bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved health-related quality of life (HR-QOL) with use of an online mindfulness tool in patients with metastatic renal cell carcinoma (mRCC) receiving immunotherapy (IO).
Authors: Bergerot Cristiane Decat , Malhotra Jasnoor , Bergerot Paulo Gustavo , Philip Errol James , Castro Daniela V. , Govindarajan Ameish , Molina Lorena Nascimento Manrique , Fuzita William Hiromi , Azeredo Andressa Cardoso , Mota Augusto C. A. , Franca Marcos V S , Anjos Gabriel dos , Filho Romildo De Araujo Periera , de Souza Douglas Manfroi , Hsu Joann , Chawla Neal , Chehrazi-Raffle Alex , Saab Bechara , Carlson Linda E , Pal Sumanta Monty
Published: March 2023

660

Background: Previous randomized studies have shown the benefit of interventions to increase mindfulness in multiple cancer types, including prostate cancer (Chambers et al JCO 2017), but limited data exists in mRCC. We sought to determine the effect of an app-based mindfulness intervention on anxiety, fear of cancer progression (FCR), fatigue and HR-QOL in this population. Methods: Eligible patients had mRCC, were receiving IO, had measurable symptoms of anxiety or FCR, had a smartphone with internet access and had not participated in a mindfulness program in the past 5 years. Patients were recruited in Brazil across 7 private centers and one academic center in the US. We evaluated the Mindfulness-Based Cancer Survivorship Journey, a program within the Am Mindfulness smartphone app (AmDTx). Patients used AmDTx for 20-30 minutes each day for a minimum of 4 days per week over a period of 4 weeks. Patients were assessed at baseline (T1) and at weeks 2 (T2), 4 (T3) and 12 (T4) using the PROMIS-Anxiety, FCR-7, Brief Fatigue Inventory (BFI), and Functional Assessment of Chronic Illness Therapy-General (FACT-G). RM-ANOVA was used to test the effect of time on symptoms and on HR-QOL. Results: A total of 41 patients were recruited; median age was 59 (range, 36-79) and patients were predominantly male (70%), white (61%), married (75%) and well educated (65% had at least a college degree). Most patients were receiving nivolumab/ipilimumab (44%), nivolumab (22%) or axitinib/pembrolizumab (9%). Symptoms of anxiety significantly decreased from 21.6 + 4.8 to 12.5 + 5.1 (P=0.001). Similar findings were found for FCR (MT1=21.4 to MT4=13.5, P=0.001) and fatigue (MT1=32.0 to MT4=19.4, P=0.001). Notably, HR-QOL increased from 81.1 + 13.4 to 92.7 + 14.9 (P=0.001). No significant differences were identified based on disease characteristics or type of therapy. Conclusions: The current study suggests that smartphone-based mindfulness intervention could improve HR-QOL and decreased FCR, anxiety and fatigue. This low-cost, easily accessible intervention may provide an important alternative to in-person psychosocial support for patients with mRCC and should be assessed in randomized trials in this disease. Funding: Kure It Cancer Research: 2020 Barry Hoeven Memorial Kidney Cancer Research Grant (PI: C D Bergerot).
C-reactive protein (CRP) as a predictive marker for outcomes with avelumab + axitinib (A + Ax) in patients with poor-risk advanced renal cell carcinoma (aRCC): Exploratory analysis from JAVELIN Renal 101.
Authors: Tomita Yoshihiko , Motzer Robert J. , Choueiri Toni K. , Rini Brian I. , Uemura Hirotsugu , Oya Mototsugu , Albiges Laurence , Fujii Yosuke , Umeyama Yoshiko , Huang Bo , Di Pietro Alessandra , Schmidinger Manuela
Published: March 2023

670

Background: Analyses from the phase 3 JAVELIN Renal 101 trial (NCT02684006) suggested that CRP levels at baseline (BL) and early after treatment may predict outcomes with A + Ax in patients with aRCC. In addition, many patients with International Metastatic RCC Database Consortium (IMDC) poor risk who had prolonged progression-free survival (PFS) and overall survival (OS) were observed at the third interim analysis of OS. We analyzed the association between CRP levels and prolonged PFS/OS with A + Ax in patients with IMDC poor risk. Methods: CRP levels were assessed at screening and on day 1 of each 6-week cycle. Patients in the A + Ax arm with 3 or 4-6 IMDC risk factors were categorized into subgroups with CRP normal (BL CRP <10 mg/L), normalized (BL CRP ≥10 mg/L and ≥1 CRP value decreased to <10 mg/L during 6-week treatment), or non-normalized (CRP ≥10 mg/L at BL and during 6-week treatment). CRP levels were compared in patients with prolonged PFS/OS (PFS ≥24 months [mo] and OS ≥30 mo) or PFS <24 mo (any OS duration). Results: In the A + Ax arm (N=442), 44 and 29 patients had 3 or 4-6 IMDC risk factors, of whom 7 and 5 had prolonged PFS/OS, and 26 and 20 had PFS <24 mo, respectively (Table). Most patients with 3 or 4-6 risk factors with prolonged PFS/OS were in the normal or non-normalized CRP group, respectively. In patients with 3 risk factors with prolonged PFS/OS, CRP levels were generally low at BL and remained low for 24 mo. In patients with 4-6 risk factors with prolonged PFS/OS, CRP levels were high at BL and decreased markedly within 6 weeks, then maintained for 24 mo. Conclusions: In patients with poor-risk aRCC treated with A + Ax, a low CRP level at BL and during treatment or a rapid decrease in high CRP levels might predict favorable long-term outcomes, although CRP levels are unspecific and may increase/decrease with other diseases/comorbidities. Clinical trial information: NCT02684006 . [Table: see text]
Effects of baseline C-reactive protein on prognosis in patients with metastatic non-clear cell renal cell carcinoma treated with systemic therapy.
Authors: Mizuno Ryuichi , Yasumizu Yota , Tanaka Nobuyuki , Matsumoto Kazuhiro , Oya Mototsugu
Published: March 2023

