bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-center analysis on a real-world cohort of patients with metastatic urothelial carcinoma studied by NGS: Molecular landscape and efficacy of targeted therapies.
Authors: Gutiérrez Pérez César , Rodríguez Ledesma Inmaculada , Pumares González María , Vela Domínguez Miriam , Espinosa Cabria Noelia , Cabrera Pinos María Liliana , Calvo Otero Laura , Valencia Cárdenas Lina Marcela , Viña Gopar Laura , Blanco Abad Carmen , Folgueira Hernández Benjamín , García Muñoz María , García Girón Carlos , García Toro Enrique , Lastra Aras Enrique , López Peraita Sandra , Ramos Reguera Irene , Saiz López Patricia , de la Torre Lázaro Sofía , Crespo Herrero Guillermo
Published: January 2024

661

Background: the median overall survival (OS) in metastatic urothelial carcinoma (mUC) treated with multiagent therapy is approximately 13 months (mo). Around 69% of these tumors harbor potential therapeutic targets. Real-world evidence on using Next Generation Sequencing (NGS) in mUC management is limited. Methods: we conducted a single-center analysis on a real-world cohort of patients (pts) with mUC. The study population included pts aged >18 years with diagnosis of mUC studied by NGS at the moment of starting immunotherapy (enrollment period: 09/04/2019 – 03/25/2022). Median OS and median progression-free survival (PFS) were determined using Kaplan-Meier curves. Results: we included 43 pts. Median age at mUC diagnosis was 67 years; 38 (88.4%) pts were men; 38 (88.4%) pts were ECOG 0-1 at mUC diagnosis; one or more adverse prognostic factors (Bellmunt Risk Score) were identified in 33 (76.7%) pts; primary tumor site was lower tract in 36 (83.7%) pts. All pts were treated with platinum-based combinations (neoadyuvant, adyuvant or first line) and immunotherapy. Pathogenic alterations were found in 25 (58.1%) pts. In the group of 25 pts with pathogenic alterations, 17 pts progressed to immunotherapy and 7 pts of them received targeted therapies; 10 pts could not receive targeted therapies due to poor prognosis. In the group of 18 pts without pathogenic alterations, 11 pts progressed to immunotherapy and 8 pts of them received other chemotherapy options; 3 pts could not receive other chemotherapy options due to poor prognosis. The median OS (time since mUC diagnosis) among 25 pts with pathogenic alterations was 30.2 (CI 95%: 18.9-41.5) mo compared to 22.9 (CI 95%: 12-33.9) mo among 18 pts without pathogenic alterations, (p = 0.557). Focusing on the subgroup of 7 pts treated with targeted therapies (Table), we found an objective response rate (ORR) of 42.9%; the median PFS was 7.3 (CI 95%: 6.7-7.9) mo and the median OS (time since beginning targeted therapies) was 10.9 (CI 95%: 2.4-19.5) mo. Conclusions: We recommend that all pts with mUC undergo NGS at the time of diagnosis, given the high percent (58.1%) of pathogenic alterations in our real-world cohort and the efficacy in terms of ORR, PFS and OS in pts treated with targeted therapies. [Table: see text]
The impact and mechanisms of gut microbiota on the efficacy of neoadjuvant therapy in patients with MIBC.
Authors: Li Tao , Qi Tianyu , Wu Kaijie
Published: January 2024

669

Background: Platinum-based neoadjuvant chemotherapy, such as gemcitabine/cisplatin (GC) or dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (ddMVAC), followed by radical cystectomy (RC), represents the current standard of care for T2-T4aN0M0 muscle-invasive bladder cancer (MIBC). Regrettably, only 40% of patients who received neoadjuvant chemotherapy achieved a pathological complete response (pCR). Recently, several trials showed a promising efficacy of immune checkpoint inhibitors (ICIs) plus neoadjuvant chemotherapy. BGB-A317-2002 study indicated that the addition of tislelizumab to GC can increase the pCR rate to 54.5%, with a pathological downstaging rate of 77.3%. Nevertheless, a subset of patients failed to derive benefits from ICIs plus neoadjuvant chemotherapy. Methods: This study aimed to explore the impact and mechanisms of gut microbiota on the efficacy of neoadjuvant therapy through the analysis of fecal samples obtained from MIBC patients who received GC or GC plus ICIs. Here, we reported the impact of gut microbiota on treatment outcomes in patients who received GC. Results: A total of 54 patients who received neoadjuvant GC chemotherapy were enrolled. Among them, 23 (42.59%) exhibited a pathological response (responsive group), and 31 (57.41%) showed no response (non-responsive group; no imaging changes or disease progression). Metagenomic sequencing on fecal samples from patients before and after therapy showed that the Shannon index in species level (1.182 vs. 0.954, p=0.016) and abundance of Ruminococcus gnavus were significantly greater in the responsive group than non-responsive group. It suggested that responsive patients displayed higher species richness of gut microbiota. Conclusions: The efficacy of neoadjuvant GC chemotherapy in MIBC patients may be potentially influenced by the number of gut microbiota populations. Additionally, the potential application value of Ruminococcus gnavus in improving the efficacy of non-responsive patients is noteworthy. A larger-scale study is needed to determine the above findings.
Effect of prednisone dosing on mineralocorticoid-related side effects with abiraterone in prostate cancer.
Authors: Goryachok Maksym , Nicklawsky Andrew , Ahmad Hiba , Flaig Thomas W.
Published: January 2024

