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Author Correction: Medical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats

Retrospective, observational analysis of real-world safety outcomes in sacituzumab govitecan (SG)-treated patients (pts) with locally advanced/metastatic urothelial cancer (la/mUC).

709 Background: In the rapidly evolving la/mUC treatment landscape, new therapies need to be integrated into management of pts. SG, a Trop-2–directed antibody drug conjugate, showed improved overall survival and manageable safety in pts with la/mUC who progressed on platinum-based chemotherapy and immune checkpoint inhibitor therapy in TROPHY-U-01 (NCT03547973). Safety of SG was previously reported in a retrospective cohort study using US Flatiron Health electronic health record–derived de-identified database of pts ≥ 18 yrs with la/mUC initiating SG from Dec 2019 - Oct 2022. We now present results from the expansion cohort with an additional year of follow-up. Methods: Pts in the expansion cohort had initiated SG from Dec 2019 - Jul 2023. Data on treatment (tx) patterns, abstracted adverse events (AEs) of interest (AEs chosen a priori based on what was observed in clinical studies), tx discontinuation, hospitalization, and granulocyte colony-stimulating factor (G-CSF) use were summarized using descriptive statistics. Results: Of 220 SG-treated pts (male, 73%; median age, 66 yrs), most (63%) received enfortumab vedotin (EV) monotherapy in the prior tx line. The most common AEs of interest were diarrhea (n = 110 [50%]), neutropenia (n = 77 [35%]), and nausea (n = 76 [35%]). Febrile neutropenia and infections secondary to neutropenia occurred in 18 (8%) and 9 (4%) pts, respectively (Table). Of the 220 pts, 141 (64%) had a documented reason for SG discontinuation; 106 (75%) pts discontinued due to disease progression and 19 (13%) due to AEs/toxicities. Of these latter 19 pts, 3 each (16%) discontinued due to neutropenia and fatigue. Discontinuation rate based on prespecified AEs of interest occurring during therapy was 3% (n = 7). Of the 220 pts, 62 (28%) were hospitalized due to AEs. During SG tx, 104 (47%) pts received G-CSF at any time; 64 (29%) received G-CSF primary prophylaxis. Of 79 pts with neutropenia onset during SG index line, 14 (18%) received G-CSF primary prophylaxis, 29 (37%) received secondary prophylaxis and 36 (46%) received G-CSF treatment. Conclusions: This is the largest analysis to date of SG use in a real-world population with la/mUC, with a significant number of EV-pretreated patients. Although AEs such as diarrhea, neutropenia, and nausea occurred frequently, tx discontinuation rate (based on prespecified AEs) was low. Observed AEs were consistent with the known safety profile of SG. Incident AEs of interest, n (%); (N = 220). Anemia 36 (16) Neutropenia 77 (35) Febrile neutropenia | Infections secondary to neutropenia a 18 (8) | 9 (4) Sepsis 25 (11) UTI 34 (15) Diarrhea 110 (50) Nausea | Vomiting 76 (35) | 41 (19) Stomatitis 21 (10) Fatigue 52 (24) Infusion-related reaction 1 (<1) a Prevalent numbers are reported since baseline status was not abstracted for these events.

Evaluating disparities in prostate cancer-related mortality among diabetic adults in the United States and Texas: A 21-year observational study (1999-2020).

30 Background: The prostate cancer (PCa) mortality risk with diabetes is poorly understood and understudied. We aim to study the annual trends and sociodemographic factors in prostate cancer-related mortality among diabetic individuals in the United States and its state of Texas from 1999 to 2020 to evaluate public health initiatives and offer insights for improving patient outcomes. Methods: Mortality trends in PCa among diabetic adults aged ≥25 years were analyzed using the CDC WONDER database, identifying through ICD-10 codes C61 “Prostate Malignant neoplasms” and E14 “Diabetes Mellitus”. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs, with 95% confidence intervals, were determined using joint point regression analysis across various demographic (sex, race/ethnicity, age) and geographic (state, urban-rural, regional) subgroups. Results: Between 1999 and 2020, 4477954 documented deaths were attributed to PCa associated with diabetes. The overall AAMR for PCa-related mortality in diabetic adults decreased in the US from an adjusted rate (AR) 109.8 in 1999 to (79.1) in 2018 (APC: -1.84%; 95% CI: -2.22% to -1.58%), then it increased to 100.4 in 2020 (APC: 10.4%; 95% CI: 2.97% to 13.4%). In Texas, AAMR for PCa among diabetic adults decreased from AR 125.5 in 1999 to 93.9 in 2018 (APC: -1.71%; 95% CI: -2.25% to -1.26%), after which it increased to 126.6 in 2020 (APC: 14.3%; 95% CI: 4.83% to 18.9%). The AAMR in U.S. men decreased from 166.8 in 1999 to 119.1 in 2018 (APC: -1.96%; 95%CI: -2.34% to -1.68%) and then increased to 147.7 in 2020 (APC: 9.66%; 95% CI: 2.66% to 12.7%). The non-Hispanic (NH) Black or African American (AA) population has the greatest AAMR (191.6), followed by the NH American Indian or Alaska Native (166.2) and the Hispanic or Latino population with AAMR (117.8). The lower-risk population was NH White with AAMR (87.2) and NH Asian or Pacific Islander (59.1). AAMR also varied by region (South: 116.5; Midwest: 101.2; Northeast: 95.5; West: 75.9), and non-metropolitan areas had higher AAMR (small metro: 100.6; micropolitan: 119.9; non-core areas: 124.3) than metropolitan areas (large central metropolitan: 102.2; large fringe areas: 84.8). The states in the upper 90th percentile of AAMRs were Oklahoma, Louisiana, Mississippi, Kentucky, Ohio, West Virginia, Maryland exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile i.e Nevada, Kansas, Arizona, Florida, MA, Wyoming, and Colorado. Conclusions: Mortality rates from prostate cancer among diabetic adults have risen in the United States and Texas over the past two decades. However, NH Black or AA, NH American Indian or Alaska Native, Hispanic or Latino men are at more risk than NH White and NH Asian or Pacific Islander.

