with or without abiraterone plus prednisone in the PEACE-1 phase 3 trial.
Authors: Roubaud Guilhem , Kostine Marie , McDermott Raymond S. , Bernard-Tessier Alice , Maldonado Xavier , Silva Marlon , Flechon Aude , Berthold Dominik R. , Ronchin Philippe , Tombal Bertrand F. , Mourey Loic , Gravis Gwenaelle , Escande Anne , Abadie Lacourtoisie Sophie , Thiery-Vuillemin Antoine , Climent Duran Miguel Angel A. , Ribault Hélène , Bossi Alberto , Foulon Stéphanie , Fizazi Karim
Published: February 2022

19

Background: Addition of abiraterone plus prednisone (AAP) to androgen deprivation therapy (ADT) with or without docetaxel (D) improved overall survival in men with de novo metastatic castration sensitive prostate cancer in PEACE-1 trial. An analysis of bone mineral density (BMD) was planned by an amendment in the last randomized patients to assess whether addition of AAP increases bone loss. Methods: Patients (pts) were randomized to receive either ADT + D + AAP or ADT + D (and also randomized for radiotherapy given to the prostate). BMD (g/cm2) of the lumbar spine (L), femoral neck (F) and total hip (H) were measured by dual x-ray absorptiometry at baseline, M6, M12 and M24 in both arms. Mean percent change in BMD values from baseline to the different time points were calculated. T-Scores were also assessed. Results: Among the 210 pts with BMD data, 182 (87%) had available data at baseline, 109 (52%) at M6, 94 (45%) at M12, and 109 (52%) at M24: 97 pts were treated with AAP and 98 without. In both arms, the median age was 65 years and 69 pts (71%) were ECOG PS 0. Median body mass index (BMI) was 25.6 and 26.5 kg/m2 in pts treated with or without AAP, respectively. BMD, T score and mean percent change in BMD values are summarized in the Table. Conclusions: This is the first prospective assessment of BMD in a randomized trial, according to an experimental treatment with AAP. Despite a bone loss increase in both arms over time, addition of AAP to ADT+D was associated with no or modest difference in bone loss during the first 2 years, compared to ADT+D. Data including fractures will be presented. Main limitations include the difficulty to reliably assess BMD in men with bone metastases, the limited sample size and the short follow-up (i.e. 2 years). Clinical trial information: NCT01957436. [Table: see text]
Real-world treatment patterns among patients with metastatic castration-resistant prostate cancer (mCRPC) in the US.
Authors: Malangone-Monaco Elisabetta , Li Weiyan , Noxon Virginia , Jiang Shan , Amin Suvina , Ghate Sameer , Swami Umang , Agarwal Neeraj
Published: February 2022

49

Background: mCRPC is an incurable disease with poor prognosis. Though multiple treatments such as novel hormonal therapies (NHT: abiraterone [abi], enzalutamide [enza], docetaxel [doce], cabazitaxel [caba], sipuleucel-T [Sip-T] etc.) are approved, real-world data regarding treatment sequencing are lacking. This study assesses the real-world treatment patterns within the context of FDA-approved life-prolonging treatments for mCRPC. Methods: The IBM MarketScan database was used to identify newly diagnosed (incident) mCRPC patients from 1/1/2014-5/31/2020. Adult males were required to have a diagnosis of PC, and subsequently evidence of metastasis and castration (medical or surgical). Incident mCRPC status (index) was determined 3 ways: 1) treatment with an NHT within 3 months after castration and an FDA-approved mCRPC treatment ≥3 months after NHT; 2) first FDA-approved treatment ≥6 months after castration; 3) first FDA-approved treatment 3-6 months after castration and a second FDA-approved treatment ≥3 months after treatment. Lines of therapy (LOT) were measured in the variable-length follow-up of ≥1 month and consisted of all drugs observed within 28 days of first observed treatment. Duration of therapy was measured as start of line to start of next line or end of enrollment. Results: A total of 2,912 mCRPC patients met all study criteria and received ≥1 LOT. Among those, 48.7% had ≥2 LOT, and 21.8% had ≥3 LOT. Patients were an average age of 71 years at index and used leuprolide (87%), abi (10%), doce (9%) and enza (8%) prior to index. In mCRPC the most common observed first line (1L) monotherapy regimens were abi (35%), enza (34%), and doce (14%). The most common observed second-line (2L) treatments were enza (36%), abi (27%), and doce (14%). Mean duration of 1L was 292 days compared to 245 days in 2L. The most frequently observed treatment sequences (1L to 2L) are reported in the table. Opioids (62%) and denosumab (47%) use was common in mCRPC patients. Conclusions: Among mCRPC patients, NHTs were the most common 1st and 2nd LOTs and alternate NHT after a first NHT was the most common sequence. With rapidly evolving treatment options in metastatic prostate cancer, these data can help guide estimation of eligible patients for different clinical trials. Further studies are needed to understand the high attrition from 1L to subsequent lines of therapy, the reasons for treatment preference and impact on clinical outcomes with different treatment sequencings.[Table: see text]
Real-world experience with relugolix.
Authors: Kasparian Saro , Wei Oren , Lehmer Christopher , Pal Sumanta K. , Lyou Yung , Dorff Tanya B.
Published: February 2022

