77
Background: In mCRPC, AR T878 and/or H875 and L702H mutations have been associated with disease progression and poor prognosis. This study characterized real-world overall survival (rwOS), testing ...practices, mutation prevalence, and treatment patterns in patients with mCRPC with and without tumors with missense mutations in the AR LBD (amino acids 671–920). Methods: In this retrospective analysis of the Guardant Inform Database (Mar 11, 2014–Jun 30, 2022), men (aged ≥18 y) with mCRPC who were tested with Guardant360 (G360) next-generation sequencing and diagnosed/treated at a clinical site in the US with a first-line (1L) treatment were included. Matched rwOS was assessed in 2 subpopulations: patients with any missense mutation in AR LBD, excluding those with AR L702H alone ( AR LBD group), and patients with AR T878 and/or H875 without L702H ( AR 878/875 group) and compared with patients without any AR LBD missense mutations (control group). Patients were matched (1:5) on key prognostic variables, including age, Elixhauser Comorbidity Index weighted score, smoking status, prior novel hormonal agent (NHA) use, and 1L treatment year. Mutation prevalence, patient demographics, frequency and timing of G360 tests, and treatment patterns were assessed in patients treated from 2018 to 2022 to reflect more recent trends. Results: In the matched rwOS analysis, patients in the AR LBD group (n=275) had statistically significantly shorter 1L median rwOS compared with the control group (n=1375): 27.3 vs 47.8 months; P<0.0001. Similarly, patients in the AR 878/875 group (n=154) had shortened median rwOS compared with the control group (n=770): 28.9 vs 44.4 months; P=0.0004. Of 4833 patients treated for mCRPC from 2018 to 2022, 20% had AR LBD mutations, 4% had AR 878/875 with L702H, and 6% had AR 878/875 without L702H. Most patients (59%) were first tested at some point after 1L therapy, with only 15% of patients receiving >1 G360 test. Mutation prevalence was higher in patients tested in fourth-line (4L) compared with 1L, particularly for AR L702H mutations (17% vs 10%) and all AR LBD mutations (27% vs 20%). Use of NHAs was lower in 4L compared with 1L (20% vs 33%), whereas use of taxanes was higher (31% vs 22%). Conclusions: Patients with AR LBD–mutated mCRPC had notably shorter rwOS than those whose tumors did not harbor AR LBD mutations, indicating an unmet need for this population. The prevalence of AR LBD mutations was higher in later lines of therapy, but repeat testing rates were low, suggesting that AR LBD mutations may go undetected.
4520 Background: Molecular characterization of anatomically distinct UCs has been limited by the rarity of UTUC; however, recent advances in real-world data curation have enabled larger UTUC cohort ...generation. Here, we investigated the somatic, germline, and immunologic landscapes of UTUC compared to UCB. Methods: From the Tempus Database, we retrospectively analyzed de-identified next-generation sequencing data from 505 UTUC (224 ureter, 281 renal pelvis) and 2,416 UCB cases (2,379 bladder, 37 urethra). Tumors were sequenced with the Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration predicted from gene expression patterns, TMB, PD-L1 from IHC, MSI, and mismatch repair (MMR) were evaluated. Incidental germline alterations were assessed in 46 genes for patients with tumor/normal-matched (T/N) sequencing (UTUC n=285, UCB n=1,359). Chi-squared, Fisher's exact, and Wilcoxon rank-sum tests were used to assess statistical significance (p<0.05, q<0.05 for false discovery rate correction for multiple testing). Results: Median age of the UTUC and UCB cohort were 73 and 70 years, respectively (p=0.003). The UCB cohort had significantly more males (75% vs 56%, p<0.001) and ever smokers (59% vs 46%, p<0.001).Alterations in TERT, TP53, CDK12, RB1, ERBB2, and CDKN1A were more frequent in UCB, while KMT2D, FGFR3, BRIP1, CDKN2B, KRAS, and MYC more frequent in UTUC (Table). Additionally, FGFR3 fusions were more frequent in UTUC. Germline variants were found in 7.1% of UCB and 7.0% of UTUC cases, with trends towards higher prevalence of alterations in lynch-associated genes ( MLH1, MSH2, MSH6, PMS2) in UTUC (0.6% vs 1.8%, p=0.059). The prevalence of TMB ≥ 10 mut/Mb was higher in UCB vs UTUC (17% vs 11%, p<0.001). UCB had increased PD-L1 positivity (p=0.013), whereas UTUC had more MSI-high (UTUC = 3.2% vs UCB = 1%, p=0.001) and deficient MMR (p=0.020) cases. There were similar proportions of total immune infiltrates in UCB and UTUC. However, UTUC harbored a higher percentage of CD4+ T cells (p<0.001), while UCB had a higher proportion of regulatory T and NK cells (p<0.001). Conclusions: Via comprehensive molecular characterization of UC, we observed distinct DNA alteration and tumor microenvironment patterns in UTUC and UCB. The germline results underline how T/N testing can identify patients with UTUC and/or UCB who can benefit from dedicated germline testing. Further research is warranted to elucidate the clinical implications of these findings. Table: see text
TPS290
Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in ...the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA
30
) and 50% (PSA
50
). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140 .