EMETPRO: A multicenter, international, retrospective analysis evaluating patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) with early progression (EP).

169 Background: Combination therapies, such as androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) +/- docetaxel, were shown to improve overall survival (OS) in pts with mHSPC. However, some pts are still characterized by EP. EMETPRO study analyzed these pts and their response to treatments administered at progression. Methods: EMETPRO is a multicenter, retrospective registry of pts with EP mHSPC defined as pts who have progression ≤ 6 months (m) under combination therapies (ADT + docetaxel or ADT + ARPI) or ≤ 9 m from ADT alone start. The primary endpoint is progression-free survival (PFS) calculated from the start of first-line (1°L) treatment for mCRPC in the entire population and in the different treatments sub-cohorts based on the treatment received in mHSPC. Secondary endpoints included OS calculated from the start of treatment for mHSPC and from the start of 1°L treatment for mCRPC. Results: From May 2005 to May 2023 431 pts were enrolled in the study. Median age was 69 years. Molecular analyses were available in 195 (45.2%) pts (Table). 206 (47.8%) pts received ADT alone for mHSPC while 123 (28.6%) and 77 (17.8%) pts received ADT + docetaxel and ADT + ARPI, respectively. 80 (38.8%) and 66 (32.0%) pts treated with ADT alone in mHSPC received ARPI or docetaxel as 1°L mCRPC treatment, respectively. 77 (62.6%) and 13 (10.6%) pts treated with ADT+ docetaxel in mHSPC received ARPI or cabazitaxel in mCRPC, respectively. 46 (59.7%) and 7 (9.1%) pts treated with ADT+ ARPI in mHSPC received docetaxel or a second ARPI in mCRPC, respectively. 14 pts (3.2%) received olaparib or radioligand treatments as 1°L mCRPC therapy. The median PFS from the start of 1°L treatment for mCRPC was 6.5, 4.9, and 5.4 m for pts that received ADT, ADT + docetaxel and ADT + ARPI, respectively. The median OS from mHSPC was 27.0, 20.0, and 19.5 m, in the same groups while the median OS from 1°L treatment for mCRPC was 18.5, 12 and 14.6 m, respectively. The 1°L therapy received in the mCRPC setting and the molecular profile did not correlate with PFS or OS. Conclusions: Pts with EP mHSPC are characterized by poor outcomes regardless of treatment received at progression. The best 1°L mCRPC therapy to use in these pts remains a crucial unmet clinical need. Future studies evaluating novel mechanisms (e.g. olaparib or lutetium PSMA) or intensification strategies (e.g. cabazitaxel and/or carboplatin) in this setting are urgently needed. Baseline characteristics. Number (N°) of pts 431 GS≥8 at mHSPC, N° (%) 278 (64.5) High-volume disease (CHAARTEED), N° (%) 302 (70.1) N° of pts with germline testing results 63 Alterations detected, N° (%) 24 (38.1) BRCA alterations detected, N° (%) 13 (20.6) N° of pts with somatic testing results 181 DNA damage response and repair gene alterations, No. (%) 47 (26.0) At least one TP53/PTEN/RB1 gene mutation detected, No. (%) 84 (46.4)

Impact of upstaging from cT2a–b to pT3a on overall survival (OS) among patients with renal cell carcinoma.

601 Background: Identifying patients with renal cell carcinoma (RCC) who may benefit from adjuvant systemic therapy has proven difficult. Approximately 40% of patients with cT2a-b tumors will be upstaged to pT3a disease following surgery. These patients, given their large tumor size, may represent a higher risk cohort compared to patients with concordant T3a staging. We assessed OS among cT2a-b patients who were upstaged to pT3a compared to their cT3a counterparts with concordant pathologic staging. Methods: Using the National Cancer Database, we identified N0M0 adult patients with cT2a, cT2b, and cT3a RCC who underwent partial or radical nephrectomy and had pT3a disease on final pathology. We categorized patients into three groups: (1) cT2a to pT3a, (2) cT2b to pT3a, and (3) cT3a to pT3a. We compared OS between the groups using Kaplan Meier estimates and multivariable analysis using Cox proportional hazards models. Subgroup analysis of overall survival was performed for histology (clear cell vs non–clear cell). Results: 11,241 patients met inclusion criteria (3,067 cT2a, 1,893 cT2b, and 6,281 cT3a). Median pathological tumor size was 8.0, 11.2, and 7.5 cm for cT2a, cT2b and cT3a tumors, respectively. Mean 5-year OS was 37% for both cT2a and cT2b disease upstaged to pT3a and 48% for cT3a disease with concordant pathological staging (log rank p < 0.0001). This finding persisted on multivariable analysis (cT3a HR 0.81 [0.77–0.85], p < 0.001). Conclusions: Patients who were pathologically upstaged from cT2 to pT3a disease had worse OS compared to patients with concordant staging, a finding likely related to differences in median tumor size. Our findings imply that it is reasonable to include well-selected cT2 tumors in the next iteration of perioperative trials. However, those designing and conducting clinical trials must power their studies to adjust for heterogeneity in pathologic restaging.

Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV

Abstract Targeting host proteins that are crucial for viral replication offers a promising antiviral strategy. We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporine A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells and have high specificity for CypA confirmed by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA-targeting PROTACs inhibit viral replication potently and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.

Deep prostate-specific antigen (PSA) decline among early participants (pts) in LIBERTAS, a phase 3 study of apalutamide (APA) plus continuous versus intermittent androgen deprivation therapy (ADT) in metastatic castration-sensitive prostate cancer (mCSPC).

147 Background: LIBERTAS is investigating APA in combination with intermittent ADT as an ADT de-escalation strategy for patients with mCSPC. The objective is to evaluate whether APA + intermittent ADT in pts who achieved PSA <0.2 ng/mL after 6 mo initial treatment with APA + ADT provides noninferior radiographic progression-free survival (rPFS) and reduces hot flash burden compared with APA + continuous ADT. In the TITAN study, 54% (263/490) of pts with mCSPC treated with APA + ADT achieved PSA ≤0.2 ng/mL within 3 mo (1). Pts who also achieved PSA ≤0.02 ng/mL vs PSA >0.2 ng/mL showed better overall survival rates (2). Here, we present initial findings of pts enrolled early in LIBERTAS. Methods: LIBERTAS enrolled pts with mCSPC, inclusive of all gender identities. Eligible pts have ≤3 mo ADT prior to enrollment, except for pts receiving ADT as part of their gender-affirming care (GAC), and ECOG PS 0 or 1. Pts have metastasis documented by conventional imaging (CT, MRI, or bone scan) and/or regional lymph node metastases by next-generation imaging (NGI); pts undergoing GAC are eligible with or without evidence of metastasis by conventional imaging or NGI. In the initial 6-mo treatment phase, all pts receive APA 240 mg/d + ADT. In the main treatment phase, 240 pts with confirmed PSA <0.2 ng/mL after the initial treatment phase will be randomized 1:1 to APA 240 mg/d + intermittent or continuous ADT. Stratification: tumor volume and prior treatment for localized PC. Primary end points: rPFS, measured by 18-mo event-free survival rate, and reduction of hot flash burden, measured by the severity-adjusted hot flash score. Results: As of September 20, 2024, 420 pts at 73 sites in 9 countries have enrolled in the initial treatment phase, completing the enrollment goal ahead of schedule. Demographics include 70.5% White, 9.5%, Asian, and 8.6% Black. At baseline, pts had a median (range) age of 70 yrs (48-88) and median PSA 15.0 ng/mL (0.02-6000 ng/mL). At data cutoff, 87 pts had been randomized to the main treatment phase. Among 350 pts with at least 2 evaluable PSA values collected during the initial treatment phase, 246 (70.3%) achieved PSA <0.2 ng/mL and 307 (87.7%) experienced ≥90% PSA decline from baseline at some point during the initial treatment phase. Hot flash compliance, defined as the percentage of data collected per protocol across all sites and visits, exceeded 80%. No new safety signals were observed. Conclusions: Treatment with 6 mo of APA + ADT in this prospective trial resulted in deep PSA responses in the majority of pts with mCSPC. The LIBERTAS study remains on track for successful completion of expected randomization for the standard APA + ADT vs APA + ADT de-escalation. 1. Chowdhury, Ann Oncol 2023. 2. Merseburger, BJU Int 2024. Clinical trial information: NCT05884398 .

Efficacy and safety of tislelizumab (T) combined with gemcitabine and cisplatin (GC) for patients with localized muscle-invasive bladder cancer (MIBC) after radical transurethral resection of bladder tumor/partial cystectomy: A prospective, phase II study.

784 Background: Transurethral resection of bladder tumor (TURBT) combined with concurrent chemoradiotherapy is the standard treatment for bladder preservation in MIBC. TURBT alone and partial cystectomy are only suitable for selected patients with solitary tumors, T2, and tumors in the bladder diverticulum while patients could have tumor recurrence after surgery. This prospective phase II study aims to explore the efficacy and safety of T combined with GC after radical TURBT or partial cystectomy as bladder preservation therapy in patients with PD-L1 positive MIBC. Methods: Eligible patients had clinical stage T2-T3N0M0, histologically confirmed PD-L1 positive urothelial carcinoma, no prior systemic treatment, and no residual tumor after radical TURBT or partial cystectomy. Patients received T combined with GC within 8 weeks of local treatment (G 1000mg/m2, d1, d8; C 70mg/m2, d1, IV, q3w, for a total of 6 cycles. T 200mg, d8, IV, q3w, for a total of 8 cycles). The primary endpoint was 1-year bladder intact disease-free survival rate. Secondary endpoints included 2-year bladder intact disease-free survival rate, metastasis-free survival, time to salvage cystectomy, overall survival, and safety. Results: From August 2022 to October 2024, a total of 13 patients were enrolled in the study. Median age was 70 years (65-75). Twelve patients were staged as pT2 and 1 patient had pT3. Twelve patients were evaluable for efficacy and 1 patient withdrew the consent. Seven patients underwent TURBT and 5 patients underwent partial cystectomy. Median follow-up time was 8.0 months. One patient had non-muscle-invasive bladder cancer recurrence and receive intravesical BCG instillation while the remains had no recurrence of disease. 1-year bladder-intact disease-free survival rate was 100%. Grade 3 or higher adverse events occurred in 33.3% of patients. No new safety signals were observed. Conclusions: The study demonstrated that combination of T and GC after complete resection of tumor seemed promising as bladder preservation strategy in selected patients. Further recruitment is ongoing. Clinical trial information: NCT05401279 .