57

Background: Gonadotropin-releasing hormone (GnRH) antagonists were developed in part to avoid testosterone flare to achieve faster and more consistent testosterone suppression. Relugolix (Rel) was given FDA approval for use in prostate cancer (PCa) based on the phase 3 HERO trial but some real-world concerns include compliance, affordability, and performance in patients transitioning from another GnRH agent or in combination with other therapeutic agents. The aim of our study was to evaluate the real-world implications of prescribing and/or switching to Rel. Methods: A single institution retrospective study was conducted on patients prescribed Rel. Treatment data including concomitant therapeutic agents were collected. Compliance data was measured via chart review and pharmacy dispensary records. Patients were classified as either newly castrated or transitioning from another agent. PSA and testosterone levels were tabulated. Reported adverse effects (AE), and reasons for discontinuation if applicable including financial toxicity were noted. Results: 50 patients were reviewed; 15 (30%) treated for adjuvant, 18 (36%) for biochemical recurrence, and 17 (34%) for metastatic PCa. 12% were on concomitant therapy with abiraterone, 4% with enzalutamide, and 2% with apalutamide. 80% reported compliance to Rel. 5 (10%) never filled the prescription. 30 (60%) were newly castrated (castration restart or naïve) while 16 (36%) were transitioned from another GnRH. No changes in PSA or testosterone were noted in patients switched form injected GnRH to Rel. The most common documented AE effects included hot flashes 24%, fatigue, 29%, and weight gain 9%. No unexpected toxicity was reported in combination with abiraterone. Of 11 patients who discontinued therapy, 45% did so due to cost, 36% due to AE, and 27% due to therapy completion. 4 of 16 (25%) of those who transitioned from injection GnRH felt symptoms were worse on Rel. Conclusions: In our early experience with Rel, patients did comply to therapy based on self-reporting, pharmacy fill dates, and laboratory evidence of castration. However, financial toxicity was and remains a significant barrier both accessing Rel and remaining on Rel therapy. While a differential toxicity was reported by those who switched from injection GnRH, sometimes leading to discontinuation, there were no new safety signals reported, especially in combination with abiraterone.
Clinical annotations for prostate cancer research: Defining data elements, creating a reproducible analytical pipeline, and assessing data quality.
Authors: Keegan Niamh M. , Vasselman Samantha E , Barnett Ethan , Nweji Barbara , Carbone Emily , Blum Alexander , Morris Michael J. , Rathkopf Dana E. , Slovin Susan F. , Danila Daniel Costin , Autio Karen A. , Scher Howard I. , Kantoff Philip W. , Abida Wassim , Stopsack Konrad H.
Published: February 2022

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Background: Routine clinical data from the electronic medical record are indispensable for retrospective and prospective observational studies and clinical trials. Their reproducibility is often not assessed. We sought to develop a prostate cancer-specific database with a defined source hierarchy for clinical annotations and to evaluate data reproducibility. Methods: At a comprehensive cancer center, we designed and implemented a clinical database for men with prostate cancer and clinical-grade paired tumor–normal sequencing for whom we performed team-based retrospective clinical data annotation from the electronic medical record, using a prostate cancer-specific data dictionary. We developed an open-source R package for data processing. We then evaluated completeness of data elements, reproducibility of team-based annotation using blinded repeat annotation by a medical oncologist as the reference, and the impact of measurement error on bias in survival analyses. Results: Data elements on demographics, diagnosis and staging, disease state at the time of procuring a genomically characterized sample, and clinical outcomes were piloted and then abstracted for 2,261 patients and their 2,631 genomically profiled samples. Completeness of data elements was generally high, between 55% to 99% for elements of clinical TNM staging, self-reported race, biopsy Gleason score, and presence of variant histologies, both for the team-based annotation and the repeat annotation. Comparing team-based annotation to the repeat annotation (100 patients/samples), reproducibility of annotations was high to very high. For 7 binary data elements, both sensitivity and specificity of the team-based annotation reached or exceeded 90%. The T stage, metastasis date, and presence and date of castration resistance had lower reproducibility. Impact of measurement error on estimates for strong prognostic factors was modest. Conclusions: With a prostate cancer-specific data dictionary and quality control measures, manual team-based annotations can be scalable and reproducible. The data dictionary and the R package for reproducible data processing tools provided (https://stopsack.github.io/prostateredcap) are freely available to help increase data quality in clinical prostate cancer research.
The changing landscape of treatment and survival for men with castration-resistant prostate cancer in the era of novel treatments.
Authors: Caram Megan Veresh , Kumbier Kyle , Tsao Phoebe A. , Burns Jennifer A. , Sparks Jordan , Bauman Jordan , Stensland Kristian , Hollenbeck Brent K. , Shahinian Vahakn B. , Skolarus Ted A.
Published: February 2022