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5004
Background: African-American (AA) men are substantially more likely to present with lethal prostate cancer (PCa) at younger ages than non-Hispanic White men. Despite this ...disparity, AA men are poorly represented in the prostate-specific antigen (PSA) screening studies on which evidence-based PCa screening guidelines are based. This limits proper PSA screening guidance for AA men, especially for those younger than 55. We examined associations of PSA screening intensity with disease severity at diagnosis and prostate cancer-specific mortality (PCSM) in AA men < 55 years of age. Methods: The earliest recommended age to begin discussion of PSA screening is 40 years. We identified AA men aged 40-55 years, diagnosed with PCa from 2004 to 2017 within the Veterans Health Administration. PSA screening was identified using procedural codes. Screening intensity was defined as percentage of years screened within the pre-diagnostic observation period. This included up to 5 years prior to diagnosis. Multivariable logistic regression assessed the influence of PSA screening intensity on metastatic disease at diagnosis. Lead-time correction using published screening-dependent lead times was performed. PCSM was evaluated using Fine-Gray regression and non-cancer death as a competing event. Additional analysis was performed stratifying PSA screening into ‘High’ and ‘Low’ groups centered on the mean. Results: The cohort included 4,654 AA men at a mean age of 51.8 years with mean PSA screening rate of 53.2%. The pre-diagnostic observation period ranged from 1 to 5 years (median = 5 years). Median follow-up was 7 years. At diagnosis, there was a higher prevalence of Gleason sum ≥ 8 (Grade Group ≥ 4) and metastatic disease in the ‘Low’ group compared with the ‘High’ group (Gleason sum ≥ 8 (Grade Group ≥ 4): 18.6% vs. 14.4%, p < 0.01; Metastatic disease at diagnosis: 3.7% vs. 1.4%, p < 0.01). Increased PSA screening intensity was associated with significantly reduced odds of metastatic disease at diagnosis (odds ratio: 0.61, 95% confidence interval (CI) = 0.47-0.81, p < 0.01) and decreased risk of PCSM (sub-distribution hazard ratio: 0.75, 95% CI = 0.59-0.95, p = 0.02). Conclusions: In this large national cohort of AA men aged 40 to 55 years, PSA screening increased intensity was associated with decreased risk of lethal disease and metastases at time of diagnosis and decreased PCSM. These data support the hypothesis that PSA screening and early prostate cancer detection may improve outcomes in younger AA men.