67

Background: Abiraterone, a 17a hydroxylase inhibitor, is used for prostate cancer and can lead to mineralocorticoid excess syndrome (e.g. hypertension and hypokalemia). Concurrent prednisone mitigates these effects; however, the optimal prednisone dosage is unclear. This study examines the occurrence of mineralocorticoid side effects from Abiraterone with 5 mg of prednisone daily versus 5 mg twice daily. Methods: Data for 1410 patients treated with abiraterone from 2011 to 2022 were identified from a large academic/community hospital system (Health Data Compass Data Warehouse project). Laboratory measures, clinical parameters, and ICD10 codes were collected from 6 months prior to abiraterone initiation through treatment duration. 348 patients were excluded for missing medication data, discordant prednisone initiation, and use of a second steroid; 1062 patients remained (5 mg daily, N = 555, 10 mg daily, N = 507). Prednisone dose was treated as a time-varying covariate due to dose-switching (N = 122). Hypokalemia and hypertension incidence over 24 weeks after abiraterone initiation was analyzed via time to event frailty cox-proportional hazard models using both CTCAE v5.0 grade and ICD 10 code outcomes. Results: Patients on 5 mg of prednisone twice daily had approximately a 96% longer average time to first event for a combined-endpoint of hypertension and hypokalemia via ICD10 code methodology at any point during the 24 weeks following abiraterone initiation (HR 0.51, CI 0.43 - 0.62, P < 0.001). This trend was durable with individual ICD10 analysis in hypertension (HR 0.52, CI 0.43 - 0.62, P < 0.001) and hypokalemia (HR 0.45, CI 0.30 - 0.66, P = <0.001). Assessing direct clinical measurements via incidentally recorded blood pressure and potassium lab values, the analysis for grade 2/3 hypertension (HR 0.81, CI 0.7-0.93, P = 0.004) and grade 3 hypokalemia (HR 0.46, CI 0.26-0.82, P = 0.008) also showed a corresponding increase in average time to first measure favoring the 5 mg twice daily cohort during the 24-week period. Conclusions: This study shows a significant delay in the development of hypertension and hypokalemia from abiraterone with 5 mg twice daily compared to 5 mg of prednisone daily. This was observed both with ICD10 coding and direct clinical measurements of these events within the EMR. Assessments of other physiologic parameters and survival are ongoing. These findings highlight the impact of prednisone dosing with abiraterone, which may merit additional consideration in specific at-risk patient populations including those with baseline hypertension or cardiovascular risk factors.
Differential mutation profiles between benign and cancerous urothelium in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Miyagi Hiroko , Linscott Joshua , Gould Billie , Murthy Prithvi , Du Pan , Jia Shidong , Li Roger
Published: January 2024

675

Background: Differentiating passenger and driver mutations of oncogenesis is essential in understanding disease biology and developing biomarkers that use genomic mutations for diagnosis or prognostication. Accumulating research shows normal urothelium harbors many mutations commonly reported in molecular profiling of urothelial carcinoma. This is especially true of NMIBC. Here, genetic profiling of the mutational landscape of pathologic NMIBC tumors (pNMIBC) was performed and compared to matched pathologically benign urothelial tissue (pBT) to determine the frequency of passenger mutations. Methods: From a prospective observational cohort, 9 patients with high-risk NMIBC and pBT on repeat TURBT were identified. Somatic mutational profiles of the index tumor (pNMIBC) and subsequent pBT of each patient was performed via PredicineWES+ whole exome sequencing. Somatic variants were identified using the Predicine DeepSea in-house algorithm as previously described. Briefly, non-synonymous variants are captured and probabilistically annotated as germline vs. somatic in comparison with matched germline PBMC WES+ sequencing. NS somatic mutations observed in pBT were compared to those in pNMIBC to evaluate for putative passenger versus driver mutations. Results: A median of 236 mutations (IQR:100-732) were detected for pNMIBC compared to 37 (IQR: 5-80) in the pBT group (p=0.018). The number of genes with likely somatic mutations in pNMIBC only, both samples, and pBT only, were 2239, 500, and 1, respectively. The most frequently mutated genes in pNMIBC tissue samples were ARID1, TERT, CREBBP, LMTK3 and NCOR1. Notably, both pBT and pNMIBC tissue shared mutations in commonly reported bladder cancer genes such as ARID1A, ERBB2, ATM, ERCC2 and CKDN2A. Somatic mutations in FGFR3, LMTK3, NCOR1, AKAP9, COL11A2, CRYBG3, KMT2A, MCM3AP, PHF3, VPS13A and ZNF28 were present solely in pNMIBC tissue, whereas OVGP1 mutation was exclusive to pBT. Analysis of the functional impact of mutations in genes that are mutated in both benign tissue and pNMIBC offers a deeper understanding of the evolution of bladder cancer via field cancerization. Conclusions: Analysis of the mutational profile of pBT and pNMIBC revealed differential patterns of somatic mutations. Many expected gene mutations were detected in pNMIBC, but surprisingly 18% of all mutated genes were shared between tumor and pathologically benign samples. The fact that only one somatically mutated gene was exclusive to pBT signifies excellent censoring of variants by the DeepSea algorithm. In summary, these preliminary findings suggest that common gene mutations in NMIBC are frequently observed as passenger mutations. This underscores the potential significance of tissue-informed biomarkers tailored to an individual's mutational profile, which may outperform panel assays.
Clinical and molecular characterization of urothelial (UC) vs. small cell carcinoma (SCC) of the urinary tract.
Authors: Chawla Neal Shiv , Mercier Benjamin D. , Govindarajan Ameish , Li Xiaochen , Castro Daniela V. , Ebrahimi Hedyeh , Barragan-Carrillo Regina , Zang Peter D. , LeVee Alexis Ann , Dizman Nazli , Hsu Joann , Meza Luis A , Zengin Zeynep Busra , Salgia Nicholas , Chehrazi-Raffle Alex , Dorff Tanya B. , Pal Sumanta Kumar , Tripathi Abhishek
Published: January 2024