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Background: Several therapies for men with castration-resistant prostate cancer (CRPC) have become available since 2010 with the hope of prolonging survival for those at the end stages of their disease. Little is known about the survival of men who receive novel therapies in the real world and the disease burden of patients initiating treatment for CRPC between 2010 and 2017. Methods: Using the Veterans Health Affairs Corporate Data Warehouse, we identified Veterans with CRPC who received first-line therapy for castration-resistant disease between 2010-2017. Therapies included ketoconazole, docetaxel, abiraterone, and enzalutamide since > 99% of patients treated for CRPC received one of these therapies first-line for CRPC. We used a Cox model to calculate the overall survival of patients from time of first CRPC treatment for each year. We then adjusted for patient and disease characteristics, such as starting PSA level, and prognostic group at the start of treatment based on hemoglobin, alkaline phosphatase, and albumin levels. Results: In a cohort of 4,998 men started on treatment for CRPC between 2010-2017, survival from start of first-line treatment gradually increased between 2010-2017. In 2010, when 38% of men received docetaxel first-line and 62% ketoconazole, the probability of surviving at least one year from start of first-line therapy was 64%. In 2017, when the landscape of first-line treatment had changed (49% abiraterone, 9% docetaxel, 41% enzalutamide, 1% ketoconazole) one-year survival from start of first therapy improved to 72%. The unadjusted hazard ratio (HR) for an additional calendar year was 0.93 (95% confidence interval [CI], 0.91-0.95). Men started on first-line CRPC therapy in 2010 had worse prognostic labs at the start of therapy, suggesting worse disease, and had a higher PSA value at the start of therapy compared to those started on CRPC therapy in 2017 (median PSA 55.1 in 2010 vs 27.8 in 2017, p-value < 0.01). When adjusting for disease characteristics, the improvement in survival we saw between 2010 and 2017 was diminished with adjusted HR for an additional calendar year of 0.97 (95% CI, 0.94-1.00). Conclusions: With the development of novel therapies, the survival of patients with similar disease burden should gradually improve over time. Although we did see a modest improvement in survival between 2010-2017, this improvement was mitigated when adjusting for disease severity, suggesting that some of the improvement in survival may be affected by a lead-time bias—treating patients earlier in their CRPC.
First look at patient reported outcomes from IRONMAN, the international registry of men with advanced prostate cancer.
Authors: Rencsok Emily , George Daniel J. , Kantoff Philip W. , Villanti Paul , Vinson Jake , Gerke Travis A. , Hyslop Terry , Mucci Lorelei A
Published: February 2022

