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Gene network analysis identifies dysregulated pathways in an autism spectrum disorder caused by mutations in Transcription Factor 4

Recent treatment patterns in US-based real-world patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC).

104 Background: Androgen deprivation therapy (ADT) intensification [ADT + androgen receptor-pathway inhibitor (ARPIs) +/- docetaxel] has been shown to improve survival outcomes in pts with mHSPC and is recommended as standard of care by all major guidelines. However, prior studies have shown underutilization of ADT intensification [PMID: 39191549]. There are limited updated and large-scale studies on the use of ADT intensification, beyond January 2023. In this study, we aimed to assess the treatment patterns of ADT intensification in real-world pts with mHSPC in the US, including data on those treated since January 2023. Methods: This retrospective study utilized the nationwide Flatiron Health Electronic Health Record (EHR) derived de-identified database. Eligibility: Pts diagnosed with mHSPC and availability of treatment information (ADT and/or line of therapy in mHSPC). The data cut-off date was 5/31/2024. Treatment patterns were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Among 24,105 pts with metastatic prostate cancer in the database, a total of 14,084 were eligible and included. The median age at metastatic diagnosis was 72 years (IQR 65 – 79), and 60% were White non-Hispanic. In the overall cohort (1/1/2013–5/15/2024), 56.8% received ADT monotherapy, and 37.7% received ADT intensification. Table summarizes the treatment patterns by year, highlightinga consistent increase in adoption of intensified ADT regimens, and a decline in use of ADT monotherapy. Notably, since January 2023, 76.8% pts with mHSPC received ADT intensification while only 17.3% of pts received ADT monotherapy. Conclusions: To our knowledge, this is the first and largest study to evaluate the current use of ADT intensification. These data indicate a notable improvement in the adoption of level 1 evidence (ADT intensification) in the treatment of pts with mHSPC. These encouraging data emphasize the benefits of continued efforts to promote guideline-concordant care and provide the current treatment landscape to design clinical trials. Treatment patterns by year in pts with mHSPC. Treatment 2013–2017n = 5,263(%) 2018n = 1,313 (%) 2019n = 1,407(%) 2020n = 1,353(%) 2021n = 1,483(%) 2022n = 1,556(%) 2023n = 1,459(%) 2024n = 250(%) ADT monotherapy 4,095 (77.8) 856 (65.2) 819 (58.2) 664 (49) 698 (47.1) 569 (36.6) 291 (20) 5 (2) ADT + ARPI 155 (2.9) 238 (18) 354 (25.1) 452 (33) 555 (37.4) 695 (44.7) 842 (58) 154 (61.6) ADT + Docetaxel 709 (13.5) 156 (12) 175 (12.4) 156 (12) 134 (9.0) 117 (7.5) 78 (5.3) 19 (7.6) Triplet(ADT + ARPI + Docetaxel) 6 (0.1) 2 (0.2) 1 (0.1) 2 (0.1) 9 (0.6) 82 (5.2) 166 (11.1) 53 (21.2) Other therapies 298 (5.7) 61 (4.6) 58 (4.1) 79 (5.8) 87 (5.9) 93 (6) 82 (5.6) 19 (7.6)

Effectiveness and safety of radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC): A systematic literature review of 48 real-world studies.

81 Background: Radium-223 (Ra-223) has been approved for men with mCRPC with bone metastases since 2013. However, as the treatment landscape has significantly changed in the last decade, a comprehensive understanding of Ra-223's real-world outcomes could inform on treatment choice in routine clinical practice. This systematic literature review aims to fill this gap by summarizing the real-world (RW) effectiveness and safety in men with mCRPC treated with Ra-223. Methods: Electronic databases (PubMed, Embase, the Cochrane Library, trial registers) and the past-two years of relevant conferences were searched systematically for RW observational studies examining outcomes of Ra-223 in men with mCRPC published between 2014 and March 2024. Study results of interest included Ra-223 treatment pattern, real-world overall survival (rwOS) and progression-free survival (PFS), pain response, change in alkaline phosphatase (ALP) or prostate-specific antigen (PSA), and safety outcomes (any or grade 3+ skeletal-related events, myelosuppressive adverse events). Results: From 1085 citations identified, 48 studies with 15,368 men with mCRPC met inclusion criteria. Most studies were retrospective cohorts (n=39) from Europe (n=22) and North America (NA) (n=18), with sample size ranging from 104 to 1,628. Median age mostly ranged from 68 to 76 Ten studies reported tumor burden and included ≥ 25% of cohort with 20+ metastases. Over 50% of Ra-223 cohort received prior chemotherapy in 23 studies, and 50% received prior ARPIs in 22 studies. Most studies in NA and Europe reported ≥ 55% and 64% completion of ≥ 5 cycles of Ra-223, respectively. Earlier line, no prior chemotherapy or immunotherapy, hemoglobin and neutrophils within lower standard limit were key factors associated with completion of ≥5 cycles of Ra-223. Median rwOS varied widely from 11 to 24 months with two exceptions and nearly a 1/3 rd reporting 15 months or longer. Completion of ≥ 5 cycles was associated with a 2 to 5-fold increase in the median rwOS. PFS ranged from 4.3 to 7.3 months with a median of 2 prior lines in the 7 studies reporting. 12 studies reporting pain outcomes showed a reduction in pain with varying magnitude. Of 13 studies reporting grade 3+ myelosuppression, incidence varied from 1-22%. Out of 14 studies reporting fractures, the incidence was <10% in most studies (N=12) with trends toward lower rates with bone health agent (BHAs) use. Conclusions: This is the most up-to-date and comprehensive review of the effectiveness and safety of Ra-223 in a modern era with more widespread use of ARPIs post landmark ALSYMPCA trial for Ra-223. Findings highlight the survival benefits of early use of Ra-223 with the completion of 5 or more cycles, along with a favorable safety profile and low rates of fracture when guideline recommended BHAs are used.