Frailty and adverse clinical outcomes in prostate cancer patients: An analysis from the RADICAL-PC cohort.

80 Background: As a disease of older individuals, prostate cancer (PC) may feature physical frailty. Most related studies are retrospective and focus on short-term surgical outcomes. Methods: We conductedan analysis of a prospective study of PC patients either diagnosed within the past year, treated with androgen deprivation therapy (ADT) for the first time within the past six months, or scheduled to initiate ADT within a month . Frailty was assessed using Fried's criteria which includes five domains [Handgrip strength, gait speed, physical activity, unintentional weight loss (>4 kg/year) and exhaustion (≥3 days/week)]. Patients were classified as frail (≥3 criteria), pre-frail (1-2 criteria), or robust (0 criteria). Participants were followed annually to ascertain the occurrence of mortality, new metastases, major adverse cardiovascular events (MACE: myocardial infarction, stroke, cardiovascular death, stroke, heart failure, peripheral arterial disease, venous thromboembolism or arterial revascularization) and hospitalization. The relationship between frailty and these events was evaluated by Cox proportional hazards models adjusted for age at enrolment, education, race, tobacco and alcohol use, diabetes, past history of cardiovascular disease, estimated glomerular filtration rate, PC risk, metastatic disease and ADT exposure. Results: We studied 4304 participants (mean age 69±8 years) from 9 countries: 1429 (33%) were robust, 2394 (56%) pre-frail and 481 (11%), frail. During a median 2.4 years, 336 (8%) died, 161 (4%) died from PC or developed new metastases, 506 (12%) were hospitalized and 262 (6%) experienced MACE. Being prefrail or frail was associated with a higher risk of death, hospitalization and MACE but not PC death or new metastases (Table). Conclusions: Pre-frailty and frailty are common among patients with PC. Frailty is associated with approximately a two-fold increase in mortality, hospitalization or MACE in PC patients independent of a wide range of prognostic factors. Relationship between frailty and clinical outcomes. Characteristic Death Hospitalization PC death or new metastases MACE Hazard ratio (95% confidence interval) p-value Hazard ratio (95% confidence interval) p-value Hazard ratio (95% confidence interval) p-value Hazard ratio (95% confidence interval) p-value Frailty Robust Pre-frail Frail Ref1.54(1.13-2.00)2.90(2.00-4.21) 0.007<0.001 Ref1.39(1.10-1.74)2.29(1.70-3.09) 0.005<0.001 Ref1.05(0.70-1.57)1.47(0.85-2.52) 0.830.17 Ref1.44(1.05-1.97)2.21(1.46-3.34) 0.023<0.001 Estimates are from Cox proportional hazards models adjusted for age at enrolment, education, race, tobacco and alcohol use, diabetes, past history of cardiovascular disease, estimated glomerular filtration rate, PC risk, metastatic disease and ADT exposure.

Reflexive paired somatic and germline testing at time of medical oncology referral in mCSPC: Impact on timely treatment.

62 Background: Use of PARP inhibitors (PARPi) improves outcomes in patients with metastatic castrate-resistant prostate cancer (mCRPC) harboring germline or somatic homologous recombination repair (HRR) mutations. To ensure timely PARPi initiation, genetic results should be available at castrate resistance, with testing initiated in the metastatic castration-sensitive (mCSPC) setting. Relying on ad hoc, provider-initiated testing risks biomarker unavailability when treatment decisions are made, leading to suboptimal therapies. This study evaluates a program of reflexive paired germline and tumor testing for mCSPC patients at medical oncology referral (typically following initial management and androgen deprivation therapy [ADT] by urology or radiation oncology) as a potentially effective time point for genetic testing. Methods: This was a single cancer centre, retrospective review of mCSPC patients offered simultaneous germline and tumor tissue next-generation sequencing at medical oncology referral. We examined test completion rates, timing of results relative to key disease timepoints (ADT initiation, first-line mCRPC treatment), and the frequency of detected pathogenic mutations. Timing of results was analyzed separately for all patients, those with HRR mutations, and those with timely referrals to medical oncology, defined as <90 days from ADT start. Results: Of 218 mCSPC patients, 212 (97.2%) completed germline or tumor tissue sequencing with interpretable results from at least one assay. Germline results were obtained in 171 patients (78.4%) and tumor tissue results in 194 (88.9%). HRR mutations were detected in 29 patients (13.3%): 15 germline, 10 somatic, and 4 of unknown origin. Median time from ADT initiation to germline and tumor tissue genetic results was 165 and 120 days, respectively. Germline results were available for 144 patients (84.2%) and tumor tissue results for 176 (90.7%) before initiation of first-line mCRPC treatment. Among the 29 patients with identified HRR mutations, 19 (76%) had germline results and 17 (81%) had tumor tissue results before first-line mCRPC treatment. In the subgroup of 175 patients referred to medical oncology within 90 days of ADT initiation, 136 patients (98.6%) had germline results and 148 (99.3%) had tumor tissue results before first-line mCRPC treatment. Conclusions: Reflexive paired genetic testing at medical oncology referral is effective in identifying HRR mutations and optimizing PARPi use based on current mCRPC indications. Ensuring timely patient identification through clear and accessible genetic testing pathways will help maximize therapeutic options for patients with advanced prostate cancer. If PARPi or other targeted agents demonstrate benefit in earlier disease states, this process may need to be shifted further upstream, requiring close multidisciplinary collaboration.