69

Background: While population-based estimates of advanced prostate cancer survivors are lacking, an estimated 180,000 men in the US are living with metastatic prostate cancer. Their survivorship experience is distinct from localized patients as they suffer quality of life detriments both due to the severity of disease and its therapies. We examined quality-of-life indictors among men in the IRONMAN global registry of advanced prostate cancer. Methods: IRONMAN (International Registry of Men with Advanced Prostate Cancer) is a population-based prospective study of men with newly diagnosed advanced, metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (CRPC) enrolled from 16 countries. We report data from first 1865 men enrolled, 1567 who completed a baseline Patient Reported Outcome Measure (PROM) in the US (N=581), Canada (N=245), Spain (N=166), UK (N=204), Australia (N=126), Switzerland (N=88), Sweden (N=70), Ireland (N=46), and Brazil (N=41). PROMs are collected at baseline and every three months using electronic (90%) or paper versions of validated questionnaires. Results: The cohort includes 1,128 men with mHSPC and 737 with CRPC. Based on self-report, 9% of men overall (18% in the US) are Black and 83% are white (78% in the US). Sleep problems were common among men at enrollment, with 59% of men reporting problems with insomnia. The prevalence was similarly high among men with mHSPC or CRPC disease. Ten percent of men reported that pain substantially interfered with daily activities, and 24% reported pain had some effect. Physical functioning was high among both mHSPC (median 93.3, 80-100) and CRPC (median 86.7, 73.3-100) patients based on EORTC QLQ-30. Global health status was similar between the two groups (median 75, 58.3 - 83.3). More than 25% of men reported some cognitive impairment at baseline. Financial difficulties due to the disease and treatment were quite high, ranging from 12% in Sweden, 16% in Canada and Spain, 34% in the US, and 46% in Brazil. Conclusions: Men with advanced prostate cancer experience a range of quality of life detriments which impair overall health. While at baseline, many of these measures were similar among men with mHSPC and CRPC, we will continue to monitor these over time to examine changes in quality of life associated with disease progression and treatments. A longer-term goal is to identify opportunities for intervention to improve quality of life and potentially improve survival. Clinical trial information: NCT03151629.
Association of functional outcomes by decision-making approach in men with metastatic prostate cancer (mPC).
Authors: Schumacher Frank , Helenowski Irene B. , Moses Kelvin A. , Benning James , Morgans Alicia K.
Published: February 2022

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Background: Multiple treatments with similar efficacy exist for mPC resulting in multifaceted treatment choices. Shared decision-making (SDM) engages patients and may be associated with superior outcomes in men with prostate cancer. We assessed the association of decision locus of control (DLOC) (SDM vs. physician- or patient-directed decisions) and measures of patient quality of life (QOL), including patient reported functional outcomes, and decision satisfaction. Methods: Patients completed surveys of decision-making practices after a clinic visit in which a decision occurred. Patients also completed the EORTC QLQ-C30 QOL instrument at baseline (time of decision), and 2- and 4-months. Scores for each QOL dimension and pain were calculated for each time point, and the least-squared means were compared among DLOC groups to evaluate for associations using a mixed effects model. Results: 101 patients participated, with median age of 69 years [range: 49-92]. Most patients were white (80%) and married (82%). A majority of patients reported experiencing SDM in the clinic visit assessed (63, 62%). At baseline, there was no significant difference in patient reported QOL dimensions among DLOC groups, but patients reporting physician-directed decisions reported significantly greater baseline pain than the SDM group (Table). At 4 months, patient reported physical functioning was superior among patients reporting patient-directed (p=0.005) or SDM (p=0.03) than those who reported physician-directed decision-making. There was a trend toward greater decision satisfaction among patients who reported patient-directed (p=0.06) or SDM (p=0.10) at 4-months compared to men reporting physician-directed decision-making. There were no differences at 4 months for social, emotional, cognitive, or role functioning between DLOC groups. Conclusions: Patients who reported greater control during treatment decisions had superior physical functioning and a trend toward greater decision satisfaction at 4 months compared with patients reporting physician-directed decisions, suggesting measurable domains of benefit from involvement in the decision-making process. Continued research evaluating the association between physical and psychological outcomes and DLOC is needed, including larger studies within more diverse populations.[Table: see text]
Targeting resistant prostate cancer, with or without DNA repair defects, using the combination of ceralasertib (ATR inhibitor) and olaparib (the TRAP trial).
Authors: Reichert Zachery R , Devitt Michael Edward , Alumkal Joshi J. , Smith David C. , Caram Megan Veresh , Palmbos Philip , Vaishampayan Ulka N. , Alva Ajjai Shivaram , Braun Thomas , Yentz Sarah Elizabeth , Tsao Phoebe A. , Dreicer Robert , Cackowski Frank Cameron , Shah Neel , Dean Emma , Smith Simon , Heath Elisabeth I.
Published: February 2022