Efficacy and safety of nanosomal docetaxel lipid suspension in Indian patients with metastatic castration-resistant prostate cancer (mCRPC): A multicenter, open-label, single-arm phase 4 study.

168 Background: Docetaxel combined with prednisone is the first line chemotherapy to improve overall survival in metastatic castration resistant prostate cancer (mCRPC). Nanosomal docetaxel lipid suspension (NDLS) is a novel formulation that eliminates the need for polysorbate 80 and ethanol, reducing infusion-related reactions and the requirement for steroid premedication. This phase 4 trial aims to assess the efficacy and safety of NDLS in patients with mCRPC. Methods: In this multicenter, open-label, single-arm trial, patients with confirmed mCRPC and at least one measurable lesion were enrolled. Exclusions included those with brain lesions or a history of hypersensitivity to taxanes. NDLS was administered at 75 mg/m 2 every three weeks for 10 cycles without steroid premedication. The primary endpoint was the overall response rate (ORR) upon completion of 10 cycles. Results: Between July 2018 and July 2023, 86 patients (safety set) received the study drug. The modified intention-to-treat (mITT) set (included 77 patients who received at least one dose and had at least one efficacy evaluation). The mean age of the mITT set was 67 (±6.2) years, with a median prostate specific antigen (PSA) value of 31.3 ng/mL. At the end of 10 cycles, the overall response rate (ORR) was 16.9% (95% CI: 9.31, 27.14), and the disease control rate (DCR) was 44.2% (95% CI: 32.84, 55.93). A ≥50% reduction in serum PSA was observed in 36 (46.8%) patients. The visual analog score (VAS) decreased significantly from baseline with a mean difference of 12.8 mm (P<0.0001). Median progression free survival (PFS) was 12 months (95% CI: 8.12, 18.12), and the overall survival rates at 1 and 2 years were 31.2% and 19.5% respectively. Adverse events were reported in 64 (84.4%) patients, with only one patient experiencing a grade ≥3 adverse event. Common grade 1/2 adverse events (≥10% of patients) included diarrhea, vomiting, asthenia, alopecia, headache, anemia, fever, infections, and pain. Conclusions: NDLS showed efficacy and safety in patients with metastatic castration-resistant prostate cancer. Clinical trial information: CTRI/2018/02/012212 . Efficacy outcomes at cycle 10 completion. Parameter mITT set (N=77) PR, n (%) 13 (16.9) SD, n (%) 21 (27.3) ORR, (95% CI) 16.9% (9.31, 27.14) DCR, (95% CI) 44.2% (32.84, 55.93) BOR, (95% CI) 26.0% (16.64, 37.23) ≥50% reduction in serum PSA, n (%) 36 (46.8) Change from baseline for VAS (mm), mean (±SD) 12.8 (±22.11) (p<0.0001) Median PFS (months), (95% CI) 12 (8.12, 18.12) Median OS (months) Not reached PR: partial response; SD: stable disease; BOR: Best overall response.

Comprehensive investigation of CPSF3's role in the progression of bladder cancer.

829 Background: Bladder cancer (BC) is a global health issue, with a significant number of new cases diagnosed annually. Despite advances in treatment, many patients experience recurrence or progression, emphasizing the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the prognostic significance and biological function of Cleavage and Polyadenylation Specificity Factor 3 (CPSF3) in BC. Methods: We analyzed CPSF3 expression using The Cancer Genome Atlas (TCGA) data and immunohistochemistry (IHC) on a cohort of 203 BC patients. A nomogram incorporating CPSF3 expression was constructed to predict overall survival (OS) and disease-free survival (DFS). In vitro experiments were conducted to assess the effect of CPSF3 knockdown on BC cell proliferation, colony formation and cell cycle distribution. Bioinformatics analyses, including Gene Set Enrichment Analysis (GSEA) and immune infiltration analysis, were performed to explore potential mechanisms. Results: High CPSF3 expression was significantly associated with poor OS and DFS in TCGA and our cohort. The nomogram incorporating CPSF3 showed superior predictive performance compared to traditional models. Downregulation of CPSF3 inhibited BC cell proliferation, colony formation and transition from G1 phase to S phase. GSEA revealed enrichment of oncogentic pathways in CPSF3 high-expression phenotype. CPSF3 expression was correlated with immune cell infiltration and expression of immune checkpoints in the tumor microenvironment. Conclusions: Our study demonstrates that CPSF3 is a promising prognostic biomarker for BC and may play a crucial role in BC progression. The nomogram incorporating CPSF3 expression provides an improved tool for predicting BC patient outcomes. These findings suggest that CPSF3 could be a potential therapeutic target for BC treatment.

