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Variants of unknown significance (VUS) in DNA repair genes in Caucasian men with muscle invasive bladder cancer (MIBC): A case of “serendipity” pushing for a BC screening program.

683 Background: In 2021 we started an enhanced PCa screening in healthy Caucasian men with germline DNA repair pathogenic variants. Over 109 enrolled men, we found two naïve patients with bladder cancer (BC), but none with PCa. This observation prompted us to investigate the prevalence of germline pathogenic variants in patients with BC and suggest genetic counselling, testing and screening for healthy relatives of subject with BC. Methods: This is a prospective ongoing study aiming to detect, by exome analysis, the prevalence of germline pathogenic (PV), likely pathogenic (LPV) variants and variant of unknown significance (VUS) in patients with BC attending the urological department from January 2024. The following DNA repair genes were considered: ATM , ATR , MRE11A , BAP1 , BARD1 , BRCA1 , NBN , BRCA2 , PALB2 , BRIP1 , CHEK2 , RAD51C , FAM175A , RAD51D , GEN1 , and XRCC1 , plus mismatch repair genes MLH1 , PMS2 , MSH2 , and MSH6 . Healthy relatives (>35 years) of patients tested positive, are being offered genetic counselling, testing and finally screening for early detection of BC. Screening consists of urine analysis, urine cytology, ultrasound abdominal assessment and cystoscopy, when indicated, every year. The study is financed/supported by Associazione Italiana per la Ricerca sul Cancro (AIRC): Protocol ICH-2812, code IG 2020-ID-25027. Results: From January to March 2024, 41 patients with BC (25 non-muscle invasive, NMIBC and 16 muscle invasive, MIBC) were tested. Overall, we found 919 variants in the 20 DNA repair genes analysed, of which 385 rare (minor allele frequency <1%). No PV and LPV were identified, while 18 VUS were found in 12 patients (29.3%; mean age 66.75 SD 11.75 vs. 69.82 SD 13.71 in negative).The reported variants affected the following genes: ATM (4); ATR (3); BARD1 (3); PMS2 (2), and BRCA2 , CHEK2 , MSH6 , NBN , PALB2 , GEN1 (1 variant each). Interestingly, all variants were found in MIBC patients or HG-NMIBC, whereas no variant was observed in low-grade NMIBC (p< 0.00001, Fisher exact test). Patients with multiple variants had a significant lower age: mean age 58.16 SD 9.02 p<0.01. Conclusions: According to Merriam-Webster dictionary “serendipity” is the phenomenon of finding valuable or agreeable things not sought for. Starting from a PCa screening in healthy men, although no clearly pathogenic variants were identified in our BC cohort, we found the presence of about 30% of VUS linked to aggressive cancers and patient low age. Those findings challenge the current (no)recommendation on genetic counselling and testing in this setting and strongly support the urgent need to raise awareness of genetic risk for BC and to design effective public health promotion policies.

Safety and efficacy of neoadjuvant immunotherapy with durvalumab (MEDI 4736) in combination with neoadjuvant chemotherapy (gemcitabine/cisplatin or carboplatin) in patients with operable high-risk upper tract urothelial carcinoma.