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Background: Men with metastatic, castration resistant prostate cancer (mCRPC) harboring DNA repair defects (̃20%) achieve a radiographic progression free survival of 7.4 months with PARP inhibitors (PARPi). Preclinical studies combining a PARPi (olaparib) and DNA damage checkpoint inhibitor (ATR inhibitor, ceralasertib) show synergy, providing the rationale to test this combination in men with mCRPC, including where single agent olaparib has been shown to be active. Methods: Two cohorts were accrued to a trial combining ceralasertib with olaparib in men a) with or b) without DNA repair defects. All patients progressed on ≥1 prior mCRPC therapy with no prior PARPi or platinum chemotherapy. The primary endpoint was disease response (confirmed PSA decline ≥50% and/or RECIST response), while disease progression was defined per Prostate Cancer Working Group 3 definition. Each cohort is analyzed independently for disease endpoints, while both groups were combined for toxicity assessments. Results: The 12 person DNA repair-deficient (DRDef) cohort allowed patients with germline BRCA2 loss (n = 4), somatic BRCA2 loss (n = 1) and ATM loss (n = 1 germline, n = 5 somatic and n = 1 somatic with unknown germline). 35 men without BRCA2/BRCA1 or ATM genomic loss were accrued to the DNA repair-proficient (DRPro) cohort. These men had next-generation sequencing (NGS) on contemporary biopsies (prior to enrolment without intervening therapy, 12), prior NGS on metastatic tissue (10), prior NGS on primary prostatic tissue (n = 3), or cell-free analyses (5). Five patients have incomplete cell-free analyses. At data cutoff (October 2021), in the DRDef cohort, the response rate by confirmed ≥50% PSA decline was 4/10 (40%) including 3 of 4 BRCA2 patients, and another is awaiting sufficient follow up; 1 of 6 ATM-deficient patients responded and another is awaiting sufficient follow up. All 4 DRDef responders remain on therapy (median of 8 months). For patients in the DRPro cohort who have completed therapy and response assessment (n = 21), 3 responded, one with a duration of 12 months, two with 6 months. An updated analysis will be presented. Conclusions: This analysis suggests potential activity of the doublet for DRDef (BRCA2 mainly) and DRPro mCRPC. Ongoing biomarker analysis (e.g. ATM IHC, contemporaneous cell-free DNA analysis rather than archived tissue) may help guide selection of patients most likely to benefit. Clinical trial information: NCT03787680.
Evaluation of drug-drug interactions among patients with metastatic prostate cancer in routine care.
Authors: Gassian Noemie , Clairet Anne-Laure , Goujon Morgan , Frontczak Alexandre , Calcagno Fabien , Almotlak Hamadi , Mouillet Guillaume , Maurina Tristan , Stein Ulrich , Nguyen Thierry , Jeannin Marie , Thiery-Vuillemin Antoine
Published: February 2022

111

Background: Prostate cancer often occurs in an elderly population, at higher risk of drug-drug interactions (DDIs). There is a medical need to increase the knowledge of DDI prevalence and their severity among patients coming from routine care. This study used a prospective approach with the aim to quantify and describe DDIs in medical prescription of prostate cancer treatments. Methods: DDIs were assessed from two perspectives: 1) “real DDI” between the patient’s comedications and the actual anti-cancer agent prescribed; 2) “modelized DDI” between the patient’s comedications and drugs that have proven activity in metastatic endocrine sensitive prostate cancer (MESPC) or castrate resistant prostate cancer (CRPC) settings with positive phase 3 trial and gained EMA approval. French national thesaurus, Micromedex software and complementary manual analysis by pharmacist were used to identified DDIs. Clinical relevance of DDIs was scored using the validated scale of Hatoum. Results: A total of 91 patients were included, 15% of whom were participating in a clinical trial. Some imbalances were observed between patients from clinical trial and routine care (age, ECOG, MESPC/MCRPC). The median number of comedications used per patient was 6 [1-16]. Among real DDI, Enzalutamide was the anticancer agent with the higher risk of interaction (18-54% of patients). In modelized DDI, Enzalutamide and Apalutamide were the two most risky drugs (35-76% and 22-73% depending on Micromedex or Thesaurus analyze). Not all DDIs discovered were clinically significant according to Hatoum scale. Conclusions: DDIs are frequents, according to Micromedex and National Thesaurus tools but pharmacist and physician advices are essentials to determine their potential impacts.
Enzalutamide versus abiraterone plus prednisolone before chemotherapy for Japanese castration-resistant prostate cancer patients: An investigator-initiated, multicenter, randomized controlled trial.
Authors: Izumi Kouji , Shima Takashi , Mita Koji , Kato Yuki , Kamiyama Manabu , Inoue Shogo , Tanaka Nobumichi , Hoshi Seiji , Okamura Takehiko , Yoshio Yuko , Enokida Hideki , Chikazawa Ippei , Kawai Noriyasu , Hashimoto Kohei , Fukagai Takashi , Shigehara Kazuyoshi , Takahara Shizuko , Kadono Yoshifumi , Mizokami Atsushi
Published: February 2022