Niacinamide and its impact on stratum corneum hydration and structure

Abstract Niacinamide (NIA) is widely used in skincare for its favorable safety profile, anti-aging effects, and proven clinical efficacy in treating various skin conditions. However, its direct impact on the hydration and molecular organization of the stratum corneum (SC), the primary skin barrier, remains unclear. This study examines how NIA influences the SC’s lipid matrix organization, soft keratin structure, and water sorption behavior across varying relative humidity (RH) levels. Using small- and wide-angle X-ray diffraction and dynamic vapor sorption measurements, we compared NIA-treated SC samples to untreated controls under different RHs. The main findings show that while NIA is non-hygroscopic, it enhances water uptake of the SC at high humidity (95% RH). At low humidity (60% RH), NIA swells the keratin monomer spacing, although the SC water content remains low, suggesting a plasticizing effect that could increase SC flexibility in dry conditions. NIA also modifies the diffraction intensities from the lipid matrix differently at 60% and 95% RH, implying that it interacts with the SC lipid matrix and influences the water distribution within the SC lipid and protein domains. These effects appear independent of the investigated dose regime, indicating a specific concentration threshold. Overall, NIA shows distinct interaction with keratin, swelling the spacing between keratin monomers in dry conditions, without acting as a traditional keratolytic agent.

Optimizing DeepHRD Interpretability for Enhanced Clinical Decision Making

Rucaparib vs docetaxel (DTX) or second-generation androgen pathway inhibitor (ARPI) therapy for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 final overall survival (OS) and safety.

155 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study of rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) in patients with chemotherapy-naive mCRPC and BRCA1/2 (BRCA) vs the control arm of physician’s choice of DTX or ARPI (abiraterone acetate [ABI] or enzalutamide [ENZ]) demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS, primary efficacy endpoint) vs physician’s choice. Here, we report final OS and safety results from TRITON3. Methods: Patients with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI, or ENZ (control). OS was a key secondary endpoint tested initially in the BRCA subgroup, followed by the intent-to-treat (ITT) population in an ordered step-down multiple-comparisons procedure. Crossover from placebo to rucaparib was allowed after radiographic progression was confirmed by independent radiology review. Results: As of March 1, 2024 (final analysis data cutoff),patients with BRCA (N = 302) and ATM (N = 103) alterations were randomized (ITT, N = 405). After an overall median follow-up of 44.0 months, median OS in the BRCA subgroup in the rucaparib arm was 23.2 months vs 21.2 months for the physician’s choice control arm (HR, 0.91 [95% CI, 0.68–1.20]; P = 0.5044; Table). Hierarchical testing did not continue due to lack of statistical significance. No OS benefit was observed in the ITT population or ATM subgroup (Table). Median duration of treatment in rucaparib and physician’s choice arms was 8.3 and 5.1 months, respectively. The most frequent any-grade treatment emergent adverse event (TEAE) in the rucaparib (n = 270) and physician’s choice (n = 130) arms was asthenia/fatigue (61.5% and 63.1%, respectively). The most frequent grade ≥3 TEAE was anemia (23.7%) with rucaparib, and asthenia/fatigue (9.2%) with physician’s choice. Of the 135 patients in the physician’s choice arm, 77 patients had radiographic progression and 70 crossed over to rucaparib. Conclusions: Rucaparib remains the only PARPi to show improved rPFS vs a DTX-containing control arm and has a similar OS even when most patients cross over to rucaparib. Safety was consistent with prior reports. These data support rucaparib as a treatment option for patients with BRCA-mutated mCRPC. Clinical trial information: NCT02975934 . Median OS at final analysis. Group Rucaparib, n Physician's choice, n Rucaparib, months Physician's choice, months HR (95% CI) a BRCA 201 101 23.2 21.2 0.91 (0.68–1.20) ITT 270 135 22.8 21.7 0.99 (0.78–1.26) ATM 69 34 18.4 22.1 1.21 (0.77–1.90) a Calculated by stratified Cox proportional hazard model.

Androgen receptor alterations and survival in veterans who develop metastatic castrate resistant prostate cancer.