680

Background: With the induction of targeted agents and immune checkpoint inhibitors, treatment strategies for systemic treatment of metastatic renal cell carcinoma (mRCC) have been changed with improved survival. However, those agents were approved based on phase 3 study results designed for clear cell mRCC. For patients with non-clear cell mRCC, those drugs designed for clear cell mRCC have also been used because no validated systemic therapy exists. This retrospective study aimed to identify patients with non-clear cell mRCC who benefit from systemic therapy. Methods: A total of 255 patients with mRCC were reviewed (Institutional review board approval No 2013-0425). Among them, 41 patients who pathologically diagnosed as non-clear cell mRCC and received systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each variable on progression free survival (PFS) and overall survival (OS) were investigated. OS for patients with non-clear cell mRCC was further investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 33.9 months after first line treatment initiation, the median PFS was 3.3 and 19.7 months for non-clear cell and clear cell RCC, respectively (p<0.0001). The median OS was 20.9 and 50.1 months for non-clear cell and clear cell RCC, respectively (p<0.0001). For patients with non-clear cell RCC, univariate analyses revealed duration of first line treatment, baseline C-reactive protein, and International Metastatic RCC Database Consortium (IMDC) risk group (favorable vs intermediate/poor) were significantly correlated with OS, respectively. Multivariate analysis revealed that the duration of first line treatment (HR: 0.997, p=0.027) and the baseline C-reactive protein (HR:1.128, p=0.004) were independent predictors for longer OS in non-clear cell mRCC patients. Conclusions: Systemic therapy for non-clear cell mRCC patients resulted in relatively shorter PFS and OS. A shorter duration of first line treatment and elevated baseline C-reactive protein are correlated with longer OS.
Phase II study of axitinib prior to partial nephrectomy to preserve renal function: An interim analysis of the PADRES clinical trial.
Authors: Hakimi Kevin , Campbell Steven , Nguyen Mimi , Rathi Nityam , Wang Luke , Rini Brian I. , Ornstein Moshe Chaim , McKay Rana R. , Derweesh Ithaar H
Published: March 2023

683

Background: In renal cell carcinoma (RCC), partial nephrectomy (PN) is indicated for patients with solitary kidney, chronic kidney disease, or bilateral tumors. A subset of these patients, however, may have large and complex renal masses not initially suitable for PN. Neoadjuvant Tyrosine Kinase Inhibitor therapy has shown promising results in cytoreducing renal tumors and may permit PN in circumstances not otherwise feasible. Methods: This was a single arm phase II clinical trial of neoadjuvant axitinib in patients with complex (RENAL nephrometry score 10-12 and cT1b-cT3M0) biopsy-proven clear cell RCC with strong indications for partial nephrectomy (PN), and in whom radical nephrectomy may result in dialysis dependence. Axitinib 5 mg was administered orally twice daily for 8 weeks prior to surgery. Primary outcome was reduction in longest tumor diameter; secondary outcomes included tumor response (RECIST), change in RENAL score, feasibility of PN, change in estimated glomerular filtration rate (DeGFR), and post-surgical complications. Results: 26 patients were enrolled. 19 (73.1%) patients had ≥ clinical T3a staged tumors. Post therapy, 17 (65.4%) patients had ≥T3a staged tumors. Axitinib resulted in reductions in tumor size (7.7 vs. 6.3 cm, p<0.001) and RENAL score (11 vs. 10, p <0.001); 9 (34.6%) had partial response, and 17 (65.4%) stable disease by RECIST criteria. PN was successfully performed in 19 (73.1%); 24 (96.8%) achieved negative margins. Six (23.1%) had Clavien III-IV post-surgical complications. Median percentage DeGFR was 14.7%; one (3.8%) patient who had a radical nephrectomy had long-term dialysis dependence. Conclusions: Neoadjuvant axitnib resulted in significant reductions in tumor size and complexity, enabling PN in a cohort of complex renal masses, and with acceptable safety and functional preservation. Clinical trial information: NCT03438708 . [Table: see text]
Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: Extended follow-up results of cohort 10 of the COSMIC-021 study.
Authors: McGregor Bradley Alexander , Agarwal Neeraj , Suárez Cristina , Tsao Kai , Kelly William Kevin , Pagliaro Lance C. , Vaishampayan Ulka N. , Castellano Daniel , Loriot Yohann , Xu Fiona , Andrianova Lana , Sudhagoni Ramu , Choueiri Toni K. , Pal Sumanta Monty
Published: March 2023

