bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients (pts) with progressive metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Alonso Gordoa Teresa , Goodman Michael Moses , Vulsteke Christof , Roubaud Guilhem , Zhang Jingsong , Parikh Mamta , Piulats Josep M. , Azaro Analía , James Gareth D , Cavazzina Riccardo , Gangl Eric , Thompson Jeff , Pouliot Gayle Pageau , Kumar Rakesh , Sweeney Christopher 
Published: March 2023

173 Background: Pts with mCRPC who progress on docetaxel and new hormonal agents (NHAs) have few therapeutic options. In the CARD study of cabazitaxel, 35.7% of pts had PSA responses and 36.5% of pts had tumor responses. While immune checkpoint inhibitors have limited single-agent activity in mCRPC, the combination of the adenosine 2A receptor antagonist, AZD4635, with durvalumab may improve response to chemotherapy. This study assessed AZD4635 in combination with durvalumab (Arm A) or with durvalumab + cabazitaxel (Arm B) in pts with mCRPC. We report interim analysis results from Arm B (Arm A to be reported elsewhere). Methods: Eligible pts had histologically confirmed mCRPC, disease progression ≤6 months prior to enrollment, and were previously treated with docetaxel and 1 NHA. Pts received AZD4635 75 mg PO QD + durvalumab 1500 mg IV Q3W + cabazitaxel Q3W (dosed per locally approved label) for up to 10 cycles. The primary endpoint was radiographic progression-free survival (rPFS), by RECIST v1.1 (soft tissue) or PCWG3 (bone). Secondary endpoints included safety, pharmacokinetics, confirmed PSA50 response, and objective response rate by RECIST v1.1. A futility analysis was planned based on PSA50 responses (confirmed + unconfirmed) after approximately 30 pts were treated. Results: As of August 10, 2021, 28 pts received AZD4635 + durvalumab + cabazitaxel, and 21 pts were still on treatment. Most common adverse events (AEs) possibly related to treatment were nausea (50.0%), diarrhea (46.4%), asthenia, and vomiting (each 28.6%). Treatment-related febrile neutropenia occurred in 7.1% pts. Twelve (42.9%) pts had a serious AE possibly related to treatment. One AE possibly related to treatment led to death (myositis). Exposures of cabazitaxel and/or durvalumab did not change when combined with AZD4635. Median rPFS was 4.4 months (95% CI: 4.2–not calculable) with low percent maturity. Of 28 PSA-evaluable pts, 8 (28.6%) had PSA50 responses (4 confirmed). There were 5 unconfirmed partial responses by RECIST v1.1. Conclusions: Although efficacy data are immature, enrollment was stopped for futility. Safety of the combination was consistent with the known safety profiles of the individual agents. Clinical trial information: NCT04089553 .
High-volume mCRPC is associated with decreased cancer specific survival in patients on second-generation hormone therapy in the post docetaxel setting.
Authors: Lehner Kelly , Ahmed Mohamed E. , Bole Raevti , Andrews Jack R. , Haloi Rimki , Bold Michael S. , Kendi Ayse T. , Karnes R. Jeffrey , Kwon Eugene D. , Bryce Alan Haruo 
Published: March 2023

192 Background: In the setting of disease progression of metastatic castrate resistant prostate cancer (mCRPC) on docetaxel, abiraterone acetate (AA) and enzalutamide are two commonly used second line therapies with data demonstrating survival benefits. Less is known about patient specific factors that contribute to success with these therapies. The objective of this study is to improve patient selection for post-docetaxel second generation hormone therapy (AA or enzalutamide) by evaluating whether overall metastatic burden is associated with treatment response in this setting. Methods: By retrospective chart review, patients with mCRPC treated with AA or enzalutamide following docetaxel failure (defined as PSA rise and radiographic progression) were identified. Patients were categorized into low volume and high volume metastatic disease based on the number of pre-treatment metastatic lesions; where low volume disease describes patients with ≤ 5 metastatic lesions (e.g. oligometastatic disease), and high volume disease represents patients with > 5 individual lesions. The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Median follow-up time was 29.5 months. Results: 75 patients were identified and included in our analysis: 39 with high volume metastatic disease, and 36 with low volume metastatic disease. Baseline characteristics of age and pre-treatment ECOG were not statistically different between these groups. Pre-treatment high-volume disease burden was significantly associated with increased risk of radiographic disease progression (HR 4.21, 95%CI 1.97-8.99, p < 0.0001) and cancer specific mortality (HR 5.84, 95% CI 1.58-21.53, p = 0.0026) during treatment with second generation androgen deprivation therapy. Conclusions: High volume metastatic disease burden is associated with significantly increased cancer specific mortality and decreased progression free survival for patients on second line therapy with AA or enzalutamide following docetaxel treatment failure.
Titration as an effective strategy to reduce apalutamide induced skin rash: A multi-institutional real-world experience.
Authors: Yu Zhixian , Yu Kaiyuan , Lv Shihui , Wen Huihuang , Fang Weijie 
Published: March 2023

197 Background: With increasing use of novel androgen receptor inhibitors to treat prostate cancer (PCa), better safety management has been spotlighted. Apalutamide (APA) is suggested for metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castrate-resistant prostate cancer (NM-CRPC). However, around 25% of patients will experience skin rash. This analysis aims to investigate whether dose titration might be effective to reduce the incidence of skin rash for apalutamide-treated patients. Methods: A retrospective analysis of 73 PCa patients received APA plus androgen deprivation therapy at 3 centers in Wenzhou, China by Aug 2022 was done. Titration was defined as starting APA from a low daily dose of 120mg or 180mg and gradually increase to 240mg. The study group was dose titration patients and compare group was patients received initial 240mg qd. 1 center used 1-week dose escalation (120mg qd in week 1, 180mg qd in week 2, 240mg qd in week 3 and after) strategy and the rest 2 centers used personalized plan (starting dose of 120 or 180mg qd, the physican decide when to increase the dose). Incidence of skin rash, Grade 3 skin rash, dose modification and termination were compared. We also compared the PSA response of two groups at 1,3 and 6 months. Results: 31 and 42 patients in study and control groups were enrolled. Median age was 75.36 years (56.0-90.0), with 1.67 m height (1.50-1.80) and 69.0 kg weight (47.5-92.0). 51% was mHSPC, 90% had Gleason score ≥ 8, 66% have a high tumor volume per CHAARTED. Incidence of skin rash was significantly lower in the study vs control (6.45% vs 26.19%, p=0.029). No patient in study vs 3 (7.5%) patients in control experienced Grade 3 rash. 2 (7.69%) and 9 (22.50%) patients in study and control had dose modification and 3 (7.5%) patients in control group terminated APA due to adverse events. PSA response was slightly lower in study group in month 1 (median PSA decline, study vs control, 85.80% vs 93.85%, p = 0.117) and was consistent in month 3 (95.17% vs 98.71, p=0.152) and month 6 (98.61% vs 99.19%, p=0.530). For selection of titration strategy, incidence of skin rash between 1-week strategy and personalized strategy was consistent (5.88% vs 7.14%, p=0.887). 1-week strategy has significantly better PSA decline at month 1 (median PSA decline, 1-week vs personalized 97.00% vs 75.54%, p=0.019) and performs slightly better in month 3 (99.29% vs 87.74%, p=0.087) vs personalized strategy, in which patients’ dose started to increase between week 2-8. Conclusions: Our results demonstrated that titration might be an effective strategy to reduce incidence of skin rash for PCa patients receiving apalutamide, with little interference to patient efficacy in PSA decline. For time frame to increase dose, 1-week plan might be a better selection. Future prospective studies are needed for validation.
Tumor transcriptomic profile in patients (pts) with advanced prostate cancer (PCa) with cribriform and signet ring-like histologies.
Authors: Seasor Tori , Balatico Michael , Chigarira Beverly , Sahu Kamal Kant Kant , Kim Jong Taek , Matynia Anna P , Barry Marc , Albertson Daniel Joseph , Mahlow Jon , Swami Umang , Agarwal Neeraj , Sirohi Deepika 
Published: March 2023

259 Background: Histological subtypes of Pca are generally associated with worse clinical outcomes. Here in, we hypothesize that histological subtypes of PCa, e.g., cribriform, and signet ring-like, may have distinct genomic characteristics that may unravel new therapeutic targets. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: Pathology slides of advanced PCa (with cribriform and signet ring-like histology, and non-cribriform/signet ring-like histology as control) with transcriptomic data available. Only Gleason grade 4 or 5 were included to ensure homogeneity in population. Histology was independently reviewed by two genitourinary pathologists. RNA-sequencing of treatment naive primary prostate tissue was performed by a CLIA certified lab. DeSeq2 analysis was implemented in Bioconductor Software to analyze differentially expressed genes in patients with cribriform versus non-cribriform and signet ring-like versus non-signet ring-like histology. DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) in order to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Statistical significance level was predetermined at 0.05. Results: 34 patients were included: cribriform histology n=17, signet ring-like n=4, control non-cribriform/signet ring-like PCa n=13 (control were matched for age, PSA and disease volume). Compared to control, upregulated pathways in cribriform histology included adipogenesis, fatty acid and xenobiotic metabolism, while the down regulated pathways included mitotic spindle, G2M checkpoint and E2F targets. In signet ring-like histology, inflammatory response pathways were upregulated; DNA repair, MYC targets and androgen response pathways were downregulated. Conclusions: Cribriform, and signet ring-like histologic subtypes were noted to have distinct genomic expression profile. These data may need further validation and will guide further drug development.
Is transrectal ultrasound or magnetic resonance imaging better at estimating prostatic volume for patients with prostate cancer?
Authors: Sandberg Maxwell , Whitman Wyatt , Rong Anita , Davis Ronald , Hemal Ashok , Tsivian Matvey 
Published: March 2023

314 Background: Determining the correct size (volume) of the prostate is imperative for patients with prostate cancer. Prostate size can affect many parameters in patient care such as cores in a biopsy taken and available treatment options. Traditionally, most patients underwent transrectal ultrasound (TRUS) during prostate biopsy to estimate prostatic volume. While TRUS is still used to estimate prostate volume, more recently prostate Magnetic Resonance Imaging (MRI) has also come into favor. Current literature indicates MRI is more accurate than TRUS for prostate size, but few studies exist, and whether differences in the two are clinically significant remains uncertain. The purpose of this study was to compare prostate volumes from TRUS and MRI to gross specimens after prostatectomy. Methods: Patients who underwent radical prostatectomy for prostate cancer between 2017–2022 were identified. TRUS and MRI measurements closest to the date of surgery were obtained. These were compared to gross prostate specimens after surgery, which was considered the gold standard. All TRUS volumes were recorded by a urologist during prostate biopsy using the ellipsoid formula (L*W*H*(π/6)). MRI measurements were done by a radiologist also using the ellipsoid formula. The weight and dimensions of gross specimens were measured by a pathologist. Ellipsoid formula was then used to calculate final volume measurements in gross specimens. Paired samples t-test was used to compare averages of TRUS and MRI to the gross specimen. Results: 83 patients were included in the study with an average age at prostatectomy of 65.47 years. TRUS volume significantly differed from gross specimen volume by an average of –4.56 mL (p=0.017) and gross specimen weight by -14.31 g (p <0.001). MRI volume was not significantly different from gross specimen volume, by an average of –0.56 mL (p=0.771) and was significantly different from prostate weight by –10.32 g (p <0.001). When compared to one another, TRUS and MRI significantly differed on average by –4 mL (p=0.033). Conclusions: MRI is more accurate than TRUS to estimate prostate volume. Both MRI and TRUS underestimate prostate weight. Urologists should be aware of potential inaccuracies when assessing preoperative prostate volume with TRUS, and recognize MRI is the best predictor of size. While imperfect, TRUS is still relatively accurate measuring prostate volume, and given its ease of availability and cost, we feel it is a useful modality to determine prostate size. [Table: see text]
US real-world first-line (1L) treatment patterns and outcomes for patients with metastatic urothelial carcinoma (mUC) following maintenance avelumab approval.
Authors: Li Haojie , Herms Lisa , Leong Traci , Conkling Paul R. , Franco Sonia , Singhal Puneet , Mamtani Ronac , Bupathi Manojkumar 
Published: March 2023

483 Background: The introduction of the immune checkpoint inhibitors (ICI) pembrolizumab and atezolizumab has dramatically changed the 1L mUC treatment paradigm. These agents are currently recommended by the National Comprehensive Cancer Network for platinum-ineligible patients (irrespective of programmed death-ligand 1 (PD-L1) status) and, in the case of atezolizumab, for cisplatin-ineligible patients whose tumors express PD-L1. More recently, avelumab, received approval as the first ICI for the maintenance treatment of patients who have not progressed on 1L platinum-containing chemotherapy. In this study, we described real-world 1L treatment patterns and outcomes for mUC patients following avelumab maintenance approval. Methods: We used electronic medical record data from The US Oncology Network, which includes 1,400 affiliated physicians operating in over 500 sites of care across states and treats approximately 1.2 million cancer patients annually. mUC patients diagnosed between 30 April 2020 (i.e., ~3 months before avelumab maintenance approval) and 30 June 2021 were included, with follow-up until 31 December 2021, last patient record or death, whichever occurred first. Chart review was conducted to verify mUC diagnosis, baseline characteristics, treatment patterns, and clinical outcomes. Avelumab maintenance was defined as receiving avelumab after 1L platinum-containing chemotherapy, with no documented progressive disease prior to avelumab start or as maintenance therapy indicated by physician notes. Results: A total of 249 eligible mUC patients initiated 1L treatment. Of these, 132 (53%) received ICI monotherapy, 99 (40%) received platinum-containing chemotherapy, and 18 (7%) received other treatments. Almost one-third (n=32) of those who received 1L platinum-containing chemotherapy received avelumab maintenance therapy. ICI monotherapy use increased with age, ranging from 36% among <65-year-olds to 67% among ≥75-year-olds. During a median follow-up of 14.5 months, 68 (27%) patients received second-line treatment. Median (95% confidence interval) overall survival (OS) for 1L ICI monotherapy and 1L platinum-containing chemotherapy was 10.9 (7.2, 13.0) and 16.8 (13.5, not reached) months, respectively. Conclusions: During the 18-month period following maintenance avelumab approval, in this US community oncology setting, ICI monotherapy was the most utilized 1L treatment for mUC patients, especially among older patients. The uptake of maintenance avelumab was modest. Longer follow-up is needed to further characterize OS, especially for those who received platinum therapy followed by avelumab maintenance.
Understanding drivers of treatment preferences in locally advanced or metastatic urothelial carcinoma: A qualitative interview study with patients, caregivers, and physicians.
Authors: Apolo Andrea B. , Simon Nicholas I. , Farrar Mallory , Grewal Simrun , Hepp Zsolt , Mucha Lisa , Michaels-Igbokwe Christine , Heidenreich Sebastian , Cutts Katelyn , Gore John L. 
