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Introduction Translating findings from cell and animal models to the clinic is difficult because these systems insufficiently capture human disease biology. Computational approaches, notably pathways modeling, have overcome interspecies differences by mapping shared signaling pathways between species. We considered whether this approach could be generalized to bridge animal and virtual drug screening data to effects measured in patients. We emphasized translational psychiatry datasets because of the unmet need for effective therapies. Methods We conducted three parallel analyses using published drug screening data in zebrafish, structure-function computational screening data, and clinically-reported efficacy data for experimental and approved antipsychotic drugs and predicted drug pathways using the PathFX algorithm Results Despite choosing screens developed for unique aspects of psychiatry and without careful curation of shared drugs, we found pathways associated with drugs that performed “well” across these distinct platforms—specifically, among drugs measured as favorable (expected to improve disease) or unfavorable (expected to aggravate disease) across screens, these drugs connected to distinct pathway proteins; however, these drugs are connected to similar protein families and shared Gene Ontology functional terms. By comparing screens, we discovered that favorable drugs may influence G-proteins, solute carrier family proteins, adrenoceptors, and steroid hydroxylase activity and that unfavorable drugs affect serotonin receptors and phosphodiesterase activity. Discussion This suggests that predictive platforms could emphasize functional information as features that could overcome differences in distinct screening platforms to eventually improve translational approaches.

PURPOSE This national study was undertaken to determine screening mammography rates among transgender and gender diverse (TGD) individuals. METHODS TGD individuals and cisgender women who qualified to receive screening mammography based on American College of Radiology guidelines were identified in the longitudinal OptumLabs Data Warehouse. The primary end point was the percentage of patients who had high rates of screening (>75% recommended screenings). Multivariable analyses were conducted in a matched population of transgender men to cisgender women to identify and adjust for factors associated with high adherence. Individuals were matched at a 1:4 ratio (transgender men: cisgender women) on age, race/ethnicity, year of enrollment in their health care plan, and duration of follow-up. RESULTS This study focused on 10,478 TGD individuals (3,778 transgender men; 1,294 transgender women; 5,406 with gender dysphoria not meeting other TGD criteria, NMOT) and 6,218,369 cisgender women. For transgender men, transgender women, individuals with gender dysphoria NMOT, and cisgender women, high mammography rates were observed in 41.1% (95% CI, 39.5 to 42.6), 7.4% (95% CI, 6.0 to 8.8), 11.9% (95% CI, 11.0 to 12.7), and 38.3% (95% CI, 38.3 to 38.4), respectively ( P < .0001). When transgender men were compared with 15,112 matched cisgender women, an age-based differential association was observed between sex and high mammography rates (interaction P = .0003); compared with cisgender women, transgender men appeared more likely to manifest high rates of screening at age 40-49 years (odds ratios [ORs], 1.38 [95% CI, 1.28 to 1.50]; P < .0001) and 50-59 years (OR, 1.57 [95% CI, 1.35 to 1.81]; P < .0001) but not in the older age groups. CONCLUSION The relatively high rates of screening mammography in cisgender women and transgender men suggest clinicians are offering mammography to individuals who are at average or high breast cancer risk, as compared with cisgender women, and not to transgender women at low risk.