684

Background: In the COSMIC-021 phase 1b study (NCT03170960) evaluating cabozantinib plus atezolizumab in advanced solid tumors, this combination therapy demonstrated encouraging clinical activity in patients with advanced non-clear cell renal cell carcinoma (nccRCC) with a median follow-up of 13 mo (Pal. JCO 2021). Results after extended follow-up in nccRCC are presented. Methods: Patients with advanced nccRCC and ECOG PS 0/1 who had ≤1 prior VEGFR-targeting tyrosine kinase inhibitor (TKI) were eligible. Prior treatment with TKIs targeting MET or immune checkpoint inhibitors was not allowed. Patients received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W until unacceptable toxicity or progression; dose reductions of cabozantinib (40 mg QD to 20 mg QD, then to 20 mg QOD) were permitted to manage adverse events. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by the investigator; other endpoints included safety, duration of response (DOR), PFS, and OS. Results: The study enrolled 32 patients with nccRCC (2 from dose escalation phase, and 30 from expansion phase of the study): median age, 62 y; male, 81%; ECOG PS 0/1, 75%/25%; histology, papillary/chromophobe/clear cell/other, 47%/28%/3%/22%; sarcomatoid feature, 13%; IMDC risk favorable/intermediate/poor, 50%/41%/9%; ≥3 tumor sites, 56%; tumor sites, lung/kidney/bone/liver, 50%/25%/16%/16%; prior nephrectomy, 63%; prior VEGFR TKI, 22%; 0/1 lines of prior therapy (locally advanced/metastatic setting), 81%/19%. As of July 21, 2022, median follow-up was 37.2 mo (range 32.1–58.5) with 5 (16%) patients remaining on study treatment. ORR by investigator was 31% (all PRs) and disease control rate was 94% (Table); median DOR was 8.1 mo. Median PFS was 9.3 mo (95% CI 5.5–12.3), and median OS was not reached (95% CI 23.0–NE). PFS and OS estimates at 12 mo were 34% and 84%, respectively; 24-mo estimates were 6% and 70%. Treatment-related AEs occurred in 97% (grade 3/4, 53%); the most common AEs included diarrhea (69%), palmar-plantar erythrodysesthesia (50%), fatigue (44%), dysgeusia (41%), hypertension (31%) and nausea (31%). One grade 5 treatment-related AE of pulmonary hemorrhage occurred. Treatment-related AEs leading to discontinuation of both study treatments occurred in 13% of patients. Conclusions: Extended 3-year follow-up reinforces the encouraging clinical activity of cabozantinib plus atezolizumab in advanced nccRCC with a manageable safety profile. Clinical trial information: NCT03170960 . [Table: see text]
The usefulness of meflin expression in cancer-associated fibroblasts as a predictive marker for immune checkpoint inhibitor in clear cell renal cell carcinoma.
Authors: Owaki Takayuki , Miyai Yuki , Naito Yushi , Sano Tomoyasu , Enomoto Atsushi
Published: March 2023

699

Background: Tumor is composed of various cells, including not only cancer cells, but also immune cells, vascular endothelial cells and cancer associated fibroblasts (CAFs). CAFs generally work to promote cancer malignancy by secreting growth factors, promoting angiogenesis and producing extra cellular matrix. However, depletion of these CAFs accelerated tumor progression. Therefore, it is a common belief that there are two kinds of CAFs, cancer-promoting CAFs and cancer-restraining CAFs. Recently, our research group identified cancer-restraining CAFs expressing Meflin as a marker in pancreatic cancer. Furthermore, our research group reported that Meflin can be a good predictive marker for ICI in non-small cell lung cancer. This time, we performed a similar analysis for clear cell renal cell carcinoma (ccRCC), to confirm whether Meflin is universally a good predictive marker for ICI or not. Methods: This analysis was performed as a retrospective observational study and conducted in accordance with the Helsinki Declaration for Human Research and approved by the Ethics Committee of Nagoya University Graduate School of Medicine (approval number: 2020-0321).We identified 21 eligible patients with ccRCC who received ICI from 2017 to Mar 2019. We collected FFPE tissue and prepared 4–µm-thick slides for the analysis of Meflin expression by RNA in-situ hybridization (ISH). Then, we assessed the number of Meflin-positive CAFs and divided the patients into Meflin-high (15% and more CAFs express Meflin) and -Low groups, followed by the evaluation of the clinical outcomes, objective response rate (ORR) and overall survival (OS). Results: Patients were followed-up until the Aug 2022. 13 patients were divided into Meflin-high and 8 patients were divided into Meflin-low groups. Analysis revealed that 9 (69.23%) of 13 Meflin-high patients responded to ICI. In contrast, none (0%) of 8 Meflin-low patients showed any significant response (p-value: 0.0046). Furthermore, Kaplan–Meier survival analysis revealed, the Meflin-high group had a significantly favorable prognosis in OS (p-value:0.0137, hazard ratio 0.2959[0.06933 to 0.7097]). Conclusions: This analysis concluded that Meflin is a good predictive biomarker for ICI in ccRCC.
Dissecting the molecular signatures underlying hybrid oncocytic tumors in Birt-Hogg-Dubé syndrome.
Authors: Wang Xiaoming , Mannan Rahul , Zhang Yupin , Hogan Margaret , King Dana , Chinnaiyan Anya , Chinnaiyan Arul , Dhanasekaran Saravana , Mehra Rohit
Published: March 2023