661 Background: Most patients following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) face a poor prognosis. Combination of chemotherapy and immunotherapy in neoadjuvant setting have demonstrated survival improvement in several tumors. Additional systemic therapy in a neoadjuvant setting may prolong survival for UTUC patients, especially those after RNU who are ineligible to receive nephrotoxic chemotherapy. Methods: Phase 2 clinical trial (NCT04617756) was conducted in 10 French centers. Eligible patients had non metastatic, high-grade disease on ureteroscopic tumor biopsy or on urine cytology and infiltrative aspect of renal pelvis/ureteral wall on CT imaging. Subjects received a combination of: Durvalumab/Gemcitabine/Cisplatin (cohort 1) or Carboplatin (cohort 2) every 3 weeks for a total of 4 cycles based on glomerular filtration rate, prior to RNU. The primary objective was to assess the pathological complete response (ypT0) rate (pCR) of each combination. Results: A total of 50 patients were enrolledbetween 2021 and 2023 (31 in cohort 1 and 19 in cohort 2). Median age was 66 years old (range 38-79), 58% were males. 90% of patients (44) received 4 cycles of treatment, 3 patients 3 cycles and 2 patients received 2 cycles. Five patients switched for carboplatin during chemotherapy. We observed in cohort 1 : 20/31 (65%) patients with non infiltrative residual tumor; In cohort 2 : 9/19 (42%) patients (table). Secondary endpoint was safety, no immunotherapy-mediated AE was observed, 2 patients had Grade 3 neutropenia, 1 grade 4, 1 patient had grade 3 thrombopenia and 1 grade 3 anemia. Conclusions: Combination of durvalumab with platin-based chemotherapy, especially cisplatin, showed promising activity in UTUC, with the occurrence of complete responses and a high rate of non-infiltrative residual tumor. Safety profile was secure without increasing surgical risk. A randomized Phase 3 controlled study comparing neoadjuvant chemotherapy with chemotherapy combined with immunotherapy in patients with high-risk localized UTUC (iNDUCT-3) will open soon to validate these encouraging results. Clinical trial information: NCT04617756 . Pathological response rate. ypT0 ypTIS /ypTa ypT1 ypT2 ypT3 ypT4 Missing data Withdrawal surgery Total Cis-Gem Durva 4 (13%) 5 (16%) 11 (36%) 1 (3%) 6 (19%) 1 (3%) 1 2 31 Carbo-Gem Durva 1 (5%) 6 (32%) 1 (5%) 3 (16%) 5 (26%) 1 (5%) 1 1 19

T suppression and recovery with AAP after early discontinuation of LHRH-A in high-risk localized (HRL), lymph node-positive (N+), or oligometastatic (OM) prostate cancer (PC).

55 Background: Intensified androgen deprivation therapy (iADT) with the addition of abiraterone acetate + prednisone (AAP) to a luteinizing hormone releasing hormone agonist or antagonist (LHRH-A) is commonly used in conjunction with radiation therapy for HRL, N+ or OM hormone-sensitive PC. However, prolonged LHRH-A has been associated with delayed or incomplete testosterone (T) recovery after discontinuation (dc). As AAP monotherapy leads to castrate T, we investigated T kinetics with early discontinuation of LHRH-A when given in combination with AAP. Methods: The Dana-Farber/Harvard Cancer Center (DF/HCC) Oncology Data Retrieval System (OncDRS) was queried to identify patients (pts) planned to receive 18-24 mo of AAP for HRL, N+ or OM PC. Pts who previously received AAP for > 12 mo, with baseline T <150 ng/dl, received AAP for castration-resistant PC, received AAP >30 mo, or LHRH-A dc > 3 mo after AAP were excluded. T values at AAP end of treatment (EOT) and at each clinical follow up visit were tabulated to assess time to T recovery (TTR) to ≥150 ng/dl in pts with LHRH-A dc ≤3 mo, 3-12 mo and ≥12 mo prior to AAP EOT. Gray’s competing risk regression model was applied to assess the relationship between TTR and time between LHRH-A dc and AAP EOT. Results: The OncDRS query returned 350 pts, 105 meeting eligibility criteria with available T follow up after AAP EOT. 99 of 105 pts had available T at EOT, 99/99 (100%) with T < 20 ng/dl across the three groups. TTR was statistically significantly shorter for pts with LHRH-A dc ≥12 months prior to AAP EOT (median 3.2 mo [95% CI 1.8, 4.1]) compared to ≤3 mo prior to LHRH-A dc (median 20.0 mo [9.0, 27.6]) with all T recovery events within 6 months of EOT in the former group (Table). Conclusions: In this real-world cohort, early discontinuation of LHRH-A when given in combination with AAP led to ongoing T suppression while on AAP and shorter TTR after AAP EOT. This strategy warrants consideration when iADT is indicated but the patient seeks rapid and reliable T recovery after completion of treatment for the actual duration of T suppression desired. DF/HCC protocol # 23-322. TTR outcome summary. Timing of discontinuation of LHRH-A ≥ 12 months (N=13) 3 – 12 months (N=36) ≤ 3 months (N=56) No. T recovery events 10 26 26 No. competing events* 0 1 6 6-month cumulative TTR rate (95% CI) 82% (38%, 96%) 39% (23%, 55%) 15% (6.8%, 26%) 12-month cumulative TTR rate (95% CI) 82% (38%, 96%) 64% (46%, 78%) 39% (25%, 52%) Median (95%), month 3.2 (1.8, 4.1) 7.5 (3.7, 15.5) 20.0 (9.0, 27.6) Hazard ratio (95% CI) ref 0.40 (0.16, 1.02) 0.20 (0.08, 0.49) p-value ref 0.06 0.01 *New treatment without T recovery.