269 Background: Despite the increasing use of comprehensive genetic tumor profiling, molecular data has limited influence in determining treatment. However, with new therapies that target the androgen receptor in metastatic castration-resistant prostate cancer (mCRPC), molecular alterations in the androgen receptor signaling pathway have increasing importance. We sought to examine the association between androgen receptor (AR) alterations and overall survival in patients with metastatic hormone sensitive prostate cancer (mHSPC). Methods: In this retrospective study, we identified patients diagnosed with de novo mHSPC and treated with androgen deprivation therapy (ADT) between 2017 to 2021 within the Veterans Health Affairs. AR gene alterations were identified using National Precision Oncology testing from samples collected within 90 days before or after the mCRPC diagnosis date. Overall survival (OS) and time to mCRPC were compared between patients with and without AR alterations in patients whose samples were collected during mCRPC. Normally distributed variables were analyzed via t-test, nonnormal continuous variables via Kruskal-Wallis, and categorical variables via chi-square. Results: We identified 2431 patients with de novo metastatic prostate cancer who had somatic tumor testing (551 mCRPC samples and 1922 mHSPC samples). In samples collected in mCRPC, 40.8% (225) had AR alterations compared to 3.3% (65) in mHSPC patients (p<0.001). Of the mCRPC samples, 68.1% (375) were obtained via liquid biopsy, 74.2% (167) had a single AR alteration, and 25.8% (58) had two or more AR alterations (p<0.001). The most frequent AR alterations identified were amplification (n=135), T878A (n=48), L702H (n=40), H875Y (n=27), exon 4-8 rearrangement or deletions (n=23), W742L (n=11), and W742C (n=11). In patients with mCRPC samples, time to mCRPC was 31.3 months in patients with AR alterations compared to 34.7 months without AR alterations, HR 1.08 (95% CI: 0.91-1.28) (p=0.4). In mCRPC samples with AR alterations, the median overall survival was 56.8 months compared to 76.7 months in patients without AR alterations, HR 1.40 (95% CI: 1.15-1.70) (p<0.001). Conclusions: There are significantly more AR alterations in tissue samples collected from de novo metastatic prostate cancer patients who have progressed to mCRPC compared to samples collected at mHSPC. In patients tested during mCRPC, presence of AR alteration was associated with shorter overall survival compared to those without AR alterations. Genomic analysis of tumors at the time of disease progression may be an informative prognostic indicator and facilitate selection of therapy. No AR alteration (n=326) AR alteration present (n=225) HR (95% CI) p-value Time to mCRPC (months) 34.7 31.3 1.08 (0.91-1.28) 0.4 Overall survival (months) 76.6 56.8 1.40 (1.15-1.70) <0.001

Real-world assessment of clinical outcomes of first-line treatment in metastatic papillary renal cell carcinoma.

471 Background: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) representing up to 15% of RCC. First line (1L) phase II trials have evaluated immunotherapy (IO) in combination with IO or tyrosine kinase inhibitors (TKI) in nccRCC, but these cohorts are heterogeneous, with few comparative results. Therefore, the specific value of IO therapy for pRCC remains unquantified. Methods: We conducted an analysis based on prospectively collected data from the Canadian Kidney Cancer information system (CKCis) database. The objective was to evaluate efficacy of 1L systemic therapy of metastatic pRCC with either IO based or VEGFR-TKI. Baseline characteristics, treatment outcome and safety were collected. Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events requiring a change in dose/schedule (TRAEs). TTF, OS and ORR were adjusted (adj) for IMDC risk groups. Results: Between 01/2011 to 01/2024,206 pRCC pts were treated: 70 on IO single agent or in combination IO-IO/IO-TKI and 136 with TKI monotherapy. The median follow-up was 20.6 months (mo) (range: 1.6-146.1). There were no significant differences in baseline characteristics between 2 groups, described in table. The median TTF with IO was 9.8 mo (95%CI: 4.5, 15.9) versus (vs) 5.7 mo with TKI (95%CI: 4.6, 8.1) (adj HR: 0.61 [0.42-0.89] p=0.01). The median OS was 36.9 mo with IO (95%CI: 26.5, not reached (NR)) vs 21.6 mo with TKI (95%CI: 18, 27.9) (adj HR: 0.51 [0.3-0.85], p=0.009). Among the 170 evaluable pts, ORR was 37% (95% CI: 24.2-49.9) with IO and 21.5% (95% CI: 14.1-29) with TKI (adj OR: 2.4 [1.0-5.6] p=0.04). The TKI-IO subgroup had better TTF and OS compared to TKI therapy, with 16.9 mo (95%CI: 5.5-22.6) (adj HR: 0.46 [0.26-0.82] p=0.009), and NR (95%CI: 18.9-NR) (adj HR: 0.24 [0.08-0.78] p=0.02) respectively. 28% of pts discontinued treatment. TRAEs of grade 3-5 were noted in 27% in IO group and in 73% in TKI group. Conclusions: This study presents comparative data on 1L treatment metastatic pRCC. It shows an improved TTF and OS in the IO group, particularly in TKI-IO treated pts. Our findings underline the need for further clinical trials evaluating 1L IO in pts with metastatic pRCC. Baseline characteristics. Overall cohortn = 206 IO treatmentn = 70 (34%) TKI treatmentn = 136 (66%) Median age (range) 67 (30-89) 69 67 Sex Male 162 (79%) 51 (73%) 111 (82%) IMDC score Favorable Intermediate Poor Unknown 31 (20%)93 (60%)30 (19.5%)52 15 (29%)30 (58%)7 (13%)18 16 (16%)63 (62%)23 (22%)34 Prior Nephrectomy 164 (80%) 56 (80%) 108 (79%) Sarcomatoid component 12 (8%) 5 (7%) 7 (5%) Therapy Nivolumab + ipilimumab Pembrolizumab + axitinib Pembrolizumab + lenvatinib Pembrolizumab Nivolumab Sunitinib Pazopanib Cabozantinib Crizotinib Savolitinib m-Tor inhibitors 27 (13%)23 (11%)7 (3.5%)11 (5%)2 (1%) 88 (43%)20 (10%)8 (4%)3 (1.5%)7 (3.5%)9 (4.5%)

Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD)

Characterizing immunogenicity of <i>MYC-</i> amplified, metastatic prostate cancer as reflected by the recovery rates of adaptive immune receptor recombinations from RNAseq files.