4601 Background: Cretostimogene grenadenorepvec is a type-5 oncolytic adenovirus designed to selectively replicate in bladder cancer cells with alterations in the retinoblastoma pathway. ...Additionally, the virus is engineered to express the GM-CSF transgene, resulting in a potent oncolytic immunotherapy mode of action. Cretostimogene monotherapy recently received Food and Drug Administration (FDA) Fast Track and Breakthrough Therapy Designations (BTD) in the BCG-Unresponsive, High-Risk, non-Muscle Invasive Bladder Cancer with Carcinoma in Situ (BCG-UR HR NMIBC with CIS) indication with a Complete Response (CR) at any time rate of 76%. This phase-2 study assessed the potential synergy between intravesical cretostimogene and pembrolizumab in patients with BCG-UR, HR NMIBC, with CIS, with or without Ta/T1 tumors. This combination has also received BTD from the FDA. Methods: 35 pts were treated with cretostimogene (1x10 12 viral particles) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. Cretostimogene induction was given as 6 weekly intravesical instillations followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Pts with persistent CIS or high-grade Ta tumors at the 3mo assessment were eligible for re-induction. Pembrolizumab was administered for up to 24mo. Response assessments included cystoscopy, urine cytology, cross-sectional imaging, and mandatory bladder mapping biopsies at 12mo. The primary endpoint was CR at 12mo. Secondary endpoints included CR at any time, duration of response (DOR), CR at 24mo, cystectomy-free survival, and safety. Exploratory endpoints included analyses of baseline viral receptor expression, free E2F levels, PD-L1 status, urinary cytokine panels and measures of viral replication. Results: 30/35 pts are evaluable per protocol for the primary endpoint. Five pts discontinued prior to the 12mo time point. The CR rate in the Intention to Treat (ITT) population at 12mo and any time, was 57% (20/35) (95% CI 40-73%) and 83% (29/35) (95% CI 66-93%), respectively. Median DOR has not been reached but exceeds 21mo. The current CR rate in the ITT population at 24mo is 46% (16/35) (95% CI 29-63%). Three pts have yet to reach the 24mo time point. Cystectomy-free survival at 21mo is 80%. Complete data on the ITT and evaluable patient cohorts will be presented. Analyses of treatment-related adverse events (AE) are consistent with the individual agents and demonstrate no synergistic toxicity. Conclusions: The efficacy and safety of cretostimogene plus pembrolizumab for treatment of BCG-UR, HR NMIBC with CIS demonstrates best-in-class CR and DOR compared to current FDA-approved therapies, with an acceptable AE profile. Further investigation of this promising combination therapy is warranted and may serve to address a considerable unmet need. Clinical trial information: NCT04387461 .
418
Background: Chemotherapy for testicular cancer (TC) is highly effective yet associated with significant consequences on long-term health-related quality of life. We evaluate the impact of ...chemotherapy on anxiety, depression, and suicidality amongst TC survivors. Methods: We conducted a retrospective cohort study of US veterans diagnosed with TC in the Veterans Health Affairs database from 1990-2016. Patients with non-primary germ cell tumor histologies were excluded. Baseline disease characteristics and treatment received were ascertained from the VA Central Cancer Registry. Anxiety or depression was a composite endpoint comprised of diagnosis codes for anxiety, depression, or administration of medications used to treat these diagnoses. Incident suicidality was defined as a diagnosis code for suicidal ideation. Time to event was defined as time from diagnosis to event or censor at the time of last follow-up. Rates of outcomes were reported through cumulative incidences. Associations with outcomes and receipt of chemotherapy were assessed through multivariable Cox regression models. Results: In total, 1684 patients (1174 seminoma, 510 nonseminoma) were included in the cohort. Median age at diagnosis in the cohort was 40 years old. Median follow up time was 7.67 years for surviving patients. 1506 (89.4%) patients were white, 114 (6.8%) were African American, and 64 (3.8%) were another or unknown race. There were 1066 (63.3%) stage I patients, 191 (11.3%) stage II, 198 (11.8%) stage III, and 229 (13.6%) unknown stage patients. 579 (34.4%) patients received chemotherapy. At the time of diagnosis, 104 (6.2%) patients already experienced anxiety or depression. At 10 years, cumulative incidence of the diagnosis of anxiety or depression as 44.1% in the entire cohort. At 10 years, cumulative incidence of the diagnosis of suicidality was 5.5%. On multivariable Cox regression, factors associated with a higher risk of anxiety or depression were older age at diagnosis (Hazard Ratio (HR): 1.11 per standard deviation increase, p=0.01), being unemployed (HR: 1.25, p=0.01), and receipt of chemotherapy (HR: 1.43, p<0.001). Race, stage, alcohol or tobacco use and seminoma type were nonsignificant. Factors associated with increased risks of suicidality were being unemployed (HR: 2.00, p=0.01) and not being married (HR: 2.50, p=0.001). Stage, age, race, alcohol and tobacco use, seminoma type, and receipt of chemotherapy were not significantly associated with suicidality. Conclusions: Psychosocial morbidity is high among TC survivors. Despite being effective and necessary for maintaining excellent oncologic outcomes, chemotherapy appears to increase the rates of psychosocial morbidity. Socioeconomic risk factors, including employment and marriage, may also impact psychosocial health. Clinicians should be proactive in identifying support systems for TC survivors.