707

Background: Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of renal tumors including the hybrid oncocytic tumors (HOT), renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC). HOT are known to exhibit morphological features overlapping between RO and CHRCC. The molecular underpinnings of HOT and the corresponding morphologic correlates remain poorly understood. Herein we aimed to understand the distinct molecular features underlying HOT and how the genomic phenotype differs from CHRCC. Methods: We performed next generation sequencing and single cell sequencing analysis to understand the clinico-pathologic aspects and tumor biology of HOT and CHRCC, including tumor development. This was followed by spatial transcriptome analysis of the distinct HOT tumor compartments, using nanoString GeoMX digital spatial profiler. The candidate biomarker expression was confirmed by immunohistochemistry (IHC) and RNA in situ hybridization (RNA-ISH), a unique gene expression visualization molecular technology. Results: We discovered unique gene expression signatures underlying the two distinct morphological patterns seen in HOT. FOXI1 and L1CAM show a striking mutually exclusive expression pattern in the two cellular populations seen within this tumor. The signature genes of RO like cells seen within HOT resembles the principal cells of the distal nephron seen in normal kidney; and the signature genes of the CHRCC like cells resembles the intercalated cells of the distal nephron. This suggests distal nephron as the cellular site of origin for HOT. We also nominated tumor specific biomarkers for HOT. Conclusions: We identified unique gene expression signatures which are definitional for HOT and nominated candidate diagnostic biomarkers to help distinguish HOT from other renal tumor subtypes with overlapping morphology. This finding would improve the diagnostic accuracy, assist familial genetic monitoring, and facilitate disease management.
Burden of surgeries and surgical complications in patients with Von Hippel Lindau (VHL) disease before and after treatment with belzutifan.
Authors: Wang Lin , Bensimon Arielle G. , Sundaram Murali , Xu Ruifeng , Lai Yizhen , Liu Yanfang , Mt-Isa Shahrul , Yang Danni , Freimark Jonathan , Song Yan , Jonasch Eric
Published: March 2023

733

Background: VHL disease is a rare hereditary condition that causes abnormal tumor growth in multiple organs, including renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (Hb), pancreatic neuroendocrine tumors (pNET), and other tumors. Repeated surgeries are often required due to ongoing tumor recurrences and can lead to complications such as chronic kidney disease, pancreatic insufficiency, and neurological deficit. Belzutifan is a hypoxia-inducible factor inhibitor approved in the US for the treatment of VHL-associated RCC, CNS Hb, or pNET not requiring immediate surgery. This study aimed to quantify the annual rate and costs of VHL-related surgeries and surgical complications before and after belzutifan initiation. Methods: Surgeries were observed during the periods before and after belzutifan initiation in the single-arm phase 2 LITESPARK-004 trial (NCT03401788) among adults with VHL-RCC. Rates of RCC surgeries were obtained by fitting exponential survival models to: time from treatment initiation to the next renal surgery; and time (looking backward) from treatment initiation to the most recent renal surgery before treatment. Rates of surgeries related to other VHL manifestations were calculated as number of surgeries divided by person-years at risk, using all available post-treatment follow up (151 person-years; median [range] per patient: 29.2 [4.2-37.5] months) and equivalent person-years in the pre-treatment period. Complication risks per surgery and unit costs of surgeries and complications were obtained from a retrospective study on VHL within the Optum Clinformatics Data Mart (2000-2020). Annual per-patient costs of surgeries and complications were estimated in 2020 US dollars over the pre- and post-treatment periods from a US third-party payer perspective. Results: Among trial participants (N=61), the rate of RCC surgeries (surgeries/person-year) decreased 87% (0.108 to 0.014) after belzutifan initiation. The rate of other surgeries decreased 98% (0.265 to 0.007), with CNS Hb surgeries decreasing from 0.185 to 0.007, pNET surgeries from 0.013 to 0, adrenal lesion surgeries from 0.007 to 0, and retinal Hb surgeries from 0.060 to 0. Belzutifan was accordingly estimated to reduce per-patient average annual costs of surgeries and complications from $57,259 to $2,536. Conclusions: Healthcare costs of surgeries and surgical complications are substantial among patients with VHL-RCC. In a trial-based cost-consequence analysis, belzutifan was estimated to decrease annual surgery and complication costs by 96%, based on observed reductions in VHL-related surgeries. [Table: see text]
Treatment and survival of de novo metastatic prostate cancer in US veterans.
Authors: Schoen Martin W. , Etzioni Ruth Douglas , Knoche Eric Marshall , Graff Julie N , Sanfilippo Kristen Marie , Luo Suhong , Eisen Seth A , Montgomery Robert Bruce
Published: March 2023