241 Background: In prostate cancer, identifying biomarkers to predict patients who are at higher risk for metastatic disease remains a key question. The interaction of oncogenes such as MYC with the adaptive immune system may be a potential marker for worse progression; for example, MYC -amplified neuroblastoma has been shown to be immunologically cold both in vitro and with respect to the amount of adaptive immune receptor (IR) recombinations recovered from genomics files. Thus, we performed a correlative study identifying the relationship between MYC amplification and detection of adaptive IR recombinations in genomics files in prostate cancer. Methods: We utilized datasets for this study: The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD, n = 475), Count Me In-Metastatic Prostate Cancer (CMI-MPC, n= 63) and West Coast Dream Team – Metastatic Castration Resistant Prostate Cancer (WCDT-MCRPC, n = 76). Copy number variation (CNV) assessments were done for the cases in these studies, identifying oncogene amplification as those with high ratios of exome, tumor to blood sequencing read counts for a given gene. We also mined productive IR recombination sequencing reads from RNAseq files, with associated V and J-IDs, as described in Chobrutskiy et al. 2020, which yielded reads for TRA , TRB , TRD , TRG , IGH , IGK , and IGL . Then, MYC-amplified cases and MYC-deficient cases were compared with a two-proportion test for progression-free survival and with a t-test for the counts of IR receptors. Results: We first determined that, for TCGA-PRAD dataset, cases representing the top 20 MYC read tumor to blood count ratios, in comparison to all other cases, represented a poorer progression free survival (p = 0.01) at the 70-month timepoint. We also noted that average MYC CN in both metastatic prostate cancer datasets (CMI-MPC and WCDT-MCRPC) was higher than in the TCGA-PRAD dataset, which represented primary tumor samples (p &lt; 0.001 for both analyses). Further, for the WCDT-MCRPC dataset, we found that MYC -amplified cases were associated with significantly reduced IGH , IGK , and IGL recombination reads in RNA-seq files (p = 0.005, 0.01, 0.004 respectively). For the WCDT-MCPRC dataset, we found that MYC -amplified cases were associated with reduced TRA and TRB recombination reads in WGS files (p = 0.008 and 0.017 respectively). Conclusions: This report further evidences the negative effects of MYC amplification with regard to immune evasion and being a key driver of prostate cancer metastasis. This report thus supports risk stratification by MYC-amplification, as well as noting that patients with MYC-amplification may benefit more from immune-boosting therapies. In particular, this report identifies immunoglobulins and by proxy, B-cells, as a major deficiency in those with MYC-amplified prostate cancer.

Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA.

659 Background: In the phase 3 NIAGARA study of patients (pts) with muscle-invasive bladder cancer (MIBC), perioperative durvalumab (D) plus neoadjuvant chemotherapy (NAC) demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) and overall survival (OS) compared with NAC alone, with a manageable safety profile and no detriment to the ability to undergo radical cystectomy (RC). We report additional outcomes and an exploratory analysis from NIAGARA. Methods: NIAGARA enrolled cisplatin-eligible pts with MIBC (cT2-T4aN0/1M0) planned for RC. Pts were randomized 1:1 to receive either neoadjuvant D (1500 mg IV Q3W) and NAC (cisplatin + gemcitabine IV Q3W) for 4 cycles followed by RC, then adjuvant D monotherapy (1500 mg IV Q4W) for 8 cycles (D arm), or NAC followed by RC alone (comparator arm). Dual primary endpoints were EFS and pCR. OS was a key secondary endpoint. Metastasis-free survival and disease-specific survival were secondary endpoints. An exploratory post hoc analysis of EFS and OS in pts with pCR vs without pCR (non-pCR) was also performed. Efficacy analyses were conducted in the intent-to-treat population (data cutoff [DCO] April 2024). Results: A total of 1063 pts were randomized (533 D arm; 530 comparator arm). Pts in the D arm had a 33% reduction in risk of developing distant metastases or death (hazard ratio [HR] 0.67; 95% CI 0.54–0.83; nominal P &lt;0.001) and 31% reduction in risk of death from bladder cancer (HR 0.69; 95% CI 0.52–0.91; nominal P =0.008) vs pts in the comparator arm. More pts in the D vs comparator arm had pCR at RC (37% vs 28%); pts who achieved pCR had better EFS and OS vs non-pCR. Pts in the D arm derived greater EFS and OS benefit vs the comparator arm in both pCR (EFS HR 0.58; OS HR 0.72) and non-pCR (EFS HR 0.77; OS HR 0.84) groups (Table). Overall, immune-mediated AEs (imAEs) were reported in 111/530 (21%) pts in the D arm (grade 3/4 3%) and 16/526 (3%) in the comparator arm (grade 3/4 0.2%). At DCO, all imAEs were resolved for 45/111 (41%) pts (D arm) and 7/16 (44%) pts (comparator arm). The most common imAEs were hypothyroid events (10% D arm; 1% comparator arm) and hyperthyroid events (3% D arm; 0.8% comparator arm). Conclusions: Perioperative D with NAC reduced the risk of developing metastases and death from bladder cancer, and exploratory post hoc analyses showed that D improved EFS and OS in both pCR and non-pCR groups. imAEs were consistent with the known profile of D and mostly low grade. These data further support perioperative D as a potential new standard treatment for pts with MIBC. Funding: AstraZeneca. Clinical trial information: NCT03732677 . pCR Non-pCR D N=199 Comparator N=146 HR (95% CI) D N=334 Comparator N=384 HR (95% CI) 24-month EFS rate (95% CI), % 92 (87–95) 86 (79–91) 0.58 (0.33–1.00) 53 (48–59) 50 (44–55) 0.77 (0.63–0.95) 24-month OS rate (95% CI), % 96 (92–98) 91 (85–95) 0.72 (0.37–1.43) 74 (69–79) 69 (64–73) 0.84 (0.66–1.07)