682

Background: SCC is an uncommon variant of bladder cancer with sparse data pertaining to its genomic landscape. Utilizing Tempus Lens, a real world clinical and genomic dataset, we investigated the clinical and genomic characteristics of SCC compared to UC. Methods: The de-identified Tempus Lens dataset was queried for patients diagnosed with UC or SCC of the bladder or ureter, of any stage. Baseline demographic, pathologic features, and results from blood or tissue-based genomic sequencing were catalogued. Clinical and pathological variables were summarized using descriptive statistics to compare the UC and SCC groups, using a Chi-square or Fisher’s exact test for a significance threshold of P<0.05. The prevalence of genomic alterations in the two groups were compared using a two proportions Z-test with a significance level of 0.00167, calculated using the Bonferroni correction for multiple comparisons. Results: A total of 4,569 pts (UC: 4429; SCC: 140) were included in the analysis. Gender, race, the proportion of patients ≥65 years, stage, and tumor grade were similar between the two groups. Use of blood based genomic sequencing was relatively similar (29.8% and 27.1%) between UC and SCC patients, respectively. Compared to UC, the SCC cohort had a significantly higher prevalence of TP53 (93.6% vs 60.8%; P<0.001), RB1 (73.6% vs 21.5%; P<0.001), and PTEN (13.6% vs 5.1%; P<0.001) alterations, and a lower frequency of CDKN2A (7.1% vs 29.5%; P<0.001), MTAP (2.9% vs 18%; P <0.001) and FGFR3 (6.4% vs 15.6%; P=0.003) mutations. Actionable alterations in SCC cohort included PIK3CA (21.4%), ERBB2 (13.6%), ATR (13.6%), ATM (9.3%), BRCA2 (8.6%), MSH6 (5.7%), TSC1/2 (4.9%), and PMS2 (4.3%). Conclusions: This is the largest study characterizing the genomic features of SCC. Our findings are consistent with prior studies suggesting a distinct genomic profile of SCC, with actionable alterations in a significant subset of patients. The impact of these alterations on outcomes and therapeutic strategies targeting these mutations warrant further investigation.
Identification of patients with metastatic urothelial cancer not able to receive maintenance avelumab.
Authors: Jackson-Spence Francesca , Chauhan Vishwani , Silva Diaz Sofia , Gurung Ayushma , Young Matthew Nicholas , Nally Elizabeth , Wells Connor , Szabados Bernadett , Powles Thomas
Published: January 2024

702

Background: Maintenance avelumab following frontline platinum-based chemotherapy for metastatic urothelial cancer (mUC) is associated with survival benefit. Eligibility to receive avelumab maintenance requires receiving 4-6 cycles chemotherapy without disease progression. Not all patients complete 6 cycles of chemotherapy or meet eligibility to receive avelumab and these patients may need to have alternative therapies. Here we present real world data to assess whether baseline characteristics can be used to identify patients unable to complete 6 cycles of chemotherapy and whom may not be eligible for maintenance avelumab. Methods: This retrospective audit was performed at Barts Cancer Centre for consecutive patients from January 2010 until August 2023. Patients who received frontline gemcitabine and cisplatin/carboplatin chemotherapy for advanced mUC were included. Eligibility for avelumab is defined as completing 4-6 cycles of chemotherapy without disease progression (PD). Characteristics of patients completing 6 cycles of chemotherapy, versus those who do not were described. Chi-squared tests were conducted to compare characteristic between the two groups, using SPSS v28. Results: 265 patients receiving frontline systemic therapy were identified over a 13-year period. 242 (91%) received Gem/Cis or Gem/Carbo chemotherapy. 151 (63%) patients were eligible to receive maintenance avelumab. 91 (38%) patients were not eligible due to receiving less than 4 cycles chemotherapy (68%) or due to PD (75%), or both. 91 (38%) patients completed 6 cycles of chemotherapy. Having a low baseline Hb <100g/dl was the only baseline characteristic associated with receiving less than 6 cycles chemotherapy (p=0.002). 33% of patients who completed less than 6 cycles chemotherapy had a Hb <100g/dl, compared to 10% of the patients who completed chemotherapy (p=0.002). Any dose delays was associated with a lower likelihood of being eligible to receive avelumab (32% and 18% dose delays in avelumab eligible vs ineligible cohorts, respectively (p<0.001). Patients with any dose delays had more frequently received carboplatin (65% vs 39%, p=0.012) and had visceral metastases including liver metastases (63% vs 39%, p=0.014), compared to those without dose delays. Conclusions: Specific baseline factors predispose to an inability to deliver 6 cycles of chemotherapy without complications or progression. These patients are less likely to receive maintenance avelumab. These data help the optimise number of cycles offered to patients in mUC.
Factors predictive of primary resistance (PrimRes) to immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Pramod Nikhil , Dawsey Scott , Patgunarajah Ubenthira , Lynn David , Wei Wei , Hobeika Charbel , Nair Monica , Martin Allison , Maroli Kimberly , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa
Published: January 2024