87

Background: Combination therapies using the androgen deprivation therapy (ADT) backbone have revolutionized treatment of metastatic hormone sensitive prostate cancer (mHSPC). Combinations include ADT plus docetaxel (DOC) or the androgen receptor targeting agents (ARTAs) abiraterone (AA), enzalutamide (ENZ), apalutamide (APA), and darolutamide (DAR). This study evaluates the utilization of these therapies in de novo mHSPC in a cohort of veterans and assesses recent overall survival (OS) of these therapies. Methods: Veterans were identified from 2012-2021 in the Veterans Affairs Prostate Cancer Data Core (VAPC) and oncology tumor registries using the initial pathological diagnosis of prostate cancer with SEER stage ‘distant’. All veterans had ADT initiated within 1 month prior and 3 months after diagnosis in VAPC. Additional therapies including DOC or ARTAs were collected from VAPC if initiated from 1 month prior to 4 months after ADT initiation. Data cut point was June 2022. Results: 5,006 patients with de novo mHSPC were identified with median age of 73.1 years (yrs), and 1338 (26.7%) identified as Black race. From 2012 to 2021, ADT alone was used in 3,569 (71.3%) of veterans, DOC in 438 (8.7%) and ARTAs in 999 (20.0%), wherein use of different ARTAs was AA in 783 (78.4%), ENZ in 204 (20.4%), APA in 10 (1.0%), and DAR in 2 (0.2%). Use of combination therapy for mHSPC increased from 3.1% in 2012-2013 to 61.2% in 2020-2021. Use of DOC peaked in 2016 and was used in 16.3% of veterans that year. Veterans treated with DOC were significantly younger (median 67.3 yrs, p<0.001) compared to veterans treated with ARTAs (73.1 yrs) or ADT alone (74.3 yrs). Veterans treated with combination therapies had longer median OS compared to ADT alone (37.2 vs. 29.3 months, p<0.001), with no significant difference between DOC and ARTA combinations (p=0.84). For 2,042 veterans with de novo mHSPC treated from 2018-2021, median OS of veterans treated with ADT+DOC (n=161, 35.3 months) and ADT+ARTA (n=849, 41.2 months) was longer than ADT alone (n=1,032, 29.3 months, p<0.001). There was no significant difference in median OS between DOC and ARTA combinations in this group (p=0.69). Conclusions: In veterans presenting with de novo mHSPC, use of initial combination therapy has increased, with the majority of veterans treated with ADT and an ARTA in 2020-2021. In this cohort, combination therapy was associated with longer OS compared to ADT alone and no significant differences were found between type of combination and OS. [Table: see text]
Identifying prostate cancer patient subgroups based on their preferences for key attributes of androgen deprivation therapies.
Authors: Collins Sean P. , Maculaitis Martine C. , Hauber Brett , Hunsche Elke , Kopenhafer Lewis , Nwokeji Esmond , Beusterien Kathleen M.
Published: March 2023

94

Background: Androgen deprivation therapies (ADTs) for prostate cancer (PC) vary in delivery mode, T (testosterone) surge occurrence, time to T recovery, adverse event profile, and costs. Data are limited on how men differ in their evaluation of ADT attributes. This study identified subgroups of men who vary in their preferences for key ADT attributes. Methods: A cross-sectional survey of US men aged >40 years, who had healthcare coverage for the past 3 years and self-reported a PC diagnosis, were recruited via healthcare research panels. Men were ineligible if they did not know/recall whether they had received ADT or were unable to complete the survey independently. Quotas ensured an approximate even split of ADT-experienced and ADT-naïve men. A discrete choice experiment assessed preferences for ADT attributes. In a series of choice tasks, men were presented with 2 ADT treatment profiles side-by-side and asked to select the one they prefer. Hierarchical Bayes models computed attribute level preference weights. Relative importance (RI), based on differences between the most and least favorable attribute level preference weight and standardized to sum to 100%, was estimated for each attribute; the higher the RI value, the more influential an attribute is to treatment choice. Latent class analysis (LCA) identified groups (Gs) of men with similar ADT preferences. Results: 304 men were included in the analyses, their mean age was 64.4±7.2 years, and 16.8% were African American. Mean PC duration was 5.4±4.8 years, 55.3% reported organ-confined PC, and 49.0% had prior ADT use. LCA identified 4 preference Gs. While impact on sexual activity was most important to G1, out-of-pocket (OOP) costs, mode of administration, and time to T recovery were choice drivers for G2. Mode of administration and OOP costs predominated in importance for G3 and G4, respectively. More than half of men in G1 and G3 were <65 years; G1, but not G3, included mainly men who planned to be sexually active. G2 and G4 were predominantly composed of men aged ≥65 years who often had Medicare insurance. Conclusions: Younger, sexually active men consider the potential impact on sexual activity when choosing PC therapy, while for older men administration burden or OOP costs are important choice drivers. Thus, ADT attributes often vary in salience to men and should be considered in shared PC treatment decision-making. [Table: see text]
Real world (rw) racial differences in treatment (tx) patterns and clinical outcomes among patients (pts) with mCRPC.
Authors: Barata Pedro C. , Du Ella X. , Yang Hongbo , Xu Chunyi , Guo Helen , Cui Caroline , Nazari Jonathan , Niyazov Alexander
Published: March 2023