Bacillus Calmette-Guérin (BCG) treatment patterns and real-world outcomes in high-risk (HR) non-muscle-invasive bladder cancer (NMIBC): A systematic literature review (SLR).

730 Background: Transurethral resection followed by induction and maintenance intravesical BCG is currently standard of care for patients with HR NMIBC. HR is generally defined as stage T1, high grade (HG), carcinoma in situ, tumors >3 cm, variant histology, BCG failure in HG tumor, or lymphovascular invasion. Considering the variability in HR definitions and BCG maintenance schedules, we analyzed the evidence on maintenance utilization and outcomes in patients with HR NMIBC. Methods: We conducted an SLR of English-language real-world evidence (RWE) studies published 01/01/2011–06/12/2024 reporting efficacy or safety outcomes with BCG in patients with HR NMIBC using MEDLINE, Embase, and Cochrane supplemented by manual searches of relevant conference proceedings 2021–2024. Studies reporting treatment patterns or progression-/recurrence-related outcomes were analyzed. Results: Among 244 RWE studies identified, 86 reported data on HR populations, which was defined by commonly accepted definitions such as T1 high grade (HG) or any HG, with 37.2% using AUA/EAU guidelines. Across studies reporting BCG maintenance patterns in the HR population, 40.7% of patients (6,795/16,712; 16 studies) received some form of maintenance. Details on maintenance duration were reported in 11 studies; among them, 27.9% of patients (1,154/4,142) completed ≥1 year of maintenance. Details on adequate BCG treatment were reported in 8 studies, defined as receipt of ≥5/6 induction instillations and ≥2/3 maintenance instillations. Across these eight studies, 59.5% of patients (10,122/17,007) did not receive adequate BCG treatment. While comparisons across studies should be interpreted with caution due to heterogeneity in study populations. Median 2-year recurrence-free survival (RFS), 5-year RFS, and 2-year progression-free survival (PFS) across studies was numerically longer with maintenance versus induction alone (table). However, median 5-year PFS across studies appeared similar with or without maintenance. Conclusions: Less than 50% of HR patients who started BCG treatment received some form of maintenance; however, studies were highly heterogenous in reporting patterns of BCG treatment and definitions of HR NMIBC. Although maintenance duration was underreported, ~30% of patients completed ≥1 year of maintenance. In patients with HR NMIBC, RWE suggests improved outcomes with maintenance versus induction alone. More studies are needed to confirm the benefit of different maintenance schedules and durations. Real-world efficacy outcomes: HR NMIBC population. Induction, median (range) [n studies], % Induction + maintenance, median (range) [n studies], % 2-year PFS 85.7 (81–95) [3] 92.0 (89–98) [8] 2-year RFS 66.7 (53–81) [2] 77.1 (62–85) [7] 5-year PFS 82.6 (72–89) [4] 84.0 (53–98) [13] 5-year RFS 53.0 (31–75) [6] 64.7 (27–78) [10]

Treatment, tolerability and outcomes of enfortumab vedotin plus pembrolizumab in advanced urothelial carcinoma: An analysis of the Austrian enfortumab registry.