703

Background: Response rates to ICIs in pts with mUC remain modest at around 20% and there are no reliable biomarkers to select pts most likely to respond to ICI. It is an unmet need to define factors associated with PrimRes (progressive disease (PD) clinically and/or radiologically after at least 2 cycles of ICI) to spare pts from unnecessary treatment and the associated physical and financial toxicity. PrimRes to ICI has not been well defined in mUC pts and we sought to study predictive factors in our real-world cohort. Methods: We retrospectively reviewed 335 pts at the Cleveland Clinic who received ≥ 2 cycles or at least 6 weeks of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Pt characteristics such as age, sex, race, BMI, primary site (bladder vs upper tract UC (UTUC)), and antibiotic (Abx) use before or after start of ICI and pre-treatment platelet to lymphocyte (PLR) ratios (divided into quartiles) were collected. PrimRes was defined as pts who had clinical and/or radiologic PD or death from disease within 14 weeks (time period of 1st assessment with imaging) of ICI initiation. Pts with PrimRes were compared to rest (responders, stable disease and subsequent PD). Multivariate cox regression models were used to identify factors associated with PrimRes. Results: Of the 335 pts, 129 (38.5%) pts had PrimRes based on our criteria. Median age was 73 yrs (35-95). PLR quartiles were clarified as (<149, 149-207, 207-308, ≥308). In our multivariate regression model, we found that pts with PLR ≥308 had a significantly higher chance of PrimRes compared to those with PLR <149 (Hazard Ratio (HR): 2.49; 95% CI: 1.22-5.15; p = 0.0133). Being underweight (BMI < 18.5) was associated with significantly higher rates of PrimRes than normal weight pts (HR: 6.91; 95% CI: 1.55-48.81; p = 0.0211). Abx use within 60 days post ICI start (HR: 2.29; 95% CI: 1.38-3.83; p = 0.0015) and UTUC (HR: 0.46; 95% CI: 0.25-0.83; p = 0.0099) were associated with PrimRes to ICI. Conclusions: In our large cohort of pts with mUC receiving ICI, we report that PLR ≥308, BMI < 18.5, use of Abx within 60 days post- ICI, and UTUC were associated with development of PrimRes to ICI. Ongoing genomic and immune correlates from tissues collected from our cohort will help us better understand the mechanisms of PrimRes to ICI. Validation and harmonization with more datasets and prospective studies can inform future steps towards patient-directed approaches. [Table: see text]
Analysis of inactivating TSC1 and TSC2 alterations in advanced genitourinary (GU) cancers from a real-world patient population in the Foundation Medicine genomic database.
Authors: Iyer Gopa , Alonzo Palma Norma , Navarro Willis H. , Kwiatkowski David J.
Published: January 2024

704

Background: Identification of genetic alterations in cancer via genomic profiling may contribute to better outcomes for patients with advanced GU cancers. Patients with perivascular epithelioid cell tumors in AMPECT (NCT02494570), who had inactivating alterations in the tumor suppressor genes TSC1 or TSC2, critical negative regulators of mTOR activity, had confirmed responses (8/9 patients with inactivating TSC2 alterations and 1/5 patients with inactivating TSC1 alterations) to the mTOR inhibitor nab-sirolimus. PRECISION 1 (NCT05103358), an enrolling tumor-agnostic study, is assessing nab-sirolimus in patients with advanced cancers bearing inactivating TSC1 and/or TSC2 alterations. We used data from a real-world genomic database to enumerate frequencies of TSC1 and TSC2 inactivating alterations in patients with GU cancers. Methods: Next-generation sequencing data from Foundation Medicine’s database of 463,546 patients with advanced cancer (as of March 29, 2022) were analyzed using the FoundationInsights web-based platform to identify inactivating TSC1 or TSC2 alterations in patients with GU cancers. TSC1 or TSC2 alterations were categorized as short variants [base substitutions, insertions and deletions], rearrangements, and copy number deletions. Tumors with these alterations were also evaluated for mutations in other genes, tumor mutational burden (TMB), and microsatellite instability status. Results: Of patients in the database, 9.6% of those with bladder cancer, 5.2% of those with kidney cancer, and 0.7% of those with prostate cancer had inactivating TSC1 or TSC2 alterations. Overall, inactivating TSC1 or TSC2 alterations were present in 1518 of the 36,920 patients with GU cancers. A majority of these 1518 patients (74%) were male and most (78%) were 51–80 years of age at the time the sample was obtained. Of samples with inactivating TSC1 and TSC2 alterations (n=1518), 84.9% were in TSC1 and 15.7% were in TSC2; alterations included short variants (76.7% and 12.2 %), rearrangements (2.4% and 2%), and copy number deletions (5.6% and 1.3%), respectively. TMB was low (<6 mutations/megabase) in 52% of tumors and most (89%) were microsatellite stable. Other commonly mutated genes in this cohort with TSC1 or TSC2 inactivating alterations were TERT (64.4%), TP53 (44.1%), and CDKN2A (40%). Conclusions: Inactivating TSC1 and/or TSC2 alterations commonly occurred in GU cancers. A proportion of GU tumors have a low TMB and/or are microsatellite stable, suggesting that TSC1 and TSC2 inactivating alterations may be driver mutations rather than passenger mutations in those tumors. Therefore, patients with inactivating alterations in TSC1 or TSC2 may benefit from mTOR inhibition via nab-sirolimus. This hypothesis is being tested in the PRECISION 1 study which is open for enrollment of patients with TSC1 or TSC2 alterations.
Real-world utilization patterns of radium-223 in metastatic prostate cancer in the United States: An administrative claims database study.
Authors: Raval Amit D , Zhang Yiqiao , Korn Matthew J. , Constantinovici Niculae
Published: January 2024