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Background: African American (AA) men with prostate cancer (PC) present with more advanced disease and have worse survival than comparable non-Hispanic White (White) men. Recent ...studies suggest that receiving care within an equal access setting may attenuate these disparities. We hypothesize that AA men receiving care within the Veterans Health Administration (VHA) will have improved outcomes compared to AA men receiving care in the general population as assessed by the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We identified AA men diagnosed with PC between 2004 and 2015 in the VHA and SEER. For comparisons of covariate distributions across subgroups, we used the chi-squared test with continuity correction. We analyzed the cumulative incidence (with 95% confidence intervals (CIs)) of PC specific mortality (PCSM) in the VHA and SEER. Additionally, multivariable Cox proportional hazards models controlling for demographic information were performed. Results: The cohort included 85,409 AA men (VHA: 27,415, SEER: 57,994). Median follow-up was 4.79 years in the VHA and 5.16 years in SEER. In the VHA, AA men were more likely to present with localized disease (VHA 94.7% vs SEER 86.4%, p < 0.001) and less likely to have metastatic disease (3.2% vs 4.3%, p < 0.001). The 5-year cumulative incidence of PCSM was lower for patients in the VHA (VHA: 3.8% CI: 3.5-4.1% vs. SEER: 5.0% CI: 4.8-5.2%, p < 0.001). The PCSM difference was largest in men with metastatic disease. In metastatic patients, cumulative incidence of PCSM at five years was significantly lower in the VHA (VHA 52.5% CI: 48.0-56.5% vs. SEER 64.8% CI: 62.3-67.1%, p < 0.001). In contrast, AA men with localized disease had similar PCSM in the VHA and SEER (VHA 2.4% CI: 2.2-2.6% vs. SEER 2.6% CI: 2.4-2.7%, p = 0.09 at five years). On multivariable analysis, VHA system was associated with lower PCSM Hazard Ratio (HR): 0.91, p < 0.001. There was a significant interaction between VHA system and distant metastases at diagnosis p < 0.001 indicating larger differences in PCSM by healthcare system in metastatic patients as compared to localized patients. VHA system was associated with reduced PCSM in metastatic patients HR 0.84, p < 0.001 but not in localized patients HR 0.96, p = 0.13. Conclusions: AA men in the VHA had a significantly lower incidence of PCSM than those in the SEER database, especially for those who presented with distant metastases at diagnosis. Future work should examine how cost and access to care affect disparities in outcomes for AA men.
3050
Background: Muscle invasive bladder cancer is associated with a significant elevated risk of mortality and morbidity due to micro metastatic spread at the time of diagnosis. Accurate biomarkers ...to guide treatment determination and evaluate response are needed. Previous studies using tumor informed ct-DNA have shown that MRD assessment may be informative in these scenarios. Methods: We conducted a retrospective multicenter analysis of real-world data obtained from commercial testing (Signatera; Natera, Inc.). This cohort of MIBC patients included those who underwent radical cystectomy with a minimum follow up of 90 days. Data were collected on patient demographics, clinical and pathological staging, histologic type, and treatments. Correlation of ct-DNA status with clinical outcomes was analyzed using Cox-regression analysis to evaluate utility of the assay for detecting residual disease post-surgery and radiological recurrence. Results: A total of 109 patients with 545 plasma samples were identified that fit the inclusion criteria. The majority of the patients 79, 72.5% were male, with a median age of 70 (range: 32-88) years. Most patients had pure urothelial carcinoma 73.4%, 80/109. Median follow-up was 13.63 (range: 3-89.04) months. On analyzing the first time point post-surgery (median 54 days), 91.55% (65/71) of ct-DNA negative patients at the first post-surgical test remained recurrence free while 65.79% (25/38) of positive patients had recurred at data cut-off. Therefore, ct-DNA positivity at the first post-surgical timepoint was associated with shorter disease-free survival (DFS) (HR=9.9, 95%CI: 4.1-24%, p<0.001). ct-DNA detected imaging recurrence with a median lead time of 61 days (range: 12-381). Similarly, on analyzing ct-DNA positivity at any time post-surgery, of those who remained ct-DNA negative (N=63), 96.83% (61/63) showed no evidence of recurrent disease. On the other hand, 63.04% (29/46) of pts with ct-DNA positivity at any time after cystectomy recurred and experienced reduced DFS (HR=25, 95%CI: 5.9-103%, p<0.001). The assay’s sensitivity for predicting radiological recurrence at any time post-surgery was 93.55%. Notably, in the multivariate analysis, anytime ct-DNA positivity after cystectomy was found to be the only significant risk factor associated with shorter DFS (HR=23.07, 95%CI: 5.1-104.4, p<0.001). Conclusions: In this initial analysis of real-world data, MRD detection via tumor-informed ct-DNA testing was highly prognostic of patient outcomes post-surgery and may guide adjuvant treatment decisions. Future studies in this setting will explore the utility of ct-DNA testing as a predictive biomarker in response to systemic therapy.