A cosmogenic 10Be anomaly during the late Miocene as independent time marker for marine archives

Abstract Cosmogenic nuclide dating relies on the constancy of production and incorporation of radionuclides in geological archives. Anomalous deviations from constancy during the Holocene or Pleistocene are frequently used as global benchmarks to harmonize different data sets. A similar dating anchor on the million year timescale was so far not presented. In this work, we report on a prolonged cosmogenic 10Be anomaly during the late Miocene recorded in several Central and Northern Pacific deep-ocean ferromanganese crusts in the time period 9–11.5 Myr ago peaking at 10.1 Myr. Potential origins of this anomaly are discussed in the light of geological, climatic, solar and astrophysical events. This anomaly has the potential to be an independent time marker for marine archives.

PERSIAN trial: Early results from a randomized phase II trial testing apalutamide and stereotactic body radiation therapy for low-burden, metastatic, hormone-sensitive prostate cancer.

160 Background: Apalutamide+androgen deprivation therapy (ADT) showed to significantly improve overall survival in low and high volume metastatic hormone sensitive prostate cancer (mHSPC) if compared to ADT alone. However, a randomized phase II trial (ARTO, NCT03449719) suggested that stereotactic body radiotherapy (SBRT) improved clinical outcomes when administered concomitantly with abiraterone acetate in metastatic castration resistance prostate cancer (mCRPC). Nonetheless, evidence related to use of SBRT in addition to androgen receptor pathway inhibitors (ARPIs) in oligometastatic HSPC is currently lacking. PERSIAN trial is aimed to test the hypothesis that metastases directed SBRT will improve outcomes in selected subgroups of patients with oligometastatic mHSPC treated with apalutamide + ADT. Methods: PERSIAN NCT05717660 is a phase II randomized trial enrolling patients affected by metachronous oligometastatic HSPC. Patients with de novo metastatic disease or with > 5 distant metastases are excluded from the trial. All patients are randomized to standard of care with apalutamide+ADT (ARM A: Control) or the same systemic treatment combined with SBRT on all sites of metastatic disease evidenced on conventional imaging (ARM B: Treatment). Here is presented the first interim analysis focused on rate of complete biochemical response (PSA < 0.2 ng/ml) after 3 months since apalutamide + ADT start. Results: Up to date, 174 patients have been enrolled (96.6% of the target sample size), 87 of these reached a minimum follow up of 3 months. Rate of patients with a complete biochemical response was 91.1% vs 92.9% in the control vs treatment arm, respectively (OR 1.27, 95% CI 0.27-6.03, p=0.765). Patients with PSMA positive lesions undetected on conventional imaging vs patients in whom number of target lesions was consistent on conventional and PSMA imaging had similar results (OR 0.74, 95%CI 0.08-6.94, p=0.791). Presence of bone metastatic lesions did not influence rate of complete biochemical response (OR 1.39, 95%CI 0.29-6.67, p-value 0.678). When adjusted for number of lesions, a significant benefit in favour of experimental arm was detected for patients with <3 metastatic sites (OR 5.88, 95%CI 1.13-33.3, p=0.03). Conclusions: Rate of early complete biochemical response showed a non significant trend in favour of experimental arm, with a 27% odds increase in the overall population for patients undergoing SBRT. Clinical benefit of SBRT is significantly improved in patients with lower burden of disease (<3 metastatic lesions). Trial accrual will be completed within the end of 2024, early results about complete biochemical response at 6 months in the complete cohort will be available in the second half of 2025. Clinical trial information: NCT03449719 .

Evaluating an integrated germline polygenic and clinical risk model (P-CARE) specifically for aggressive prostate cancer.

237 Background: Polygenic scores are strongly associated with age at diagnosis of prostate cancer (PCa) but have not been clearly shown to discriminate between indolent and aggressive PCa. P-CARE (Prostate CAncer integrated Risk Evaluation) is an integrated model that combines a 601-variant polygenic hazard score (PHS601), genetic ancestry, and family history. We hypothesize that among men diagnosed with PCa, those with higher P-CARE scores are more likely to develop metastatic disease. Methods: We analyzed genetic and phenotypic data from a diverse, national cohort of men diagnosed with PCa (Million Veteran Program, n=69,901, 6413 metastatic). We used Cox proportional hazards models to test P-CARE and PHS601 for association with age at onset of metastatic PCa (birth-met analysis). We also tested P-CARE for association with metastasis-free survival after diagnosis of localized PCa, with or without accounting for PSA, stage, and age at diagnosis (localized-met analysis). PCa was detected/treated too late if the patient had definitive treatment for localized disease but developed metastasis. Thus, onset of metastasis was time of first treatment or diagnosis of metastasis, whichever occurred first. Participants who never experienced metastasis were censored at time of first treatment or last follow-up/death.We repeated this analysis within men with African genetic ancestry (n=16,889). Confidence intervals for hazard ratios (HR) were estimated using 100-fold bootstrapping. For external validation of direction of effect, we tested P-CARE for association with age at diagnosis of clinically significant PCa in cohorts from the PRACTICAL Consortium (Cohort of Swedish Men [COSM, n=2163], ProtecT [n=1583]). Results: P-CARE was associated with birth-met and localized-met in the full MVP cohort and among men with African ancestry. In the full cohort, patients in the highest 20% of P-CARE (based on percentiles of men of European ancestry with PCa) compared with the lowest 20% had a HR (HR 80/20 ) of 1.58 [95% CI 1.48–1.68] and 1.32 [1.23–1.40] for birth-met and localized-met, respectively. The corresponding HR 80/20 values for PHS601 alone were 1.29 [1.20–1.37] and 1.16 [1.07–1.25]. When accounting for PSA, stage, and age at diagnosis, P-CARE HR 80/20 was 1.05 [0.99-1.11] for localized-met. Among men with African ancestry, HR 80/20 was 1.43 [1.26–1.62] and 1.17 [1.03–1.34] for birth-met and localized-met, respectively. Within the PRACTICAL cohorts, P-CARE was associated with development of clinically significant PCa (COSM: 1.33 [1.16–1.57], ProtecT: 1.67 [1.34–2.10]). Conclusions: Among men diagnosed with PCa, P-CARE and PHS601 are moderately specific for metastatic disease. We are currently studying P-CARE in ProGRESS (ClinicalTrials.gov ID NCT05926102), a nationwide randomized clinical trial to evaluate precision PCa screening in the VA healthcare system.