736 Background: The treatment of advanced urothelial carcinoma (UC) has dramatically changed with the introduction of antibody-drug conjugates and immunotherapy. Since the report of the EV-302 trial data in October 2023, enfortumab vedotin (EV) in combination with pembrolizumab (P) is the preferred standard of care in 1 st line therapy. Methods: Clinical data were derived from 17 clinics participating in the Austrian EV registry. Patients receiving 1 st line EV + P for advanced UC from 09/2023 to 09/2024 were included. The main objectives of the registry were to evaluate patient characteristics, including comorbidities, treatment duration, efficacy and safety in a real-world setting. Results: In total 103 patients were included, 24 females and 79 males with a median age of 71 years (range 32 - 92). The majority of patients (89.3%) had an eastern cooperative oncology group performance status (ECOG PS) of 0 to 1, 6.7 % patients had an ECOG PS of 2 and 3.8% had an ECOG PS of 3. Liver metastasis was present in 19.4% of patients. At the time of data cut-off, 81.6% of patients were alive. Therapy with either EV or P was ongoing in 67.0% of patients. First response evaluation was performed in 88 patients, of these the objective response rate (ORR) was 65.9% with 12.5% complete remissions. After a median follow up of 4.0 months, the median overall survival (OS) and progression free survival (PFS) was not reached. Adverse events occurred in 69.9% of patients, with ≥ grade 3 toxicities in 30.1% of patients. Therapy with either EV or P was discontinued due to toxicity in 20.4% of patients. Patients with a high (≥5) Charlson comorbidity index (CCI) had significantly worse outcomes in terms of ORR (p = 0.02), PFS (p = 0.02) and OS (p = 0.04) as compared to patients with a lower CCI (0-4). There was also a trend for more severe adverse events in patients with a high CCI (p = 0.07), however, the overall adverse event rate, dose reductions and treatment discontinuations were similar in both groups. Renal function, body mass index and known diabetes mellitus had no influence on efficacy or tolerability in our analysis. In patients with ECOG PS 2 the ORR was 71.4% which is numerically similar to patients with ECOG PS 0-1. Conclusions: These first Austrian real-world data evaluate the efficacy and tolerability of EV plus P in routine clinical practice. Our data confirm the ORR to the pivotal EV-302 phase III trial, however patients with significant comorbidities as reflected by a higher score in the CCI had significantly worse outcomes. Updated data with longer follow up will be presented at the meeting.

Real world evidence from a retrospective multi-center analysis on first-line therapy for metastatic renal cell carcinoma with chromophobe histology.

488 Background: Chromophobe (chRCC) renal cell carcinoma are rare cancers and obtain a worse prognosis. We evaluated real-world treatment outcomes of 1 st line treatment in these cohort in Germany. Methods: We retrospectively analyzed patients with metastatic chRCC treated at 17 German tertiary cancer centres being treated from 2008-2023. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to local standard of radiological and clinical judgement. Progression free survival (PFS) and overall survival (OS) were calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 39 patients with a median age of 59 (IQR 55-71) years. ECOG PS was 0/1/≥2 in 70/17/12%. IMDC risk was favorable/intermediate/poor in 13/61/26%. 87% received prior nephrectomy. Lymphatic (58%), pulmonary (37%) bone (34%) and metastases were the most common metastatic sites. 52% patients received first-line IO-combinations (IO-IO: 43%, TKI-IO: 57%) and 48% patients TKI-monotherapy, predominantly sunitinib. Subsequent therapy was mostly Cabozantinib (after IO-IO), Lenvatinib/Everolimus (after IO-TKI) or Nivolumab (after TKI mono). AE of all grades occurred in 59% and 71% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥3 in 29% or 25%, respectively. ORR and survival outcomes with median follow-up of 14 months (IQR 7-28) are described in the table. Conclusions: IO-combinations are frequently applied in chRCC. Our data suggests that first-line IO-/TKI-based combinations yields higher ORR compared to IO-/IO-based combinations and single agent TKI, but did not translate into an improved PFS or OS. The retrospective nature and small sample size are major limitations of our analysis. However, the rarity of metastatic chRCC contributes to inconsistent findings not only in our dataset but also across previously published studies, making it difficult to establish clear treatment guidelines. Further research is essential to refine treatment strategies for patients with metastatic chRCC. ORR and survival outcomes of study population. Parameter All therapies (n=31) IO/IO (n=8) IO/TKI (n=10) TKI (n=13) ORR (CR+PR) 19% 12,5% 30% 15% SD 16% 12,5% 40% 0% PD 65% 75% 30% 85% ORR vs. SD vs. PD - p=0.05 Parameter All therapies IO/IO IO/TKI TKI mPFS, months, 95% CI 3 (0,0-10,2) 3 (2,4-3,6) 8 (0,0-19,2) 4 (0,0-10,2) - P=0.077 mOS; months, 95% CI 24 (22,7-25,3) 12 (2,3-21,7) NR (NR-NR) 24 (22,5-25,5) - p=0.183

Targeting more than tumors: The impact of enfortumab vedotin and pembrolizumab (EV/P) on skeletal muscle loss and sarcopenia in metastatic urothelial carcinoma (mUC).