Local definitive therapy (LDT) utilization patterns and outcomes in chromophobe renal cell carcinoma (chRCC) with metachronous metastasis: A multi-institution study.

503 Background: LDTs, including surgical resection, radiation treatment and ablation/embolization, can be employed to achieve a disease-free state in indolent oligometastatic RCC irrespective of subtype. However, the efficacy of LDTs in chRCC, a rare subtype, has not been investigated. We utilized a multi-institutional chRCC dataset to examine LDT use patterns and associated duration of disease control. Methods: Clinical and treatment characteristics of patients with chRCC and metachronous metastases were retrospectively collected from four institutions. Patients with LDT as the first metastasis-directed intervention comprised the LDT cohort, while those who started systemic treatment (ST) upfront were included in the ST cohort. Wilcoxon rank-sum test and Fisher’s exact test were used for comparison of continuous and categorical variables, respectively. Systemic treatment-free survival (STFS, duration between upfront LDT and subsequent ST initiation or last follow-up) was calculated by Kaplan-Meier method. Results: 104 patients were included: 48 in the LDT cohort and 56 in the ST cohort.Median age and gender were comparable across the two cohorts. Compared to patients who initiated ST, patients who underwent LDT had a longer interval between nephrectomy and metastatic disease diagnosis (49 months [IQR 30. 93] vs 14 months [IQR 4, 47], p &lt;0.001), were less likely to have tumors with sarcomatoid dedifferentiation (6% vs 34%, p &lt;0.001), had an earlier disease stage at initial diagnosis (Stage I 33% vs 9%, Stage II 12% vs 31%, Stage III 55% vs 56%, p=0.004) and were more likely to have a single metastatic site (79% vs 52%, p=0.002). In the LDT cohort, 39 (81%) patients underwent surgery, 7 (14%) radiation and 4 (8%) ablation/embolization. The majority (30 [61%]) underwent a single LDT, while serial LDTs were utilized in the remainder: 12 (25%) with 2 LDTs and 6 (12%) with ≥3. The most frequently treated sites with LDT were the lymph node (27%), soft tissue (23%) and liver (15%). The median interval between first and second LDT was 20 months (IQR 7, 32), and between the second and third LDT was 7 months (IQR 1, 10). At a median follow-up of 60 months, median STFS was 32 months (95% CI, 20, 46). One- and two-year STFS rates were 84% and 62%. Conclusions: This is thefirst study to systematically evaluate LDT use and outcomes in chRCC managed at centers of expertise. LDTs were more frequently utilized in patients with single-organ metastasis, longer time between nephrectomy and recurrence, and absence of sarcomatoid dedifferentiation. In a carefully selected population, LDTs can lead to clinically meaningful treatment-free interval in chRCC.

Phase I trial of hypofractionated radiotherapy and pembrolizumab in the treatment of muscle invasive/metastatic bladder cancer: Results of the PLUMMB trial.