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Background: Enzalutamide and abiraterone plus prednisolone demonstrated improvement of survival for castration-resistant prostate cancer (CRPC). However, it remains quite unclear which agent is better in terms of efficacy and safety for Asian patients. Methods: An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. CRPC patients before chemotherapy were randomly assigned to the enzalutamide or the abiraterone plus prednisolone arm (1:1). The primary endpoint is time to prostate-specific antigen (PSA) progression and secondary endpoints include PSA response rate (≥50% decline from baseline), overall survival, radiographic progression-free survival, and safety assessment. Results: Between February 20, 2015 and July 30, 2019, 203 patients were enrolled. After randomization, 92 in the enzalutamide and 92 in the abiraterone plus prednisolone arm were treated and analyzed. Time to PSA progression was not significantly different between arms (median 21.2 and 11.9 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.81, 95% CI 0.51-1.27, p = 0.1732). There was a significant difference in PSA response rate between arms (72% and 57% in the enzalutamide and the abiraterone plus prednisolone arm, respectively, p = 0.0425). There were no significant differences in overall and radiographic progression-free survival between arms (median 32.9 and 35.5months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 1.17, 95% CI 0.72-1.88, p = 0.5290 and median 17.6 and 14.0 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.92, 95% CI 0.63-1.34, p = 0.6532). Grade ≥3 of adverse events were observed in 11% and 21% in the enzalutamide and the abiraterone plus prednisolone arm, respectively ( p = 0.1044). Conclusions: Enzalutamide did not show any survival benefits compared with abiraterone plus prednisolone but showed better PSA response rate with no significant differences of severe adverse event rate for Japanese CRPC patients. Our data suggest that antecedent use of enzalutamide to abiraterone plus prednisolone have potentially clinical benefits in Asian CRPC populations. Clinical trial information: UMIN000015529.
BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Carneiro Benedito A. , DeSouza Andre , Golijanin Dragan , Wood Roxanne , Olszewski Adam J , Holder Sheldon L. , El-Deiry Wafik S. , Aggarwal Rahul Raj , Mega Anthony E.
Published: February 2022

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Background: mCRPC with alterations in genes associated with homologous recombination (HR) DNA repair (e.g., BRCA1/2) is sensitive to poly ADP-ribose polymerase inhibitors (PARPi). Preclinical studies showed that PI3K inhibitors (PI3Ki) impairs HR and sensitize cancer cells to PARPi even in the absence of HR gene mutations. These results support our hypothesis that dual PI3K and PARP inhibition may improve clinical outcomes in progressive mCRPC. We describe preliminary results of a phase Ib/II study investigating safety of the combination of copanlisib (pan-class I PI3Ki) and rucaparib (PARP-1, -2 and -3 inhibitor). Methods: Enrollment criteria included progressive mCRPC, prior androgen inhibitors (abiraterone, enzalutamide, and/or apalutamide); prior taxane chemotherapy was allowed. HR-deficiency was not required for the phase Ib. The phase I followed a standard 3+3 escalation design. Dose schema: rucaparib (continuous oral administration twice daily) 400mg (dose level [DL] -1, 1), 500mg (DL 2) or 600mg (DL 3,4) and intravenous copanlisib (45mg D1, D15 (DL -1, -2); 45mg, D1, D8, D15 (DL 1, 2, 3); 60mg, D1, D8, D15 (DL 4); 28-day cycle). Adverse events (AE) were graded by CTCAE v5.0. The primary aim of the phase I was to establish the MTD and the recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Results: Eleven pts were enrolled with a median age of 63 (55-78) and median PSA of 12 ng/mL (0.018–2,101). Seven pts (63%) received prior chemotherapy (docetaxel [7], cabazitaxel [3]). Pathogenic HR mutations included BRCA1 (1), BRCA2 (3), CDK12 (1), and FANCA (1). Treatment-related AE included grade 2 (G2) leukopenia (30%), G2 anemia (20%), G2 rash (20%). Two dose-limiting toxicities (DLTs) were observed in DL 1: G3 rash and G3 AST/ALT elevation attributed to both drugs. Six pts were treated at DL -1 without DLTs. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle). There were 2 confirmed PSA50 responses among 7 evaluable pts (28%). One pt had BRCA2 loss and 1 had PALB2 VUS (ongoing PSA response for 14 mo). Three stable disease and 1 partial response were observed among 6 pts evaluable by RECIST 1.1. Conclusions: The combination of rucaparib and copanlisib is well tolerated. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle) with signal of efficacy. Enrollment in a phase 2 expansion cohort in HR-mutated mCRPC is ongoing. Clinical trial information: NCT04253262.
Association of RB1 mutational status with overall genomic landscape in neuroendocrine prostate cancer (NEPC).
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Necchi Andrea , Spiess Philippe E. , Danziger Natalie , Lin Douglas I. , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Sokol Ethan , Tukachinsky Hanna , Levy Mia Alyce , Ross Jeffrey S.
Published: February 2022