689 Background: Sarcopenia and skeletal muscle loss are associated with poor prognosis and limited survival in metastatic cancer patients. This study aims to assess the impact of systemic treatment with enfortumab vedotin and pembrolizumab (EV/P) on skeletal muscle index (L3SMI) in patients with metastatic urothelial carcinoma (mUC). Methods: We conducted a retrospective analysis of mUC patients treated with EV/P at a single German tertiary care center. L3SMI was measured at baseline (before treatment) and at the first radiographic staging, approximately three months post-treatment on routinely obtained CT (computed tomography) or PET CT (positron emission tomography) imaging. L3 muscle area was measured using OsiriX software and normalized by height squared to calculate L3SMI. Sarcopenia was defined using L3SMI cutoffs based on body mass index (BMI): for men with BMI <25 kg/m², L3SMI <43 cm²/m²; for men with BMI ≥25 kg/m², L3SMI <53 cm²/m²; and for women, regardless of BMI, L3SMI <41 cm²/m². Results: Between November 2023 and October 2024, 24 patients with metastatic urothelial carcinoma (mUC) who had available imaging were included in the analysis. The median time between baseline and first follow-up imaging was 84 days. At baseline, 46% of patients met the criteria for sarcopenia, and by the first follow-up, 33% had experienced significant L3SMI loss (>4%), leading to 50% of patients being classified as sarcopenic. Despite this, significant L3SMI loss was not associated with poorer radiographic staging outcomes. Of the patients, 62.5% achieved a partial response (PR), 25% had stable disease (SD), and 12.5% showed progressive disease (PD). Conversely, 16% of patients showed a significant gain in L3SMI during the same period. A moderate, non-significant correlation was found between sarcopenia at first follow-up and treatment-related adverse events (r=0.339, p=0.11 ). In contrast, a significant correlation was observed between the onset of therapy-induced peripheral neuropathy and sarcopenia (r=0.418, p=0.042 ). Conclusions: This study emphasizes the high prevalence of sarcopenia in real-world mUC patients undergoing EV/P therapy, along with notable muscle loss within the first few months of treatment. Interestingly, this early decline in L3SMI did not correlate with poorer radiographic outcomes. Given that EV/P is a continuous therapy with the inevitable development of cumulative toxicities, monitoring muscle loss may help to implement strategies to avoid them. Our findings suggest a potential causal relationship between EV/P therapy and L3SMI loss, warranting further investigation. Larger studies with extended follow-up are needed to gain deeper insight into the long-term impact of sarcopenia in patients receiving EV/P treatment.

Survival outcomes based on line of therapy and treatment trends with cabazitaxel in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

162 Background: Pts with mCRPC after progression on docetaxel and androgen receptor pathway inhibitors (ARPIs), have limited treatment options. Even with the changing landscape, cabazitaxel remains an effective approved therapy in this setting for these pts. However, real-world data on the efficacy and trends of cabazitaxel usage remain limited. Herein, we aimed to assess the survival outcomes and treatment patterns in pts with mCRPC receiving single-agent cabazitaxel in a real-world setting. Methods: This retrospective study utilized the nationwide Flatiron Health electronic health record (EHR) derived de-identified database. Eligibility: Diagnosis of mCRPC and receipt of single-agent cabazitaxel for the first time. Survival was calculated from the date pts received their first treatment with cabazitaxel. Time to next treatment (TTNT) and overall survival (OS) were summarized using Kaplan Meier survival estimates and its 95% confidence intervals (CI). Results: Among 24,105 pts with metastatic prostate cancer in the dataset, 1,315 pts diagnosed between 1/1/2013 and 1/26/2024 received single-agent cabazitaxel. Median age of pts was 73 years (IQR 67 – 78). The majority were non-Hispanic White (62%), treated in community practice (84%), had commercial insurance (81%), and received treatment in the third line or later (86%). The number of pts receiving cabazitaxel per year steadily increased from 2 (0.2%) in 2012 to a peak of 181 pts (14%) in 2021. Following the approval of lutetium-177-PSMA-617 (Lu) in 2022, cabazitaxel usage declined to 126 pts (9.6%) in 2023, indicating a shift in treatment patterns. The median TTNT was 4.7 months (95% CI, 4.4–5.0), and the median OS was 8.6 months (95% CI, 8.0–9.3) for pts treated with cabazitaxel. Median TTNT and OS by line of therapy are summarized (Table) . Conclusions: Despite proven OS benefit, the overall utilization of cabazitaxel is low in real-world pts in the US. The number of pts with mCRPC receiving cabazitaxel steadily increased until 2021 and declined following the approval of Lu in 2022, highlighting the evolving treatment landscape. Cabazitaxel continues to be an effective therapy regardless of line of therapy. Median TTNT and OS by line of therapy in pts with mCRPC receiving cabazitaxel. Line of therapy Number of pts, n (%) Median TTNT (mo) (95% CI) Median OS (mo) (95% CI) 2 183 (13.9) 5.7 (4.8, 6.3) 11 (9.5, 14) 3 378 (28.7) 4.3 (3.8, 4.7) 7.5 (6.6, 8.4) 4 430 (32.7) 4.5 (4.1, 4.8) 8.5 (7.5, 9.4) 5 219 (16.7) 5.1 (4.4, 5.9) 9.2 (8.0, 12) 6 71 (5.4) 5.1 (4.1, 5.9) 7.7 (5.9, 11) 7 22 (1.7) 6.8 (2.8, 12) 11 (8.2, 18) 8 6 (0.5) 4.9 (1.8, -) 6.3 (1.8, -) 9 6 (0.5) 4.2 (2.8, -) 14 (9.7, -)