95

Background: Contemporary rw data is needed to describe the heterogeneity of the tx landscape among diverse pt populations. This study assessed rw tx patterns and clinical outcomes among US pts receiving tx for mCRPC. Methods: Data from pts with mCRPC initiating first line (1L) tx between 2016 and 2019 were abstracted from medical charts. Clinical characteristics and tx patterns stratified by race (White [W], Black [B], and Other [O]) were compared using descriptive statistics. Rw progression-free survival (rwPFS) and overall survival (OS) were analyzed using Kaplan–Meier method. A multivariate Cox model explored associations between race and rwPFS/OS, controlling for confounders. Results: 122 physicians contributed data from 260 charts (W n=127, B n=81, O n=52 pts). The median age was 69 years; 64 (25%) had ECOG score ≥2. Common sites of metastases (mets) were bone (73%) and lymph nodes (34%); median Gleason score (GS) was 8.0, with no significant differences in sites of mets or GS among B and W pts. Most common txs prior to mCRPC included androgen deprivation therapy (ADT) monotherapy (39%), chemotherapy (CT; 15%), and novel hormonal therapy (NHT; 9%). Prior to mCRPC, more B pts were offered tx intensification with NHTs or CT compared with W pts (35% vs 14%). NHT was the most common 1L mCRPC therapy, followed by CT (Table). Compared with W pts, more B pts were offered NHT (65% vs 59%, P=0.44) and CT (26% vs 20%, P=0.38) in the 1L setting. Adjusted median rwPFS on 1L tx was 43.7 months (mo; 95% CI: 27–not estimable [NE]). A longer rwPFS was observed for B vs W pts; median rwPFS NE (95% CI: 34.7–NE) vs 34.7 mo (95% CI: 21.0–NE), hazard ratio (HR)=0.58 (95% CI: 0.35–0.97; P<0.05). B pts had numerically greater OS vs W pts, HR=0.58 (95% CI: 0.31–1.1; P=0.09). Conclusions: In this rw study of pts receiving 1L tx for mCRPC, rwPFS was better compared with clinical trial data, particularly among B pts, who were more likely to receive life-prolonging txs in the 1L setting. These data suggest B pts might respond better to systemic therapies compared with W pts, and disparities observed in other settings may be attributed to access barriers. [Table: see text]
Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the Phase 3 IMvigor130 study.
Authors: Bamias Aristotelis , Davis Ian D. , Galsky Matt D. , Arranz Arija Jose Angel , Kikuchi Eiji , Grande Enrique , Garcia del Muro Xavier , Park Se Hoon , De Giorgi Ugo , Alekseev Boris , Mencinger Marina , Izumi Kouji , Puente Javier , Li Jian-Ri , Bene-Tchaleu Fabiola , Mariathasan Sanjeev , Lee Chooi Peng , Bernhard Sandrine , De Santis Maria
Published: March 2023