756 Background: The objective of the PLUMMB trial (NCT02560636) was to assess the safety, tolerability and efficacy of the addition of the anti-PD1 antibody Pembrolizumab with hypofractionated weekly bladder radiotherapy (RT) in patients with advanced/metastatic bladder cancer. We present the final results, subject to database lock and statistical QC. Methods: The trial aimed to recruit 28 patients planned for RT to the bladder with a dose escalation phase (modified 3+3) of 7 dose cohorts to determine the primary endpoint maximum tolerated dose (MTD), and a dose expansion phase to answer the secondary endpoints: acute toxicity (up to 6 weeks post RT); late toxicity (until 28 days post Pembrolizumab (CTCAE - Common Terminology Criteria for Adverse Events) or 2 years post RT (RTOG - Radiation Therapy Oncology Group)); progression free survival (PFS); overall survival (OS); and local control of bladder cancer. Exploratory endpoint was control of bladder related symptoms. Results: Between Sep 2016 and Nov 2023, 28 patients were recruited: median age 75 (IQR 69-85), white, majority male (79%), ever-smokers (75%). Three (11%) had locally advanced (T2a-T2b N0 M0) and 25 (89%) had nodal/metastatic bladder cancer (T1b-T4 N0-N3 M0-M1b). Two patients did not receive any Pembrolizumab or RT so were excluded from endpoint analyses. Three patients remain on Pembrolizumab (all ≥6 months post RT). Five patients experienced dose limiting toxicity (DLT) (see table) and the MTD was confirmed at 24Gy in 6 fractions (f) and Pembrolizumab 200mg, which was the expansion cohort. The rates of worst acute toxicity in patients who had ≥2 doses of Pembrolizumab, ≥4f of RT and had a toxicity assessment 6 weeks post RT were: 4/20 (20%) grade 1; 12 (60%) grade 2; and 4 (20%) grade 3. For late toxicity in patients who had ≥1 dose of Pembrolizumab, 1f of RT and survived to 6 weeks post RT: 15/24 (63%) reported grade 2+ and 8 (33%) grade 3+ using CTCAE; and 5 (21%) reported grade 2 using RTOG not within 3 months of disease progression (0 grade 3+). For patients who had ≥1 dose of Pembrolizumab and 1f of RT: 13/26 (50%) had a response as per RECIST 1.1 (7 CR, 6 PR, 6 SD, 6 PD - best response). PFS and OS was 31% (95%CI: 15-49) and 62% (95%CI: 40-77) at 1 year, and 16% (95%CI: 5-34) and 33% (95%CI: 15-51) at 2 years, respectively. Finally, 12/24 (50%) patients were free of grade 2+ bladder symptoms at 3 months post RT, and 8 (33%) at 6 months. Conclusions: DLT is seen when combining 6Gy fractions of radiotherapy and Pembrolizumab 100-200mg, but 24Gy in 6f radiotherapy with Pembrolizumab is safe and effective in the treatment of advanced bladder cancer with 50% of patients having a favourable response. Clinical trial information: NCT02560636 . Dose Cohort Radiotherapy Pembrolizumab Number registered (%) Number with DLT A-1 36Gy in 6f 100 6 (21) 3 A-2 36Gy in 6f 200 B-1a 24Gy in 6f 100 1 (4) B-1b 24Gy in 6f 200 12 (43) B-2a 24Gy in 4f 100 4 (14) B-2b 24Gy in 4f 200 5 (18) 2 B-3a 30Gy in 5f 200

Molecular-dipole oriented universal growth of conjugated polymers into semiconducting single-crystal thin films

Unveiling the drivers of active participation in social media discourse

The effect of circadian rhythm–based medication timing adjustments on the efficacy and safety of novel hormonal therapy.

TPS277 Background: Neoadjuvant hormonal therapy (NHT) serves as the primary treatment approach for metastatic hormone-sensitive prostate cancer (mHSPC) by either inhibiting androgen synthesis or blocking androgen receptor binding, thereby suppressing tumor growth. Despite its effectiveness, patients with mHSPC inevitably develop resistance to NHT over time, advancing to metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis. Androgen synthesis and secretion exhibit a prominent circadian rhythm, with accelerated synthesis in the early morning, peaking around 8:00 AM, followed by a decline to nadir by approximately 8:00 PM. Administrating NHT agents during nighttime may enhance therapeutic efficacy by preemptively inhibiting androgen synthesis and receptor binding before the peak secretion period. Consequently, we have designed a prospective study to evaluate and compare the efficacy and safety of daytime versus nighttime administration of NHT agents in patients with mHSPC. Methods: This prospective, open-label, phase II study will enroll 70 patients with mHSPC. Key eligibility criteria include histologically or pathologically confirmed prostate cancer, classified as mHSPC, without prior NHT or chemotherapy. Patients currently receiving other systemic antitumor therapies, those who have undergone organ transplantation within the past 3 months, or been diagnosed with autoimmune disease will be excluded. Eligible patients will be randomized in a 1:1 ratio to receive NHT agents either between 7:00 and 9:00 AM or between 10:00 and 12:00 PM. Treatment is continued until disease progression. The primary objective is to evaluate the effect of nighttime administration of NHT agents by assessing PSA response rate (PSA-RR), defined as the proportion of patients achieving &gt; 90% reduction in PSA from baseline after 3 months of NHT. Secondary endpoints include circulating tumor cell (CTC) clearance rate, clinical benefit rate, objective response rate (ORR), duration of response (DoR), time to objective response, radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Differences in response rates between the 2 groups will be analyzed using the Chi-square test. Survival endpoints will be estimated using the Kaplan-Meier method, with between-group comparisons conducted by the log-rank test. Currently, 14 of a planned total of 70 participants have been enrolled. Clinical trial information: NCT06505278 .

Cadonilimab combined with lenvatinib for neoadjuvant therapy in early-stage renal cell carcinoma with indications for partial nephrectomy but high surgical risk: A prospective single-arm phase II clinical trial.