156

Background: NEPC is a high-grade aggressive form of prostate cancer. We queried whether RB1 mutation status would impact the genomic features of NEPC. We hypothesized that there would be differences in GA frequencies in RB1 mutated vs non mutated cases. Methods: From a series of 13,496 cases of clinically advanced PC, 415 (3.1%) histologically defined NEPC were sequenced using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. Results: 253 (61%) of NEPC feature GA in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 GA in the non-NEPC (P <.0001). The RB1 mut+ NEPC featured a slightly greater number of driver GA/tumor than the RB1 mut- NEPC (5.1 vs 4.2). Age and TMPRSS2-ERG fusion frequency were similar between the groups. RB1 Mut- NEPC was associated with significantly higher amplifications (amp) and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured significantly greater frequency of PTEN GA. GA frequencies in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were similar in both groups. For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of low positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 ( PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were very uncommon in both groups. Conclusions: In NEPC, the presence of RB1 mutation is associated with various GA that may have clinical relevance. Limitations include possible selection and confounding biases, and lack of clinical annotation. Further study of RB1 status as a guide of trial designs on therapy selection for men with NEPC is warranted.[Table: see text]
Health-related quality of life as a prognostic indicator of biochemical recurrence free survival in high-risk prostate cancer patients following radical prostatectomy.
Authors: Westhofen Thilo , Buchner Alexander , Schlenker Boris , Becker Armin , Stief Christian G. , Kretschmer Alexander
Published: February 2022

235

Background: Several studies have shown baseline health-related quality of life (HRQOL) to be a valuable prognostic indicator of survival outcomes for various cancer entities in the metastatic setting. To date, there is no evidence regarding the prognostic value of baseline HRQOL for patients undergoing radical prostatectomy (RP) due to localized prostate cancer (PC). The objective of this study was to assess the impact of baseline preoperative HRQOL on survival prognosis for high-risk PC patients following RP. Methods: 1029 patients with high-risk PC according to NCCN risk stratification and prospectively assessed baseline HRQOL prior RP were included. Patients were stratified by the global health status (GHS) domain of the EORTC QLQ-C30 questionnaire, good general HRQOL was defined as GHS≥70 based on validated cut-off levels. Subsequently, a propensity score-matched analysis of 636 patients [n=318 (GHS≥70), n=318 (GHS<70)] was conducted. Primary endpoint was biochemical recurrence-free survival (BRFS), secondary endpoint was metastasis-free survival (MFS). Multivariate Cox regression models were performed to assess prognostic significance of baseline GHS on survival outcomes. Harrell’s discrimination C-index was applied to calculate the predictive accuracy of the model (p<0.05). Results: Median follow-up was 40mo. Applying matching variables age, PSA, pT stage, Gleason grade, positive surgical margin rate, and lymph node involvement, patients subcohorts were well-balanced. 5-yr-BRFS (61% vs. 28%; p<0.001) and 5-yr-MFS (86% vs. 68%; p=0.003) were significantly increased in the GHS≥70 cohort. In multivariate analysis GHS≥70 was confirmed as an independent predictor for increased BRFS (HR 0.60, 95%CI 0.44–0.82; p=0.013) and MFS (HR 0.51, 95%CI 0.30–0.87; p=0.026). Adding baseline HRQOL to our model improved predictive accuracy of BRFS by 8% (Harrell’s C-index of 0.69 vs 0.65). Conclusions: Our findings highlight baseline HRQOL to be a valuable and robust prognostic factor for patients with localized high-risk PC prior RP. Baseline good general HRQOL accurately predicts increased BRFS and MFS.[Table: see text]
Pathological and oncological outcomes of off-criteria radical prostatectomy in patients opting for active surveillance: From PRIAS-JAPAN.
Authors: Tohi Yoichiro , Kato Takuma , Nakamura Masaki , Matsumoto Ryuji , Sasaki Hiroshi , Mitsuzuka Koji , Inokuchi Junichi , Hashine Katsuyoshi , Yokomizo Akira , Kinoshita Hidefumi , Hara Isao , Kawamura Norihiko , Hashimoto Kohei , Inoue Masaharu , Teishima Jun , Kanno Hidenori , Fukuhara Hiroshi , Maruyama Satoru , Sakamoto Shinichi , Sugimoto Mikio ,   PRIAS-JAPAN
Published: February 2022