Rationale: Neuromuscular blocking agents (NMBAs) show potential benefits on mortality and other complications of acute respiratory distress syndrome (ARDS) in adult patients. Evidence-based decisions and processes ensure appropriate use of neuromuscular blockade in adult patients with ARDS. Objectives: The objective of these guidelines was to develop evidence-based recommendations for the administration of NMBAs in critically ill adult patients with ARDS. Design: The American College of Critical Care Medicine Board convened a 21-member multidisciplinary panel of experts in critical care medicine, nursing, respiratory therapy, pharmacology, surgery, neurology, and anesthesiology. The panel included two expert methodologists specialized in developing evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guidelines development including task force selection and voting. Methods: The panel members identified and formulated five Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and assessed the certainty of the evidence using the GRADE methodology. We used the GRADE evidence-to-decision framework to formulate the recommendations. Results: The panel generated two conditional recommendations. One recommendation is to use NMBAs in adults with ARDS with Pa o 2 /F io 2 less than 150. For the other recommendations, there was equipoise in the recommendation for and against using titratable vs. fixed-dose NMBA dosing, a monitoring-based strategy for assessing depth of sedation and analgesia in adults with ARDS before initiating or while receiving neuromuscular blockade, and administration of NMBAs for patients who are proned, due to overall lack of evidence in critically ill patients and due to considerations of patient safety and experience concerns. Conclusions: These guidelines provide additional perspectives on the use of NMBA in patients with ARDS, recognizing that institutional and patient-specific considerations must help to guide the decision-making process.

88 Background: The VISION (NCT03511664) and PSMAfore (NCT04689828) clinical trials have demonstrated the effectiveness of 177 Lu-PSMA-617 in patients with mCRPC who have previously received androgen receptor pathway inhibitors (ARPIs) with or without taxane-based chemotherapy. Sipuleucel-T is used for treatment of mCRPC in routine clinical practice, particularly among community urologists; however, to date, there are no data available to understand the effectiveness of 177 Lu-PSMA-617 in patients previously treated with sipuleucel-T. Methods: This was a retrospective, observational study of adult patients with a diagnosis of mCRPC who received 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, and had a history of treatment with sipuleucel-T. Data were obtained from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US that integrates electronic health records and claims data from community, academic, urology, and medical oncology settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and prostate-specific antigen (PSA) response rates were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was analyzed using Kaplan–Meier curves. Results: A total of 290 patients met the inclusion criteria, of whom 72% were White and 12% were Black. At index, 32% of patients were treated in urology and 68% in oncology settings. The median age was 74 years, the median baseline PSA was 35.3 ng/mL (interquartile range [IQR] 10.0–99.2 ng/mL), and 57% of patients had a Gleason score of ≥8. In addition to sipuleucel-T, prior to 177 Lu-PSMA-617, 97% of patients had received ≥1 ARPI and 79% had received ≥1 taxane. The median follow-up for this cohort was 9.4 months (IQR 5.3–17.5 months). Among 144 patients with available PSA values both before and during 177 Lu-PSMA-617 treatment (representing 50% of the cohort), PSA response rates were as follows: a ≥50% reduction in PSA from baseline (PSA50) was observed in 60%, PSA80 in 42%, and PSA90 in 33% of patients. Overall, the median PFS was 15.2 months (95% confidence interval [CI] 11.6–19.4 months). Conclusions: In this real-world analysis of patients who received 177 Lu-PSMA-617 after sipuleucel-T treatment, the median PFS was similar to that observed in clinical trials, suggesting that 177 Lu-PSMA-617 can be sequenced after sipuleucel-T treatment in appropriate patients.