A phase 2 study of neoadjuvant PARP inhibition followed by radical prostatectomy (RP) in patients with unfavorable intermediate-risk or high-risk prostate cancer with <i>BRCA1/2</i> gene alterations (NePtune).

TPS430 Background: Patients with localized high-risk prostate cancer face an elevated risk of recurrence after radical prostatectomy (RP). Approximately 6% of these patients carry germline mutations in DNA repair pathways, most commonly involving BRCA1/2 genes. These mutations are linked to more aggressive disease, a higher likelihood of distant metastasis, and worse survival outcomes compared to those without them. Olaparib, a PARP inhibitor, has improved overall survival in metastatic castration-resistant prostate cancer with BRCA1/2 germline or somatic mutations. Additionally, olaparib has shown efficacy as adjuvant therapy in improving invasive disease-free survival in patients with germline BRCA1/2 mutations and HER2-negative breast cancer. Multimodal treatment strategies for high-risk localized prostate cancer patients with BRCA1/2 mutations, whether germline or somatic, may improve clinical outcomes. Methods: We initiated a multicenter, phase 2, single-arm study to evaluate neoadjuvant olaparib combined with an LHRH agonist for 6 months, followed by radical prostatectomy (RP). Eligible patients include those with a Gleason score ≥4+3=7, PSA &gt;20 ng/mL, or T3 disease (determined by DRE or prostate MRI) with lymph nodes &lt;20 mm. Patients with intraductal carcinoma are eligible regardless of Gleason score, PSA level, or T stage. All participants must have germline or somatic BRCA1/2 pathogenic or likely pathogenic alterations identified through standard of care molecular profiling. Eligible patients will receive olaparib 300 mg orally twice daily along with an LHRH agonist for 6 months before undergoing RP. The primary endpoint is the rate of pathologic complete response (pCR) or minimal residual disease (MRD, defined as tumor ≤5 mm) as assessed by central pathology review. Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, time to testosterone recovery, and safety. Exploratory endpoints include quality of life assessments, the proportion of downstaging observed on multiparametric MRI (mpMRI), correlation of mpMRI findings with pathologic response, and tissue-based molecular predictors of response and resistance. Sample size was calculated using a Binomial Exact test to evaluate the null hypothesis of a pCR/MRD rate ≤10% at a one-sided 5% significance level. Assuming an observed rate of ≥32.5% in this study, to conclude that the pCR/MRD rate is above 10% with 90% power, a total of 30 patients will be enrolled. At least 7 responses are needed to reject the null hypothesis. This trial is enrolling through the Hoosier Cancer Research Network, with active sites at the University of California San Diego, University of Pennsylvania, Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, Columbia University, and the University of Buffalo. Clinical trial information: NCT05498272 .

Impact of pre-existing diabetes mellitus on acute care use in older patients with metastatic prostate cancer on androgen receptor signaling inhibitors.

119 Background: Androgen receptor signaling inhibitors (ARSIs) are mainstay treatments for metastatic prostate cancer. Hyperglycemia is a common side effect but limited data exists on outcomes such as hospitalizations in patients with diabetes mellitus (DM) starting on ARSIs. Methods: We used the SEER-Medicare linked data for patients aged 66 and older with de novo metastatic prostate cancer who were prescribed abiraterone, enzalutamide, or apalutamide per part D files from 2011 to 2019. Eligible patients had continuous Medicare Part A/ B coverage before and after drug initiation, and Part D coverage before initiation. Patients were excluded if they died within 6 months of diagnosis or received chemotherapy prior to ARSI (&lt;1%). Univariate associations between covariates and DM were assessed using chi-square tests or t-tests. Negative binomial regression was used to calculate incidence rate ratios of acute care use (total number of hospital or emergency admissions divided by total time at risk) for each model covariate among DM and non-DM patients after initiation of ARSI. Results: 2697 patients met eligibility criteria, of which 17.4% (469) had DM. The average age of the cohort was 75.0 years ±7.0 SD. 85.3% (2300) of patients received androgen deprivation therapy (ADT) prior to ARSI, and 0.9% (24) received ADT afterwards. 28.3% (773) of patients received abiraterone only, 23.8% (641) received only enzalutamide or apalutamide, and 47.6% (1283) received both treatments. Patients with DM (vs without) differed significantly with regards to lower high school education, higher NCI comorbidity score (excluding DM), and less receipt of abiraterone, but not in age, race, marital status, prior ADT treatment, or receipt of enzalutamide or apalutamide. 29.5% (797) of patients had acute care use within 6 months, with 39.9% (187) in the DM group and 27.4% (610) in the non-DM group ( p &lt;.0001), Adjusted for covariates, patients with DM had a 41% increased rate of acute care use ( p =0.0016) compared to those without DM. Additionally, compared to those prescribed only enzalutamide or apalutamide, patients prescribed abiraterone had a 47% increased rate of acute care use ( p =0.0026); this was independent of having DM (interaction p =0.77). Conclusions: Patients with pre-existing DM on ARSIs experienced higher rates of acute care use compared to those without DM, regardless of ARSI type. Future studies should assess potential interventions in older patients with diabetes on ARSIs, such as close monitoring of glycemic status or adherence to risk reduction medications.