250

Background: Trigger for definitive treatment in active surveillance (AS) is strictly criteria-based, but some patients might be surgically treated without adherence to the criteria. We aimed to evaluate whether oncological outcomes differ depending on adherence to the criteria in patients who opting for AS. Methods: We retrospectively reviewed data of 1,035 patients enrolled in a prospective cohort of PRIAS-JAPAN. Of 162 patients underwent radical prostatectomy, 136 patients were analyzed, excluding those with Gleason score 3+4 at diagnosis, RP within one year of enrollment. Triggers for RP due to pathological reclassification on repeat biopsy was defined as on-criteria. We compared pathological findings on RP and prostate specific antigen (PSA) recurrence-free survival of on-criteria with off-criteria. Results: Off-criteria was 35 patients (24.7%). There were significant differences in the median time to RP (16 vs. 18.5 months, p<0.001) and median PSA before RP (6.1 vs. 8.3 ng/mL, p=0.007) when comparing patients with on-criteria and off-criteria. Fifty percent of off-criteria received RP within 35 months. On pathological findings of RP, pathological T3≤ (10.5 vs. 9.4%, p=0.183), Gleason score 4+3≤ (33 vs. 28.6%, p=0.679), and pathological N positive (4.3 vs. 0%, p>0.999) were not significantly different. At a median postoperative follow-up of 36 months, no significant difference in PSA recurrence-free survival was found (log-rank p = 0.828). Conclusions: Although half of off-criteria patients underwent RP within 3 years of starting AS, their oncological outcomes were not different from on-criteria. Our result suggested the potential for tailoring the inclusion criteria of AS within the strict protocol. Clinical trial information: 000002874. [Table: see text]
Real-world management of metastatic castration-resistant prostate cancer (mCRPC): A national multicenter cohort study.
Authors: Lavallee Luke , Morash Chris , Saad Fred , Yip Steven , Kapoor Anil , Kolinsky Michael Paul , Pouliot Frederic , Antebi Elie , Drachenberg Darrel , Ferrario Cristiano , Gotto Geoffrey , Hamilton Robert James , Ko Jenny J. , Noonan Krista , So Alan , Malone Shawn , Zardan Anousheh , Chi Kim N. , Hotte Sebastien J. , Niazi Tamim
Published: February 2022

252

Background: The management of patients with mCRPC has evolved since the introduction of androgen-receptor axis targeted agents (ARATs). The Genitourinary Research Consortium (GURC) initiated a prospective, phase 4, multicentre, non-interventional, longitudinal cohort study of Canadian men with advanced prostate cancer to determine real-world treatment patterns and outcomes. Methods: 25 sites across Canada participated in this study including patients managed by urologists, medical- and radiation-oncologists between 2018 to 2021. Baseline patient characteristics and mCRPC treatment patterns are reported here. Treatment patterns reviewed included time to second-line treatment use and time to progression or death. Results: 136 mCRPC patients were enrolled. Median age was 73 years (range 66 to 80) with 54 (40%) having a Gleason score of >8 at diagnosis. Median PSA at enrollment was 8.9 (2.4 to 25.1) ng/ml. At study entry, 90/132 (66%) patients with mCSPC and 42/132 (31%) patients nmCRPC had progressed to develop mCRPC. One hundred and twenty-one (89%) of patients in this cohort received first-line treatment for mCRPC, the most common was abiraterone acetate + prednisone in 67 (49%) and enzalutamide in 41 (30%), followed by docetaxel in 6 (4.4%), and Radium-223 in 5 (3.7%) patients. During the 25-month median follow-up period (range 6-28), 59 (49%) of the patients receiving first line mCRPC therapy had documented disease progression or death. At the time of last recorded follow-up, 37 (28%) patients who progressed received a second-line therapy for mCRPC. Median time to progression in this cohort was 21 months (95% CI: 15.2 - NE), with ARAT-to-ARAT being the most common sequencing pattern observed in 15 (39%) patients, followed by ARAT to chemotherapy in 14 (37%). Conclusions: In this real-world analysis of mCRPC patients, ARAT therapy was the preferred approach for first-line treatment intensification in over 108 (80%) patients. Despite evidence of poor response rates, ARAT-to-ARAT was the most common sequencing for second line therapy, followed by ARAT-to-chemotherapy treatment. Further analysis and follow-up will help define optimal mCRPC management, in real world setting.
A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.
Authors: Zibelman Matthew R. , Carducci Michael Anthony , Ged Yasser , Molina Ana M. , Ravilla Rahul , Shaffer David R. , Lambert Courtney , Tafseer Mahvish , Basiura Rachel , Weismann Danielle , Kokate Rutika , Devarajan Karthik , Ruth Karen , Alpaugh R. Katherine , Anari Fern , Ghatalia Pooja , Geynisman Daniel M. , Plimack Elizabeth R.
Published: February 2022

291

Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]