79

Background: Radium (Ra)-223 is approved for use in men with symptomatic castration resistant prostate cancer (CRPC) with bone metastases, demonstrating benefits in terms of overall survival and quality of life with a reliable safety profile. In the rapidly evolving treatment landscape for prostate cancer, real-world (RW) data on Ra-223 utilization are limited. We aimed to examine the RW utilization patterns of Ra-223 in patients with metastatic prostate cancer using a large administrative claims database in the US. Methods: A retrospective cohort of men treated with Ra-223 was identified using the closed claims private payor database of the Komodo Research Dataset covering the period from 01/01/2017 to 06/30/2022. The earliest administration of Ra-223 in men with bone metastatic prostate cancer was considered as index date. Individuals were required to have continuous insurance coverage at least 12-month pre-index (baseline) and least 6-month post index or until death if patients survived < 6 months (follow-up). Logistic regression was used to identify baseline demographic, clinical, medications, or healthcare resource use-related factors associated with receiving 5+ cycles of Ra-223. Results: The study cohort comprised of 1,376 men with a median age of 68 years at the time of Ra-223 initiation. Most men were treated by oncologists (52.2%), having bone only metastases (51.5%), having Charlson comorbidity index (CCI) ≥ 1 (76.2%). Diabetes (34.1%), peripheral vascular disease (29.9%), pulmonary disease (25.9%) and mild liver disease (25.1%) were the most common pre-existing comorbidities. Therapies received prior to Ra-223 were androgen receptor pathway inhibitors (75.4%), chemotherapy (32.1%), sipuleucel-T (13.7%) and bone health agents (73.7%). Ra-223 was utilized as a combination therapy by 26.0% of the overall population, predominately with enzalutamide. Nearly 15%, 38%, and 31% received Ra-223 (mono or combination therapy) as 1st, 2nd, and 3rd line therapy, respectively. Approximately 46% of the overall cohort and 54% of those who survived ≥ 6 months had received 5+ cycles, respectively. In regression analysis, men with short survival (<6 month) [Odds ratio, OR: 0.05, 95% confidence interval (CI): 0.03, 0.10], low CCI (0 vs. 4+) (OR: 0.38, 95% CI:0.19, 0.76), and pulmonary disease (OR: 0.71, 95% CI: 0.52, 0.97) had lower likelihood of completion of 5+ cycles. Conclusions: Nearly half of men completed 5+ cycles of Ra-223 therapy in a large US cohort of relatively young mCRPC men with private health insurance. Advanced disease state with short survival and low comorbidity were key factors associated with lower completion of 5+ cycles. The findings highlight the importance of utilizing Ra-223 early after mCRPC diagnosis, when the probability of >6-month survival is higher, to enhance treatment completion that has been shown to result in better outcomes.
Real-world analyses of mortality risk after androgen deprivation therapy initiation in Black vs. White patients with prostate cancer.
Authors: Moul Judd W.
Published: January 2024

84

Background: 2 studies found significantly longer overall survival in Black vs. White patients with metastatic castration-resistant prostate cancer (PCa): a 2019 meta-analysis of 9 phase III trials and a 2020 registry study. Our real-world data study compared all-cause mortality risk for Black vs. White PCa patients. Compared to the prior studies, our study encompasses a broader scope and is not exclusive to men with castration-resistant PCa. Methods: Data were collected from the Decision Resources Group Real World Evidence repository, which links medical and prescription claims, and US Electronic Healthcare Records. The analysis set included PCa patients who received ≥1 androgen deprivation therapy (ADT) injection between 1991-2020. Cox regression was used to compare all-cause mortality rates between White and Black patients. Multivariable regression model accounted for the following variables: baseline metastasis, BMI, oncology vs. urology setting, antagonist vs. agonist, personal major adverse cardiovascular event (MACE) history, tobacco history, baseline PSA (>4 vs. ≤4 ng/mL), race (White vs. Black), statin use, increasing age per year, ethnicity (non-Hispanic vs. Hispanic), increasing ADT exposure per year, diabetes, hypertension, and family MACE history. Results: 44,439 patients were included for the all-patient analyses. 34,762 patients were included in the Black vs White analyses: 5,817 and 28,945 were Black and White, respectively. Overall, mortality risk was 2.6% and 17% at 1 and 4 years after ADT initiation, respectively. Mortality risk after ADT initiation was 1.6% and 2.6% at 1 year and 11.7% and 18.1% at 4 years for Black and White patients, respectively. Both unadjusted (HR=1.66, 95% CI 1.53-1.80, p<0.05) and adjusted (HR=1.24, 95% CI 1.01-1.52, p<0.05) mortality risks were higher for White vs. Black patients. Conclusions: All-cause mortality incidence was higher in White vs. Black patients. Adding to the body of evidence, our research also reveals that Black race is associated with a protective effect on survival for all-cause mortality in men undergoing ADT. Potential hypotheses for higher mortality in White vs. Black patients include survival bias to MACE (i.e., Black patients may have died from PCa before having MACE), survival bias to be diagnosed with PCa (i.e., Black patients may have higher rate of CV death and kidney failure prior to PCa diagnosis), and protective effects of higher BMI in Black patients against cancer cachexia. The large size (~45,000 patients from a database with >300 million patients), long follow-up (10 years for some patients), recent clinical experience (99% from 2010-2020), and diversity of the dataset give weight to the results being an accurate representation of current clinical experience. Future studies should confirm our findings that White PCa patients have higher mortality risk and investigate the above hypotheses.
Real-world genomic testing patterns in patients with prostate cancer.
Authors: Kaakour Dalia , Mar Nataliya
Published: January 2024