Laser-driven proton acceleration beyond 100 MeV by radiation pressure and Coulomb repulsion in a conduction-restricted plasma

KEYMAKER-U03 Substudy 03B: Pembrolizumab (pembro) and targeted therapy combinations for advanced clear cell renal cell carcinoma (ccRCC).

440 Background: The phase 1/2 KEYMAKER-U03 Substudy 03B (NCT04626518) is being conducted to evaluate combination treatments for previously treated advanced ccRCC. We present results for targeted therapy–containing regimens from arm B4 (pembro + belzutifan [HIF-2α inhibitor]), arm B5 (lenvatinib [VEGF-TKI] + belzutifan), and the reference (ref) arm (pembro + lenvatinib). Methods: Adults with histologically confirmed locally advanced/metastatic ccRCC and disease progression on or after PD-(L)1 inhibitor and VEGF-TKI treatment were randomly assigned 1:1 to arms open for enrollment. Arms B4 and B5 had a safety lead-in phase where ~10 patients (pts) were initially enrolled before randomization. Treatment doses were pembro 400 mg IV Q6W + belzutifan 120 mg PO QD (arm B4), lenvatinib 20 mg PO QD + belzutifan 120 mg PO QD (arm B5), or pembro 400 mg IV Q6W + lenvatinib 20 mg PO QD (ref arm). Primary end points were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DOR, clinical benefit rate (CBR; CR + PR + SD ≥6 months), and PFS per RECIST v1.1 by BICR, and OS. Efficacy was evaluated in all enrolled (allocated and randomized) pts; safety was evaluated in all pts who received ≥1 dose of treatment. No formal comparisons across arms occurred. Enrollment was planned for 50 pts in each arm, although enrollment would be stopped if the 6-mo PFS rate was ≤40%. Results: Overall, 62 pts were assigned to arm B4, 64 to arm B5, and 73 to the ref arm. Median (range) follow-up was 16.6 mo (6.5-38.7) in arm B4, 17.6 mo (6.5-35.9) in arm B5, and 19.4 mo (6.7-33.2) in the ref arm. Efficacy is reported in the table. Grade 3-5 treatment-related AEs (TRAEs) occurred in 26/62 pts (42%) in arm B4, 38/63 pts (60%) in arm B5, and 36/73 pts (49%) in the ref arm. TRAEs led to death in 2 pts in arm B5 (cerebral hemorrhage and intracranial hemorrhage) and 1 pt in the ref arm (esophageal perforation). Conclusions: Lenvatinib + belzutifan (arm B5) exhibited durable antitumor activity and a safety profile consistent with the individual profiles of the drugs. Results from Substudy-03B support further investigation of lenvatinib + belzutifan combination for pts with advanced RCC, as in LITESPARK-011. Clinical trial information: NCT04626518 . Arm B4Pembro + belzutifann = 62 Arm B5Lenvatinib + belzutifann = 64 Ref armPembro + lenvatinibn = 73 ORR (95% CI), % 19 (10-31) 47 (34-60) 40 (29-52) CR, n (%) 2 (3) 1 (2) 0 (0) PR, n (%) 10 (16) 29 (45) 29 (40) CBR (95% CI), % 32 (21-45) 59 (46-72) 58 (45-69) DOR, median (range), mo Not reached (1.4+-33.0+) 22.1 (1.4+-32.8+) 8.3 (2.6+-25.6+) PFS, median (95% CI), mo 5.4 (2.8-6.9) 12.5 (5.9-26.3) 9.4 (6.9-11.2) 6-mo PFS rate, % 42 63 67 OS, median (95% CI), mo 27.4 (12.6-not reached) 32.3 (22.4-not reached) Not reached (21.8-not reached) 12-mo OS rate, % 68 80 82

Racial disparities in secondary metastasis in patients with bladder cancer: A 5-year National Inpatient Sample study.

671 Background: Bladder cancer is one of the most common cancers globally, with significant variations in disease outcomes observed across racial groups. Secondary metastasis plays a critical role in determining disease prognosis and overall survival in bladder cancer patients. However, racial disparities in the metastatic progression of bladder cancer remain underexplored. This study aims to investigate how race influences the patterns of metastasis in bladder cancer patients using a large national database. Methods: A retrospective analysis of the National Inpatient Sample (NIS) from 2016 to 2020 was performed to identify adults diagnosed with bladder cancer using ICD-10 codes. Patients were categorized based on the presence of metastasis. Multivariable logistic regression models were used to assess the impact of race on secondary metastasis to key organ systems, including the lung, liver, bone, and brain, while adjusting for potential confounders. Caucasians were used as the reference group, and statistical significance was defined as p-values ≤ 0.05. Results: The study cohort included 411,360 patients with bladder cancer, of whom 66,805 (16.2%) had secondary metastasis. The mean age of patients with metastasis was significantly lower (71.00 years, 95% CI: 70.78–71.22) compared to those without metastasis (74.02 years, 95% CI: 73.90–74.14) (p &lt; 0.001). Racial disparities were observed, with African American patients having higher odds of lung metastasis (OR 1.23, 95% CI: 1.11–1.38, p &lt; 0.001) and liver metastasis (OR 1.18, 95% CI: 1.05–1.33, p = 0.005). Asian patients were more likely to develop bone metastasis (OR 1.29, 95% CI: 1.13–1.47, p &lt; 0.001) and brain metastasis (OR 1.46, 95% CI: 1.03–2.09, p = 0.036). Other factors associated with higher metastasis risk included radiation therapy (OR 3.71, 95% CI: 2.16–6.38, p &lt; 0.001), while comorbidities like diabetes (OR 0.64, p &lt; 0.001) and hypertension (OR 0.86, p &lt; 0.001) were associated with lower odds of metastasis. Conclusions: This study highlights significant racial disparities in the metastatic progression of bladder cancer, with African American and Asian patients showing higher odds of metastasis to key organ systems compared to Caucasians. These findings underscore the need to consider racial differences in the clinical management and treatment strategies for bladder cancer patients. Further research is required to explore the underlying causes of these disparities and their impact on long-term survival.