LBA441

Background: Two interim OS analyses from IMvigor130 demonstrated non-statistically significant OS benefit with atezo monotherapy (Arm B) vs placebo + platinum (investigator [INV] choice of carboplatin or cisplatin [carbo or cis])/gemcitabine (plt/gem; Arm C) in patients (pts) with PD-L1–high (IC2/3) mUC, as well as a favorable safety profile vs chemo (Galsky Lancet 2020, Davis AACR 2021). Exploratory data showed clinical benefit with atezo monotherapy in cis-ineligible pts with IC2/3 tumors. Here, we report the final OS analysis from IMvigor130 Arms B and C. Methods: Pts were randomly assigned 1:1:1 to Arm A (atezo + plt/gem; not reported here), B or C. Due to the statistical testing hierarchy, no formal comparison of OS (co-primary endpoint) in Arm B vs C was performed in ITT and IC2/3 pts. ORR and DOR, both per INV-assessed RECIST 1.1 (secondary endpoints), and safety were assessed. Subgroup analyses of OS in cis-ineligible pts and disease control rate (DCR, confirmed CR, PR or [SD ≥6 mo]) were exploratory. Results: As of data cutoff Aug 31, 2022, time since last pt randomly assigned was 49 mo. OS data (Table) did not show benefit for ITT pts, while an HR of 0.56 (0.34, 0.91) was seen in the cis-ineligible IC2/3 subgroup. In the ITT population, the 24-mo OS rates were 34% in Arm B and 32% in Arm C. ORR was 24% (87/359; 38% DCR) in Arm B and 44% (158/356; 59% DCR) in Arm C; median DOR was 29.6 and 8.1 mo, respectively. In cis-ineligible IC2/3 pts, ORR was 40% (20/50) in Arm B and 33% (14/43) in Arm C. Median DOR was not evaluable in Arm B and 6.2 mo in Arm C. Of safety-evaluable pts, 57 of 354 in Arm B (16%) and 312 of 389 in Arm C (80%) had a Gr 3/4 treatment-related AE (TRAE); 3 (1%) and 4 (1%), respectively, had a Gr 5 TRAE. Gr 3/4 AEs of special interest occurred in 36 pts (10%) in Arm B and 17 (4%) in Arm C. Conclusions: The final OS analysis was consistent with previous data. Atezo monotherapy continued to show better tolerability vs chemo with no new safety concerns. These exploratory data support the benefit-risk ratio of atezo monotherapy vs chemo for first-line cis-ineligible IC2/3 mUC. Clinical trial information: NCT02807636 . [Table: see text]
Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial.
Authors: Necchi Andrea , Roumiguié Mathieu , Esen Ahmet Adil , Lebret Thierry , De Wit Ronald , Shore Neal D. , Bajorin Dean F. , Krieger Laurence E. M. , Kandori Shuya , Uchio Edward M. , Seo Ho Kyung , Boormans Joost , Kamat Ashish M. , Singer Eric A. , Grivas Petros , Nishiyama Hiroyuki , Nam Kijoeng , Kapadia Ekta , Van den Sigtenhorst-Fijlstra Margot , Kulkarni Girish S.
Published: March 2023

LBA442

Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of >20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]
Extended follow-up results from the CheckMate 274 trial.
Authors: Galsky Matt D. , Witjes Alfred Alfred , Gschwend Jürgen E. , Schenker Michael , Valderrama Begoña Pérez , Tomita Yoshihiko , Bamias Aristotelis , Lebret Thierry , Shariat Shahrokh F. , Park Se Hoon , Agerbaek Mads , Jha Gautam Gopalji , Stenner Frank , Dutta Santanu , Nasroulah Federico , Zhang Joshua , Brophy Lynne , Bajorin Dean F.
Published: March 2023

LBA443

Background: The 2 primary endpoints of the CheckMate 274 trial were met as nivolumab (NIVO) improved disease-free survival (DFS) versus placebo (PBO) in the intent-to-treat (ITT) population and in patients with tumor programmed death ligand 1 (PD-L1) expression ≥ 1%. We report extended follow-up data. Methods: CheckMate 274 is a phase 3, double-blind trial of adjuvant NIVO versus PBO for high-risk muscle-invasive urothelial carcinoma (MIUC) (bladder, ureter, or renal pelvis) after radical resection. Patients were randomly assigned 1:1 to NIVO 240 mg every 2 wk or PBO for ≤ 1 year of treatment. Patients had pathologic evidence of UC at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1. Primary endpoints were DFS in ITT patients and in patients with PD-L1 ≥ 1%. DFS was also analyzed in prespecified subgroups. Overall survival and non–urothelial tract recurrence-free survival (NUTRFS) in ITT patients and in patients with PD-L1 ≥ 1% were secondary endpoints. Distant metastasis-free survival (DMFS) and safety were exploratory endpoints. Results: There were 353 patients randomly assigned to NIVO (PD-L1 ≥ 1%, n = 140) and 356 to PBO (PD-L1 ≥ 1%, n = 142). With median follow-up of 36.1 months (minimum follow-up, 31.6 months), median DFS was 22.0 months with NIVO versus 10.9 months with PBO in ITT patients and 52.6 months with NIVO versus 8.4 months with PBO in patients with PD-L1 ≥ 1% (Table). DFS benefit was seen in most subgroups analyzed including age, sex, ECOG PS, nodal status, prior cisplatin-based chemotherapy, and PD-L1 status. NUTRFS and DMFS benefits with NIVO versus PBO were also observed in both populations (Table). Grade 3–4 treatment-related adverse events occurred in 18.2% and 7.2% of patients in the NIVO and PBO arms, consistent with the primary analysis. Overall survival will be assessed at a future database lock. Conclusions: With extended follow-up, NIVO continued to show DFS, NUTRFS, and DMFS benefits versus PBO. The hazard ratio (HR) for DFS and NUTRFS in PD-L1 ≥ 1% patients and for DMFS in both ITT and PD-L1 ≥ 1% patients also continued to improve versus the primary analysis. No new safety signals were identified. These results further support adjuvant NIVO as a standard of care for high-risk MIUC after radical resection. Clinical trial information: NCT02632409 . [Table: see text]
Cell-free urinary tumor DNA to detect minimal residual disease prior to repeat-transurethral resection of bladder tumor in non–muscle-invasive bladder cancer: A prospective study.
Authors: Rose Kyle M. , Murthy Prithvi , Gould Billie , Huelster Heather L , Davaro Facundo , Du Pan , Jia Shidong , Li Roger
Published: March 2023