97

Background: The armamentarium of therapies for metastatic prostate cancer (PCa) has now expanded to include genomically targeted agents and CPIs. Men with both somatic and germline alterations in the DNA damage repair (DDR) pathway, most commonly BRCA2, are candidates for PARP inhibitors. Recent data from the PROPEL and MAGNITUDE trials led to approval of PARP inhibitors in combination with novel hormonal therapies earlier in the PCa continuum, in the first-line metastatic castrate-resistant space. Some PCas harbor genomic alterations, such as TMB>10 m/Mb and MSI high, which predispose to increased responses to CPIs, leading to tumor agnostic approval of pembrolizumab in these patient populations. However, it is imperative to perform timely genomic testing to assess for presence of these alterations. Methods: We conducted a 15-question survey using the Qualtrics XM software to assess genomic testing patterns of various providers in academic and community settings managing PCa patients. The survey link was distributed electronically to providers predominantly in the Western United States. Results: A total of 47 survey responses were received, with 59.6% (28/47) self-identifying as medical oncologists (Onc), 21.3% (10/47) as urologists (Uro), 4.3% (2/47) as radiation oncologists, 8.5% (4/47) as advanced practitioners, and 6.4% (3/47) as other. Academic Onc comprised 23.4 % (11/47), community Onc comprised 36.2% (17/47), academic Uro comprised 17.0% (8/47), and community Uro comprised 4.6 % (2/47) of providers. Timing of ordering of germline and somatic genomic testing by selected provider type is outlined in the Table. Conclusions: Given availability of targeted therapies in PCa management, ordering germline and somatic germline genomic testing is imperative. Despite the small sample size, several trends emerge from this dataset. Oncs at academic centers tend to order genomic testing earlier than Oncs at community practices, while Uros were less likely to order genomic testing when compared to Oncs in general. [Table: see text]
Preliminary reliability of the FACT-RNT in standard-of-care Lu-PSMA therapy of metastatic castration-resistant prostate cancer.
Authors: Gudenkauf Lisa Marie , Murthy Vishnu , Lam Ethan C. , Li Xiaoyin , Gardner Linda , Tagawa Scott T. , Dicker Adam P. , Cella David , Czernin Johannes , Calais Jeremie , Gonzalez Brian D.
Published: January 2024

99

Background: The Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) was recently developed as the first patient-reported outcome (PRO) measure designed to monitor RNT-relevant symptoms and toxicities for patients with advanced metastatic castrate-resistant prostate cancer (mCRPC). This study aimed to examine preliminary reliability of the FACT-RNT in patients receiving RNT as part of standard of care. Methods: Patients scheduled to start 177Lu-PSMA-617 for advanced mCRPC December 2022 – August 2023 who were fluent in English or Spanish completed the FACT-RNT on day 1 of each RNT cycle administered at UCLA. The FACT-RNT is a 15-item measure assessing symptoms and toxicities on a 0-4 scale; total scores range from 0-60, with higher scores indicating better quality of life. Reliability was assessed in R using data from cycles 1-4 with Cronbach’s alpha test of internal consistency, Guttman’s Lamba 6 test of split-half reliability, inter-item correlations, and test-retest reliability. Results: Patients (N=43) were, on average, 69 years old (SD = 9, range = 51-91) at RNT cycle 1, were mostly non-Hispanic (79%) and White (58%) with Gleason score ≥ 7 (67%) at diagnosis. Patients had undergone surgery (35%), chemotherapy (98%), radiation (65%), hormone therapy (100%), and/or immunotherapy (28%). Some patients who recently began therapy were not yet due for follow-up cycles, and 9 (21%) died during the study period. Completion of the FACT-RNT ranged from n=43 (Cycle 1) to n=19 (Cycle 4). The FACT-RNT total score ranged from 18-60 across cycles. Internal consistency reliability ranged from 0.82 (good) to 0.91 (excellent), and split-half reliability ranged from 0.92 to 0.99 (excellent). Average inter-item correlations were acceptable for scaling purposes (all exceeding 0.20). Within-subject correlations between scores were r=0.75 for cycles 2 vs. 3 and r=0.94 for cycles 3 vs. 4, indicating good measurement stability across cycles. Conclusions: In preliminary analyses, the FACT-RNT demonstrates good to excellent internal consistency across the first four cycles, moderate to strong consistency of measuring a common underlying construct, and good measurement stability. Findings support reliability of the FACT-RNT and its use in future research.
EORTC GUCG 2238 De-escalate: A pragmatic trial to revisit intermittent androgen-deprivation therapy in metastatic hormone-naïve prostate cancer in the era of new AR pathway inhibitors.
Authors: Grisay Guillaume , Turco Fabio , Patrikidou Anna , Gallardo Díaz Enrique , McDermott Raymond S. , Litiere Saskia , Fournier Beatrice , Gillessen Silke , Tombal Bertrand F.
Published: January 2024

TPS232

Background: The development of androgen receptor pathway inhibitors (ARPI) - abiraterone acetate, apalutamide, darolutamide and enzalutamide - has profoundly reshaped the management of metastatic hormone naïve prostate cancer (mHNPC). Seven trials demonstrated that combining these drugs with androgen deprivation therapy (ADT) reduces the risk of death by 20-40%, delays further treatment, and improves health-related quality of life (HR-QoL). These trials, however, suffer from two critical limitations: treatment duration and patient selection. Treatment usually continues until biochemical, radiological, or clinical progression, sometimes many years after drug initiation, exposing patients to chronic side effects affecting their QoL. Furthermore, registration trials include those not representative of the general population. Several sub-analyses of the registration trials demonstrated that patients achieving a PSA ≤0.2 ng/ml have prolonged overall survival (OS). In this study, we hypothesized that patients reaching PSA ≤ 0.2 ng/ml may benefit from treatment interruption without compromising OS. Methods: The primary goal of this academic-led, open-label, multicenter, pragmatic, randomized phase III study is to investigate whether intermittent maximum androgen blockade (iMAB) can be safely administered to mHNPC patients who reached a PSA ≤ 0.2 ng/mL at 6-12 months of continuous treatment (cMAB), as compared to continuing cMAB. Recommendations for restart include increasing clinical or radiological progression or PSA to ≥ 50% of diagnostic PSA with a maximum of 5 ng/mL.This will be demonstrated through the following co-primary objectives: 1) The proportion of patients who do not need to restart their MAB within one year of interruption is not less than 70%. 2) OS using an iMAB regimen at three years is non-inferior to continuous treatment. Secondary objectives include toxicity comparisons, HR-QoL (physical functioning, role functioning and fatigue scales of EORTC QLQ-C30, sexual activity scale of EORTC QLQ PR25), and assessing the impact on treatment resources of using an intermittent schedule. The study will include 1600 patients treated by cMAB for mHNPC for 6-12 months presenting with a PSA ≤ 0.2 ng/mL. Patients may have received docetaxel and radiotherapy as part of standard treatment. The PRECIS-2 (Pragmatic-Explanatory Continuum Indicator Summary) will be used to evaluate the study as a pragmatic trial. Clinical trial information: NCT05974774 .
Clinical study of rezvilutamide inhibiting the flare effect of GnRH agonists in the treatment of newly diagnosed metastatic prostate cancer.
Authors: Wang Shaogang , Wang Zhihua , Hu Zhiquan , Yang Chunguang
Published: January 2024

TPS233

Background: To prevent ‘flare-up’ phenomenon, mainstream guidelines recommend offering a first-generation antiandrogen for ≥7 days to metastatic prostate cancer starting GnRH agonist. Our previous study found that in the 3-day regimen of a new AR antagonist apalutamide (that is, GnRH agonist was given 3 days after application of apalutamide), PSA decreased by 5-10% on day 1, and PSA decreased by about 1/3 after 3 days of oral administration, which was equivalent to the inhibition of PSA synthesis by bicalutamide for 4 weeks, and no clinical symptoms were worsened. Since the blood concentration of the new AR antagonists could reach nearly 80% of the peak concentration after 1 hour of oral administration, our research group further tried the 1-hour regimen (that is, GnRH agonist was given after 1 hour of application of apalutamide), and 8 patients showed an increase in serum testosterone, but no increase in PSA and aggravation of clinical symptoms, which initially indicated the feasibility of the 1-hour regimen. The objective of this study is to explore the efficacy and mechanism of the combined application of rezvilutamide and GnRH agonist (Goserelin Microspheres for Injection) on mHSPC to prevent flare-up. Methods: This is a multicenter, prospective, randomized controlled study (ChiCTR2300076106). Key inclusion criteria: Age ≥ 18 years, first diagnosis of prostate adenocarcinoma by histologically confirmed within 1 month; at least one distant metastasis (extrinsic pelvic lymph node metastasis, bone metastasis, or visceral metastasis); PSA ≥ 2ng/ml and serum testosterone ≥ 150ng/dl. Sixty mHSPC patients are expected to be enrolled and treated with rezvilutamide combined with GnRH agonist. The patients will be randomized 1:1 into the 1-day regimen (oral rezvilutamide 1 day in advance) and the 1-hour regimen (oral rezvilutamide 1 hour in advance) with 30 patients each. The GnRH agonist treatment is 3.6 mg Goserelin Microspheres for Injection i.m. every 4 weeks. Collect patient baseline data: Age, tumor size, pathological classification, TNM stage, Gleason score, clinical symptoms, PSA level, testosterone level. Periodic review of laboratory tests (PSA, LH, testosterone, etc.), imaging changes (magnetic resonance, CT, PET/CT, etc.), changes in clinical symptoms, changes in survival status, etc. The occurrence of flare-up effects and hormone levels on day 1, day 3, day 7, day 14, and day 28 after medication will be described. Kaplan-Meier survival analysis and Cox proportional-hazards model were used to evaluate the above indicators. Clinical trial information: ChiCTR2300076106 .
Apalutamide and stereotactic body radiation therapy for low-burden, metastatic, hormone-sensitive prostate cancer: A randomized trial (PERSIAN).
Authors: Francolini Giulio , Porreca Angelo , Facchini Gaetano , Santini Daniele , Bruni Alessio , Simoni Nicola , Trovò Marco , Osti Mattia Falchetto , Fornarini Giuseppe , Sisani Michele , Di Cataldo Vanessa , Detti Beatrice , Garlatti Pietro , Bertini Niccolò , Burchini Luca , Frosini Giulio , Bonaparte Ilaria , Serni Sergio , Minervini Andrea , Livi Lorenzo
Published: January 2024