Evaluating the efficacy of cabozantinib in patients with advanced renal cell carcinoma with bone metastasis: An open-label phase 2 study.

535 Background: Bone metastasis negatively impacts patients with advanced renal cell carcinoma (aRCC), leading to poor prognosis and quality of life. Some tyrosine kinase inhibitors, including cabozantinib, have been used as standard care for aRCC. However, there have been no reports demonstrating the effects of cabozantinib on bone metastasis. Here, we report the clinical effects of cabozantinib on bone metastasis in patients with aRCC. Methods: Patients with aRCC who had at least one measurable bone target lesion were enrolled. Patients received cabozantinib 60 mg once daily until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) of bone target lesions based on independent review committee (IRC) assessment using the MD Anderson Cancer Center (MDA) criteria, which are the response criteria specific to bone metastases. Key secondary endpoints included disease control rate (DCR), bone metastasis-free survival (BMFS), progression-free survival (PFS), overall survival (OS), frequency of symptomatic skeletal events (SSE) and safety. Results: In total, 31 patients were enrolled, with a median age of 70.0 years, and most patients (77.4%) had a history of systemic treatments for aRCC. All patients had bone metastasis. The ORR of bone target lesions by IRC-assessed MDA criteria was 6.5% (90% CI: 1.2–18.9), with a disease control rate (DCR) of 90.3% (90% CI: 76.8–97.3). No progressive disease was observed. The median BMFS was not reached (95% CI: 11.5–NR). The median PFS and OS were 11.9 (95% CI: 5.7–NR) months and 24.9 (95% CI: 19.1–NR) months, respectively. Three patients (9.7%) experienced SSE. No new safety concerns were identified. Conclusions: Cabozantinib demonstrated favorable clinical effects on bone metastasis in patients with aRCC, as suggested by a high DCR. Our results may provide useful insights for selecting optimal treatments for the management of aRCC with bone metastasis. Clinical trial information: jRCTs031210220 .

<i>FGD1</i> splice variants as predictors of brain and bone metastatic organotropism in clear cell renal cell carcinoma.

577 Background: Approximately 30% of patients with ccRCC present with metastatic disease (stage IV) and close to half of patients with stage III disease will recur during follow-up surveillance. Two of the most common and morbid sites of metastatic development are brain and bone metastasis. Existing treatment guidelines do not recommend routine brain or bone directed imaging during either initial staging or surveillance in the absence of clinical signs or symptoms. A group of recurrently altered aberrant splice variants in primary ccRCC tumors associated with metastatic progression have previously been identified. Our study aims to investigate metastatic organotropism of the FGD1 -splice variant ( FGD1 -SV) to refine risk stratification and therapeutic decision-making as cabozantinib is drug with activity at these disease sites. Methods: This study leveraged the ORIEN AVATAR network, a data-sharing alliance of 18 NCI-designated cancer centers, to evaluate the presence of FGD1 -SV in a cohort of 1,001 clear cell renal cell carcinoma (ccRCC) patients using bulk RNA-sequencing (RNA-seq). Samples with three or more FGD1 -SV reads were classified as positive. Clinical and survival data were collected, and Kaplan-Meier curves were generated. Odds ratios (ORs) evaluated the presence of FGD1 -SV on brain and bone metastases, while hazard ratios (HRs) assessed association with cabozantinib response. Of 1,037 RNA-seq samples, 84 were metastatic tumor specimens. The relationship between FGD1 -SV positivity and metastasis to common sites was assessed with Fisher's exact test. Results: Brain and bone metastases demonstrated the highest FGD1 -SV positivity (50% and 44%, respectively). A grouped comparison of brain and bone metastases versus all other common metastatic sites (adrenal, lymph node, pancreas, lung, and liver) revealed significant enrichment of FGD1 -SV in these metastases (OR 5.33, 95% CI [1.64 - 18.42], p=0.002). FGD1 -SV positivity in primary tumors was associated with greater risk of recurrence after surgical resection (p=0.0029). Furthermore, FGD1 -SV positive tumors were associated with poor survival when not treated with cabozantinib (HR 2.04, 95% CI [1.20 - 3.45], p=0.01). Conclusions: FGD1 -SV positivity is significantly associated with brain and bone metastatic organotropism in ccRCC. Our findings warrant prospective studies to validate these results and investigate the integration of FGD1 -SV into clinical decision-making, potentially guiding surveillance and therapeutic approaches in high-risk and metastatic patients.