81 Background: In the PSMAfore clinical trial, 177 Lu-PSMA-617 achieved a PSA50 (defined as a ≥50% reduction in prostate-specific antigen [PSA] from baseline) response rate in 58%, a median radiographic progression-free survival (PFS) of 12 months, and a median overall survival (OS) of 25 months among taxane-naïve patients with mCRPC who had received one prior androgen receptor pathway inhibitor (ARPI). The aim of the present study was to evaluate the real-world effectiveness of 177 Lu-PSMA-617 in taxane-naïve patients with mCRPC who had received one or more prior ARPIs. Methods: This retrospective, observational study included taxane-naïve adults with mCRPC initiating 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, after ≥1 prior ARPI. All data for the study were extracted from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US treated in a variety of clinical settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and PSA response rates were evaluated descriptively. PFS, defined as the time from 177 Lu-PSMA-617 initiation to progression or death, was estimated using Kaplan–Meier methodology. Results: A total of 500 patients were included. The median age was 75 years, 75% of patients were White and 8% Black, and 18% were treated in urology centers while 82% were treated in oncology centers. The most common site of metastasis was bone (77%), followed by lymph node (21%), visceral (12%), and unknown (5%). Overall, 51% had received 1 previous ARPI while 49% had received ≥2. The median baseline PSA was 26.7 ng/mL (interquartile range [IQR] 10−105 ng/mL) and the median time from mCRPC diagnosis to 177 Lu-PSMA-617 initiation was 23.6 months. The median number of 177 Lu-PSMA-617 cycles received was 4 (IQR 2−6). Among 219 patients with available PSA measurements both before and during 177 Lu-PSMA-617 treatment (representing 44% of the cohort), PSA response rates were as follows: PSA50 in 137 (63%), PSA80 in 86 (39%), and PSA90 in 56 (26%) patients. Overall, the median PFS was 13.5 months (95% confidence interval 11.7–14.7 months). Conclusions: The effectiveness of 177 Lu-PSMA-617 as a standard-of-care treatment in real-world, taxane-naïve patients with mCRPC who had received prior treatment with ≥1 ARPI is consistent with results from the PSMAfore trial, confirming the applicability of those findings to the real-world population now eligible for 177 Lu-PSMA-617. Further research on sequencing 177 Lu-PSMA-617 after one or more prior ARPIs in taxane-naïve patients with mCRPC is needed to guide optimal treatment sequencing in clinical practice.

79 Background: In March 2025, the indication for 177 Lu-PSMA-617 was expanded to include prostate-specific membrane antigen (PSMA)-positive patients with mCRPC treated with ≥1 androgen receptor pathway inhibitor (ARPI) and considered appropriate to delay taxane-based chemotherapy. With 177 Lu-PSMA-617 moving earlier in the treatment journey, it is important to understand the clinical activity of other systemic therapies after 177 Lu-PSMA-617. The aim of this study was to evaluate the clinical outcomes among patients with mCRPC receiving a systemic therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis representative of patients with advanced prostate cancer in the US from diverse clinical settings. Patients with mCRPC treated with 177 Lu-PSMA-617 who received a systemic therapy ≥14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, were included. Systemic therapies included ARPIs (abiraterone, enzalutamide, darolutamide, apalutamide); chemotherapy (cabazitaxel, docetaxel, carboplatin, cisplatin, etoposide, mitoxantrone); immunotherapy (pembrolizumab, sipuleucel-T); poly (ADP-ribose) polymerase (PARP) inhibitors (niraparib, olaparib, talazoparib, rucaparib); and radium-223. Patient characteristics and prostate-specific antigen (PSA) response were evaluated descriptively. Progression-free survival (PFS) from subsequent therapy initiation was estimated using Kaplan–Meier methodology. Results: A total of 442 patients receiving any subsequent systemic therapy after 177 Lu-PSMA-617 were included. Overall, 95% of patients received ≥1 ARPI and 76% ≥1 taxane pre- 177 Lu-PSMA-617. The median age was 73 years. Most patients received a taxane (n = 188), an ARPI (n = 176), or a PARP inhibitor (n = 33) as their subsequent therapy. The median time to subsequent therapy initiation was 70 days (interquartile range 38−137 days) from the last 177 Lu-PSMA-617 administration. Among 299 patients receiving a systemic therapy after 177 Lu-PSMA-617 with PSA values available both pre-index and during subsequent treatment, 48% achieved a ≥50% reduction in PSA from baseline (PSA50), 31% a PSA80, and 18% a PSA90. The median PFS from the initiation of subsequent therapy was 8.6 months in the entire cohort; this was 10.7 months with a subsequent ARPI, 7.2 months with a subsequent taxane, and 7.1 months with a subsequent PARP inhibitor. Conclusions: In this real-world analysis, meaningful clinical responses were observed in a subset of patients who received subsequent systemic therapies after 177 Lu-PSMA-617.