LBA445

Background: Cell-free urinary tumor DNA (utDNA) generated from tumor genomic sequencing is an emerging biomarker showing tremendous potential for detecting minimal residual disease (MRD) in muscle-invasive and metastatic bladder cancer. We performed a prospective study to assess utDNA’s ability to measure MRD at the time of standard-of-care repeat transurethral resection of bladder tumor (rTURBT) in non-muscle invasive bladder cancer (NMIBC). Methods: Patients with high-risk NMIBC were enrolled prior to rTURBT. Index tumor and rTURBT mutational profile was performed via PredicineWES whole exome sequencing across 20,000 genes. Genes with non-synonymous (NS) mutations observed in index and rTURBT specimens identified in a minimum of two samples are reported. Urine samples were taken immediately prior to r-TURBT. utDNA detection was performed by ultra-deep sequencing of urinary cfDNA using a custom panel of up to 50-baseline mutations per patient together with a fixed core panel covering hotspot regions and actionable variants via PredicineBEACON. Urinary tumor fraction was used to call utDNA positivity. The primary endpoint was the detection of utDNA to predict MRD at the time of repeat-TURBT. Results: Eleven patients underwent rTURBT for high-risk NMIBC. Residual tumor was detected at rTURBT in 8/11 (73%) patients. Fifty genes with NS mutations found in at least two samples were identified including TP53, PIK3CA, RB1, MYC, CDKN1A and ARID1A. A median of 146 (range 39-418) and 91 NS (range 2-312) mutations were identified in the index and re-TUR specimens, respectively. Concordance rates were 83% on average between index and rTURBT, highest for patients upstaged to T2 disease, and lowest for patients harboring CIS. New somatic variants not observed in the index tissue were detected in rTURBT for 4/6 patients and 7/14 were also detected in the pre-operative urine. Overall, 50% of utDNA mutations were concordant with index tumor tissue, 39% were concordant with rTURBT tissue, and 33% were concordant with both. The tumor fraction of utDNA was higher in patients with residual disease (mean 2.5% vs. 0.2%, p=0.10). Using tumor-fraction to predict MRD, the area under the receiver-operator curve was 0.85. Using an optimal threshold of ≥3.3% tumor-fraction to define utDNA positivity, the test had a sensitivity of 75% at 100% specificity. Conclusions: Urinary tumor DNA shows promise as a surrogate for minimal residual disease and may predict TURBT pathology for NMIBC. Genomic alterations between index and rTURBT tumors are highly concordant in papillary tumors even in the setting of upstaging, which may aid in targeted intravesical or systemic therapy selection. Larger cohorts and long-term follow up is needed to determine if utDNA can risk-stratify patients prior to rTURBT and predict long-term recurrence.
A multi-center, open-label, randomized dose expansion study of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Calvo Mariona , Penkov Konstantin , Spira Alexander I. , Moreno Candilejo Irene , Shore Neal D. , Zhang Tian , Mellado-Gonzalez Begoña , Alonso Gordoa Teresa , Paz-Ares Rodriguez Luis , Tarantolo Stefano R. , Soto Juan José , Alter Robert S. , Andreu-Vieyra Claudia , Bowler Timothy , Maity Arnab K , Hariharan Subramanian , Schweizer Michael Thomas
Published: March 2023

TPS282

Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977 ) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977 .
DASL-HiCaP: A randomized, phase 3, double-blind trial of darolutamide with androgen-deprivation therapy and definitive or salvage radiation for localized very high-risk prostate cancer.
Authors: Niazi Tamim , McBride Sean Matthew , Williams Scott , Davis Ian D. , Stockler Martin R. , Martin Andrew James , Chung Hans T. , Roncolato Felicia , Ebacher Annie , Khoo Eric , Martin Jarad , Lim Tee Sin , Hughes Simon , Pryor David , Catto James W.F. , Kelly Paul , Gholam Rezaei Leily , Morgan Scott C. , Rendon Ricardo A. , Sweeney Christopher ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2023

TPS396

Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is a standard of care for patients with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of patients with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT used either as primary definitive therapy, or as salvage therapy, for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind, international trial for patients planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by previous RP; planned use of adjuvant docetaxel; clinical or pathological pelvic nodal involvement. 1100 participants will be randomized to receive darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC (LHRHA for 96 weeks, plus RT starting week 8-24 from randomization). Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints of overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353 .
A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.
Authors: Spratt Daniel Eidelberg , McKay Rana R. , Dorff Tanya B. , Lowentritt Benjamin H , Fallick Mark , Hanson Sarah , Ross Ashley
Published: March 2023

TPS398

Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients > 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .