bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 .