Published: March 2023

492 Background: The development and selection of treatments for locally advanced or metastatic urothelial carcinoma (la/mUC) have historically focused on clinical outcomes while stakeholder preferences are often considered less frequently. To facilitate the consideration of various perspectives, this study explored factors that may influence preferences of patients, caregivers, and physicians around aspects of la/mUC treatments. Methods: Interview guides elicited perspectives on disease impact (symptoms, health-related quality of life [HRQOL], survival), therapy goals and unmet needs and were conducted with patients with la/mUC, their caregivers, and medical oncologists in the US. Qualitative semi-structured data were collected on symptoms, treatment expectations, and hypothetical treatments that required trade-offs between overall survival (OS), progression-free survival (PFS), cancer pain, and the risk of severe adverse events (SAEs). Participant’s willingness to accept AEs was also explored. Results: Thirty participants, including: 10 patients (mean age 58 years; 60% female, ineligible for cisplatin: 50%), 10 caregivers (mean age 50 years; 70% female), and 10 physicians (mean 17 years treating la/mUC; 30% female) were interviewed. The most frequently reported symptom at diagnosis was pain (patients 90%, caregivers 90%) and blood in urine (physicians 100%). All three groups reported emotional impacts with depression/sadness the most common. Patients (n=7) and caregivers (n=7) relied on physicians for decision-making but felt that alternative treatments were not discussed (patients: n=5; caregivers: n=3). All groups were willing to accept some level of risk of experiencing an AE, but the accepted risk of SAEs varied (patients: 0-50% risk of SAEs; caregivers: 5-100%; physicians: 3-30%). Physicians focused treatment discussions on AEs (n=8), and overall response rate (ORR; n=6), and rarely discussed survival (n=3). All three groups described PFS and treatment response as very or most relevant to them. In the hypothetical choice tasks, all would make trade-offs between OS, PFS, pain reduction and risk of SAEs; consistent with an approach that weighs benefits and risks in treatment selection. Conclusions: Patients likely may benefit from shared, informed decision-making to identify the most appropriate treatment option for them based on clinical outcomes, AEs, HRQOL, and pain control. All groups were willing to make benefit-risk trade-offs but preferences were heterogeneous. While this study included a relatively small number of patients, planned research informed by these results will expand and further identify which treatment attributes are most important to patients.
Efficacy and safety of derazantinib (DZB) in patients with metastatic urothelial carcinoma (mUC) with activating FGFR1/2/3 genetic aberrations (GA): Results from the phase 1b/2 FIDES-02 study.
Authors: Necchi Andrea , Todenhöfer Tilman , Deville Jean-Laurent , Häckl Manuel , Marszewska Michalina , McKernan Phil , Saulay Mikael , Engelhardt Marc , De Santis Maria 
Published: March 2023

501 Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which showed meaningful clinical benefit in cholangiocarcinoma patients (pts) with FGFR2-driven (fusions, mutations or amplifications) tumors (NCT03230318). The current study explored the activity of DZB in patients with mUC and FGFR1-3 GA (NCT04045613). Methods: Eligible pts with advanced mUC and ≥1 prior lines of standard treatment and FGFR1/2/3 mutations/short variants and rearrangements/fusions confirmed by central/local NGS testing received DZB 300 mg QD (N = 32) or 200 mg BID (N = 17). Primary efficacy endpoint was objective response rate (ORR) by central radiology review per RECIST v1.1. Key secondary efficacy endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events were assessed according to NCI CTCAE v5.0. Results: From 01/2020 to 01/2022, 282 pts were screened and 49 pts were included in the study and received DZB. The median age was 67 years, 30.6% of pts were female, 94% had an ECOG 0/1, 75.5% had ≥2 prior treatment lines, 77.6% had received prior immune-checkpoint inhibitors. At data cutoff (30-Aug-2022), all pts had discontinued treatment. Confirmed ORR was 8.2% (95% CI 2.2, 19.6) based on 4 PRs (all with FGFR3 S249C mutation/ FGFR3 TACC3 fusion) and the DCR was 28.6% (95%CI: 16.6, 43.3). PFS ranged 0.3-8.8 months, and OS ranged 0.3-21.4 months. Median duration of response was 6.9 months, and longest time on treatment was 18 months. Most common all-grade treatment-emergent adverse events were transaminase increased (40.8%), nausea (38.8%), fatigue (32.7%) and decreased appetite (30.6%). Drug-related retinal events (12.2%), nail toxicities (6.1%), stomatitis (4.1%) and palmar-plantar erythrodysesthesia (PPE) (0%) were infrequent. Safety and efficacy results were similar in patients receiving 300 mg QD or 200 mg BID. Conclusions: Derazantinib showed signals of clinical activity in some patients with mUC and FGFR1-3 GA but the observed ORR and PFS did not meet contemporary benchmarks that would support further clinical development of derazantinib as monotherapy in this indication. Derazantinib showed a well-manageable safety profile with low rates of hand-foot syndrome, stomatitis, nail toxicity and retinal side effects. Clinical trial information: NCT04045613 .