78 Background: 177 Lu-PSMA-617 is currently under investigation in combination with an ARPI in those with metastatic hormone-sensitive prostate cancer (PSMAddition trial: NCT04720157). This observational study was performed to assess the effectiveness of 177 Lu-PSMA-617 in combination with an ARPI in patients with mCRPC in the real-world setting. Methods: This was a retrospective cohort study of adults with mCRPC in the PRECISION data platform, a comprehensive database of prostate cancer patients compiled from diverse clinical settings in the US. Patients who received 177 Lu-PSMA-617 during March 23, 2022–June 27, 2025 were identified, among whom two cohorts were selected for inclusion: those who had evidence of ARPI use (apalutamide, darolutamide, abiraterone, or enzalutamide) at any time during 177 Lu-PSMA-617 treatment (concomitant ARPI cohort), and those who had no other treatment for mCRPC during 177 Lu-PSMA-617 treatment (no concomitant therapy cohort). The index date was initiation of 177 Lu-PSMA-617. Patient characteristics and prostate-specific antigen (PSA) responses were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was estimated using Kaplan–Meier analysis. Results: A total of 1,880 patients treated with 177 Lu-PSMA-617 were identified, 140 in the concomitant ARPI cohort and 1,740 in the no concomitant therapy cohort. The median age was 74 years. Demographic characteristics were balanced between the groups, except that median baseline PSA was lower in the concomitant ARPI cohort when compared with patients in the no concomitant therapy cohort (18 ng/mL vs. 32 ng/mL). Before 177 Lu-PSMA-617 initiation, 94.3% and 73.6% of patients in the concomitant ARPI and 80.9% and 56.7% in the no concomitant therapy cohort had received ≥1 prior ARPI and ≥1 prior taxane, respectively. PSA response rates were broadly comparable between cohorts. The median (95% confidence interval) PFS was 14.7 (11.7–21.3) months among patients in the concomitant ARPI cohort vs 12.5 (11.5–13.6) months in the no concomitant therapy cohort. Ongoing follow-up aims to evaluate the impact of combining ARPI with 177 Lu-PSMA-617 on long-term clinical outcomes, including overall survival. Conclusions: The results of this study demonstrate that 177 Lu-PSMA-617 delivers clinical benefits inpatients with mCRPC with or without ARPI; however, addition of an ARPI may potentially improve these benefits. Prospective randomized controlled studies are needed to confirm this.

77 Background: The incidence of metastatic hormone-sensitive prostate cancer (mHSPC) is increasing in the US, likely due to a decrease in screening practices. There has also been a rapid increase in recent years in the number of treatment options that can improve progression-free and overall survival (OS) for these patients. The objective of the current study was to evaluate the clinical outcomes among patients with mHSPC treated in contemporary US clinical practice (2020 to 2025). Methods: This retrospective, observational cohort study used data from PRECISION, a harmonized dataset on advanced prostate cancer in patients in the US treated in a range of clinical settings. Patients aged ≥18 years who were diagnosed with mHSPC during 01/01/2020–01/01/2024 and who initiated ≥1 therapy (index date = first-line [1L] treatment initiation) were included. The study period was from 01/01/2010 to 06/30/2025. Patient characteristics at mHSPC diagnosis and treatment utilization were evaluated descriptively. Castration resistance-free survival (CRFS; defined as the time to castration-resistant prostate cancer or death) and OS were evaluated from index using Kaplan–Meier analysis. Results: A total of 27,708 patients were included (median age, 72 years); 20,015 (72%) were treated in community urology, 4994 (18%) in community oncology, and 2669 (10%) in academic oncology centers at index. Almost half of patients (47%) initiated 1L treatment with androgen-deprivation therapy (ADT) monotherapy, 44% initiated a 1L doublet regimen (36% ADT + androgen receptor pathway inhibitor [ARPI], 5% 1L ADT + radiotherapy, 2% 1L ADT + docetaxel), and 5% a 1L triplet regimen (ADT + radiotherapy + ARPI or docetaxel); the remaining patients received other regimens. The 5-year CRFS rate was 41%; this was significantly higher in patients with a 1L doublet (45%) or triplet (58%) regimen compared with patients with 1L ADT monotherapy (31%; p<0.001). Similarly, the 5-year OS rate was 59% overall and was significantly higher in patients with a 1L doublet (61%) or triplet (59%) regimen compared with patients with 1L ADT monotherapy (55%; p<0.001) (Table). Conclusions: Though both CRFS and OS rates appear to be increasing among real-world patients with mHSPC, >40% of patients in this study died within 5 years of initiating 1L treatment. Patients who received guideline-recommended combined systemic treatment regimens experienced improved CRFS and OS, confirming the importance of implementing therapies in practice that prolong survival. CRFS and OS rates from start of 1L therapy, by therapy type. CRFS rate (%) OS rate (%) 1 y 2 y 3 y 4 y 5 y 1 y 2 y 3 y 4 y 5 y Overall 68 58 51 46 41 93 84 76 67 59 ADT monotherapy 59 49 41 36 31 92 83 74 65 55 Doublet therapy 72 62 55 49 45 94 85 76 68 61 Triplet therapy 85 77 70 68 58 94 89 82 74 59

75 Background: Although the number of life-prolonging treatment options for pts with mHSPC has increased, initial real-world evidence has demonstrated slow uptake. This study utilized a large, contemporary, real-world dataset to evaluate the characteristics and treatment utilization among US pts with mHSPC in recent years. Methods: This retrospective, observational study used data from PRECISION, a harmonized dataset on pts with advanced prostate cancer. Adult men who were diagnosed with mHSPC during 01/01/2020–01/01/2024 (index date) and who initiated ≥1 therapy were included; the study period was 01/01/2010–06/30/2025. Pt characteristics were described at index. Treatment utilization was evaluated from index until progression to metastatic castration-resistant prostate cancer, death, or last follow-up. If an androgen receptor pathway inhibitor (ARPI), docetaxel, or radiotherapy was started within 4 months of index/androgen-deprivation therapy (ADT) start, it was considered a first-line (1L) combination; if it was started after >4 months, it was considered treatment intensification. All analyses were descriptive. Results: Among the 27,708 pts who met the inclusion criteria in PRECISION, 72%, 18%, and 10% were treated in community urology, community oncology, and academic oncology centers at index, respectively. Median age was 72 years; 62% were White; 43% were from the US South; 53% had synchronous and 54% had metachronous metastases (2% unknown). Median prostate-specific antigen level was 9 ng/mL (mean, 130 ng/mL). Prior to mHSPC diagnosis, 19% of pts had a prostatectomy and 17% had radiotherapy. Almost half of pts (47%) initiated 1L treatment with ADT monotherapy; 36% initiated 1L ADT + ARPI, 5% 1L ADT + radiotherapy, 2% 1L ADT + docetaxel, 5% 1L ADT + radiotherapy + ARPI or docetaxel, and 5% other regimens. From 2020 to 2023, 1L ADT monotherapy use decreased, while 1L combination use increased (Table). In addition, 19% of pts with 1L ADT monotherapy had evidence of subsequent treatment intensification, mainly the addition of an ARPI. Conclusions: In this study, use of 1L ADT monotherapy declined over time, accompanied by an increase in 1L combinations and treatment intensification. Nonetheless, approximately 1/3 of pts still did not receive a combination or intensification. Further research is needed to understand treatment trends in pts with mHSPC. Treatment patterns by index year. Pts, % 2020(n=5278) 2021(n=6203) 2022(n=7701) 2023(n=8526) 1L ADT monotherapy* 54 52 45 40 Subsequent treatment intensification* 18 19 20 18 1L ADT + ARPI* 29 33 38 42 1L ADT + radiotherapy 5 5 5 6 1L ADT + docetaxel* 3 2 2 1 1L ADT + radiotherapy + ARPI or docetaxel* 3 3 5 7 *p<0.001 for trend across years.