TPS235

Background: TITAN trial showed that apalutamide + ADT improved OS in patients with metastatic hormone sensitive prostate cancer (mHSPC), both in low and high-volume disease. On the other hand, SABR-COMET trial suggested that stereotactic body radiotherapy (SBRT) improved outcomes in oligometastatic patients if compared to systemic therapy alone. Recently, one trial suggested that SBRT may offer significant benefit in terms of biochemical response and progression free survival within oligometastatic castrate resistant prostate cancer patients undergoing first line abiraterone acetate treatment (ARTO trial, NCT03449719). However, there are no data specifically assessing the benefit offered by SBRT in oligometastatic mHSPC treated with apalutamide. PERSIAN trial is aimed to test the hypothesis that metastases directed SBRT will improve outcomes in select subgroups of pts with oligometastatic mHSPC treated with apalutamide + ADT. Moreover, we implemented baseline blood sample tests at enrollment/randomization, to evaluate the status of PIK3CA/AKT1/PTEN and BRCA1/BRCA2 mutations, and to investigate the predictive value of these alterations on treatment response. Furthermore, oncometabolites expression will be evaluated through metabolomic analysis before and after start of SBRT. Methods: PERSIAN trial is a prospective phase II randomized superiority study. All patients are affected by metachronous oligometastatic HSPC defined as presence of < 5 non-visceral metastatic lesions. Patients with de novo metastatic disease are excluded from the trial. Patients will be randomized to receive standard systemic treatment alone with apalutamide + ADT (Arm A: Control) or the same systemic treatment combined with SBRT on all sites of metastatic spread (Arm B: Treatment). This trial design will allow us to evaluate the benefit of SBRT in a selected cohort of patients with identical systemic treatments. Primary endpoint of the trial is the rate of patients with complete biochemical response (PSA < 0.2 ng/ml) 6 months after apalutamide + ADT start. Assuming a rate of complete biochemical response of 61% in the control arm, a sample size of 180 patients will have 80% statistical power to detect an absolute benefit of 19% in the treatment group, with alpha 0.05. Secondary endpoints are: time to PSA progression, radiologic progression free survival, frequency of treatment severe adverse events, overall and cancer specific survival, quality of life (measured with EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires). Enrollment started in March 2023, 31 patients have been enrolled to date. Clinical trial information: NCT05717660 .
Cohort expansion from the phase 1 JEWEL-101 study investigating the tissue factor–targeting antibody-drug conjugate XB002 in patients with advanced solid tumors: Metastatic castration-resistant prostate cancer cohort.
Authors: Ulahannan Susanna Varkey , Johnson Melissa Lynne , Weiss Mia C. , Vandross Andrae L. , Vidal-Cardenas Sofia Luz , Syed Mustafa , Tolcher Anthony W.
Published: January 2024

TPS237

Background: There is a high unmet need for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that has progressed on novel hormonal therapies (NHTs) due to acquired resistance to treatment. Tissue factor (TF) is a transmembrane protein that functions as a factor VIIa receptor and initiates the extrinsic coagulation cascade. Its overexpression has been associated with disease progression and poor prognosis in multiple solid tumor types, including mCRPC. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to zovodotin, an auristatin-based payload with a protease-cleavable linker. The zovodotin payload of XB002 is designed to have lower off-target payload deconjugation and improved tolerability compared with other auristatin-based ADCs. In preclinical studies, XB002 demonstrated antitumor activity and encouraging safety without affecting coagulation. JEWEL-101 (NCT04925284) is a phase 1, open-label, multicenter, first-in-human study evaluating XB002 alone and in combination regimens. The study consists of a dose-escalation stage to determine the recommended dose and/or maximum tolerated dose of XB002, and a tumor-specific cohort expansion stage to evaluate the safety and preliminary antitumor activity in pts with advanced solid tumors. Preliminary results from the dose-escalation stage showed XB002 was well tolerated at multiple dose levels, with low-grade ocular toxicity and no bleeding events or treatment-related peripheral neuropathy (PN).1 Presented here is the design of the expansion cohort in pts with mCRPC. Methods: Pts with mCRPC and primary histology of adenocarcinoma are eligible; neuroendocrine differentiation and other histological features are also permitted. Pts must have documented progressive disease after 1–3 prior systemic therapies, including at least 1 prior NHT for metastatic castration-sensitive or castration-resistant disease. Prior taxane-based chemotherapy is optional, and bone-only disease without soft-tissue tumor components is allowed. No prior treatment with TF-targeting or auristatin-based ADCs is allowed, and pts with significant ocular disorders are excluded. PN not impacting activities of daily living is acceptable, and concomitant use of anticoagulants is permitted. Pts in the mCRPC cohort will be treated with XB002 single agent. The primary outcome is objective response rate per investigator assessment. Secondary outcomes include safety, pharmacokinetics, immunogenicity, progression-free survival, duration of response, and overall survival. Enrollment is ongoing in the United States, Europe, and the Asia-Pacific region. 1. Ulahannan et al. ENA 2022. Clinical trial information: NCT04925284 .
ProstACT GLOBAL: A phase 3 study of best standard of care with and without 177Lu-DOTA-rosopatamab (TLX591) for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug.
Authors: Hawkins Charlotte , Lenzo Nat , Gibson Julie , Brown Tracey , Patel Neel , Martina Stefanie , Hayward Colin
Published: January 2024

TPS256

Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the 177Lu-labeled, chelator-conjugated antibody, 177Lu-DOTA-rosopatamab, as a potential RIT candidate for the treatment of PC. Methods: In this multinational, multicenter, prospective, randomized, open label phase 3 study (NCT04876651), 387 patients with PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior treatment with a novel androgen axis drug will be enrolled in a 2:1 ratio to receive either the best standard of care (SoC) or 2 single intravenous (IV) injections of 76 milicuries (mCi) each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC. Eligible patients must have received prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x109 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, progression free survival, and number of participants with treatment-related adverse events. Clinical trial information: NCT04876651 .