530 Background: Partial nephrectomy is the standard treatment for early-stage renal cell carcinoma; however, in some patients, although the tumor is early-stage, the surgical difficulty may preclude its implementation. This study aims to evaluate the efficacy and safety of Cadonilimab combined with Lenvatinib in neoadjuvant therapy for renal cell carcinoma with indications for partial nephrectomy but high surgical risk. Methods: This is a single-center, single-arm Phase II clinical trial. Eligible patients included those with biopsy-confirmed clear cell renal carcinoma who had indications for partial nephrectomy but were at high surgical risk (criteria: 1. tumors measuring 4-7 cm located at the renal hilum or endophytic ≥75%; 2. tumors larger than 7 cm). Patients received Lenvatinib at a dosage of 8 mg or 12 mg QD combined with Cadonilimab at 6 mg/kg every two weeks for 3-6 cycles, for a total treatment duration of 6-12 weeks. Cadonilimab is a first-in-class bispecific antibody targeting both PD-1 and CTLA-4. All patients are scheduled to undergo partial nephrectomy after neoadjuvant therapy. The primary endpoint was the objective response rate (ORR) based on RECIST 1.1 criteria. Secondary endpoints included the renal preservation success rate, safety, and incidence of perioperative complications. Results: A total of 27 patients were enrolled in the study. Sixteen patients completed 6 cycles of Cadonilimab treatment, 6 patients completed 3 cycles, and 5 patients did not complete the pre-set treatment cycles. One patient underwent surgery after experiencing a grade 4 adverse event (diabetic ketoacidosis) following the second cycle of Cadonilimab; four patients discontinued treatment for subjective reasons and proceeded to surgery after the second cycle. All 27 patients underwent surgical procedures. The primary endpoint ORR was 55.6% (15/27), with a tumor control rate of 100%. All patients demonstrated tumor reduction prior to nephrectomy, with an average maximum tumor diameter reduction rate of 26.5%. Furthermore, 100% of patients completed partial nephrectomy. Two patients achieved pathological complete response, and all patients exhibited tumor necrosis, with an average tumor necrosis rate of 45%. Adverse events (AEs) of grade ≥3 occurred in 10.5% of patients, including hyperglycemia and elevated ALT/AST. One patient experienced a grade 4 AE, and no grade 3 postoperative complications were reported. The main limitation of this study is that it is a single-center, small-sample study. Conclusions: Cadonilimab combined with Lenvatinib for neoadjuvant treatment in early clear cell renal carcinoma with indications for partial nephrectomy but high surgical risk demonstrates clear efficacy and safety, warranting further clinical validation. Clinical trial information: NCT06138496 .

Paclitaxel, ifosfamide, cisplatin (TIP) in patients with advanced urethral adenocarcinoma: A single center, retrospective analysis.

656 Background: Urethral adenocarcinoma (UA) is a very rare subtype of cancers arising in urethra, which is known for female predominance and poor prognosis. Rarity of UA impedes the conduction of prospective clinical trial, thus the treatment option for advanced UA is very limited. Usually platinum-based chemotherapy is given based on case reports. We conducted retrospective single center cohort review of TIP regimen in patients (pts) with locally advanced, recurrent or metastatic UA to evaluate its efficacy and safety. Methods: Clinical data of 18 pts with locally advanced, metastatic, or recurrent UA who received TIP regimen at the Department on Oncology, Asan Medical Center from Jul 2016 to Jan 2024 were collected. To be eligible, pts should have histologic confirmation of adenocarcinoma, adequate clinical information, and baseline and follow-up imaging test results. TIP regimen consists of paclitaxel 200 mg/m 2 over 3 hours intravenously (iv) on day 1 (D1), ifosfamide 1,500 mg/m 2 over 1 hour iv on D1-3 with mesna 300 mg/m 2 3 times a day iv on D1-3, and cisplatin 70 mg/m2 over 1 hour iv on D1. We recommended pegylated G-CSF for prevention of severe neutropenia and febrile neutropenia. The primary endpoint was objective response rate (ORR) according to RECIST v1.1, and secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. Results: A total of 18 pts were enrolled. All pts were female, and median age was 62 (range 43-74). Disease status was locally advanced (32%), recurrent (47%), and initially metastatic (16%), and ECOG PS were 0 (22%), 1 (72%), and 2 (6%). Most common site of metastasis were lymph nodes (50%), surgical bed (22%), lung (22%), and peritoneum (17%). Patients received TIP as 1 st line (67%) and 2 nd line (33%). Thirteen pts received prophylactic pegylated G-CSF. Median 4 cycles (range 1-6) of TIP were administered, and ORR was 44% (partial response 44%, stable disease 50%, and progressive disease 6%). With a median follow-up duration of 38.7 months, median PFS and OS were 7.0 months [95% confidence interval (CI) 3.8-10.2] and 40.0 months (15.6-63.7), respectively. Most common adverse events included anemia, peripheral neuropathy, anorexia, nausea, fatigue, neutropenia, thrombocytopenia. Most adverse events were manageable, and no unexpected toxicities were found. Conclusions: TIP showed promising efficacy in pts with advanced UA. TIP might be considered as one of treatment options for pts with advanced UA, although efficacy and safety should be validated in larger cohort.