457
Background: Plasma cell-free DNA (pcfDNA) has shown great promise for non-invasive, multi-cancer early detection (MCED), but has lower sensitivity for early-stage urological cancers due to low ...tumor fraction in plasma. Urine cfDNA (ucfDNA) has the potential to improve detection and monitoring of early-stage urological cancers due to its proximity to the affected organs and ease of collection. We conducted an exploratory study to assess the utility of methylation patterns in ucfDNA to detect BC in patients with suspicious bladder lesions, and compare to detection using matched pcfDNA. Methods: Urine and blood were collected from patients with suspicion of new (N=17) or recurrent (N=20) non-muscle invasive BC (NMIBC), and from non-cancer (NC) patients with urological conditions (N=16). Patients with suspicion of NMIBC were diagnosed and staged by transurethral resection of bladder tumor (TURBT) and conventional imaging. Tumor allele fraction (TAF) estimates from ucfDNA were inferred using a method trained on methylation patterns enriched in BC tissue (N=49) relative to an external reference dataset of NC ucfDNA (N=176). We set a detection threshold, using a maximum TAF value from a separate set of NC urine samples (N=50), to determine ucfDNA sensitivity for detecting BC in our study. Sensitivity in pcfDNA was determined using a validated MCED test classifier at 99% specificity. Results: Of 17 patients with suspicion of new NMIBC, 12 were diagnosed with BC after TURBT (Stage 0: N=6, I: N=5, II: N=1), and 10/12 were high grade (HG). Among patients with confirmed BC, ucfDNA sensitivity was 91.7% overall (11/12; 95% CI 61.5-99.8%) and 90% for HG (9/10). Whereas, pcfDNA sensitivity was 16.7% overall (2/12) and 10.0% for HG (1/10). Of 20 patients with suspicion of recurrent NMIBC, 14 were confirmed as BC (Stage 0: N=10, I: N=2, II: N=2) and 11/14 were HG. Sensitivity of ucfDNA for recurrence detection was 78.6% overall (11/14; 95% CI 49.2-95.3%), and 100% for HG (11/11), while pcfDNA sensitivity was 14.3% (2/14) overall and 18.2% (2/11) for HG. Notably, TAF in urine from NC patients (N=16) and patients with suspicion of new NMIBC found to be benign by TURBT (N=5) were all below the detection threshold. Among patients with suspicion of recurrent NMIBC but not found to have BC by TURBT, TAF estimates for 4/6 (66.7%) were above the detection threshold. Conclusions: We observed increased sensitivity in urine compared to matched plasma in patients with NMIBC, consistent with local shedding of bladder tumors into stored urine. A urine-based cfDNA assay with high sensitivity at high specificity, combined with non-invasive sampling, could be an ideal tool to use alongside the standard of care (e.g., cystoscopy) for clinical diagnosis and monitoring of BC. Further studies are needed to validate these findings and determine the clinical utility of ucfDNA in the diagnosis and surveillance of BC.