A phase 1/2 study of nezastomig (anti-PSMA×CD28) with or without cemiplimab (anti–PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and clear cell renal cell carcinoma (ccRCC).

TPS293 Background: Advanced mCRPC and metastatic ccRCC are urologic malignancies with poor prognoses, and novel therapies that can improve long-term outcomes remain an unmet medical need. Prostate-specific membrane antigen (PSMA) is a validated therapeutic target for prostate cancer. It is a transmembrane protein with enzymatic activity highly expressed by prostate cancer cells and ccRCC neovasculature. Nezastomig (REGN5678) is a first-in-class, PSMA×CD28 co-stimulatory bispecific antibody (bsAb) that facilitates T-cell mediated tumor killing by bridging PSMA-expressing cells with the costimulatory receptor, CD28, on T cells. Preliminary results have been reported from an open-label, Phase 1/2, first-in-human, multicenter study of nezastomig + cemiplimab in heavily pretreated pts with mCRPC (NCT03972657). In the dose escalation phase, nezastomig (30–300 mg) intravenously (IV) once weekly (QW) + cemiplimab (350 mg) IV once every 3 weeks (Q3W) reduced prostate-specific antigen levels and induced radiographic responses, providing the first evidence of clinical activity with a ×CD28 bsAb in solid tumors. The study has been amended to continue evaluation of nezastomig monotherapy in mCRPC based on the observed clinical activity and possible toxicity from the combination. Nezastomig is also being evaluated in pts with metastatic ccRCC. Methods: Pts with mCRPC must have received ≥2 prior lines of systemic therapy approved for metastatic and/or castration-resistant disease, including a second-generation androgen receptor signaling inhibitor. Pts with metastatic ccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including an anti-programmed cell death-(ligand) 1 therapy and either ipilimumab and/or a tyrosine kinase inhibitor. Nezastomig IV QW monotherapy starting dose for the mCRPC and ccRCC cohorts was informed by tolerability and clinical activity. Dose escalation of nezastomig monotherapy will occur in separate cohorts for mCRPC and ccRCC. When a maximum tolerated dose/presumptive recommended Phase 2 dose is identified, additional expansion cohorts may be evaluated. In pts with progressive disease after ≥6 weeks of nezastomig monotherapy, low-dose cemiplimab IV Q3W may be added. Dose escalation primary objectives are to determine safety, tolerability, and pharmacokinetics of nezastomig. Dose expansion primary objective is to assess efficacy of nezastomig (measured by objective response rate per modified Prostate Cancer Working Group 3 criteria [mCRPC cohorts] and per Response Evaluation Criteria in Solid Tumors version 1.1 [ccRCC cohorts]). The study is open and enrolling; 101 pts (97 with mCRPC; 4 with ccRCC) have been enrolled as of September 12, 2024. Clinical trial information: NCT03972657 .

Real world effectiveness of systemic treatment in patients (pts) with advanced upper tract urothelial carcinoma (UTUC) with histological variants.

722 Background: Upper tract urothelial carcinoma is a rare and heterogeneous disease that accounts for up to 5% of all urothelial neoplasms. Variant histology is an important prognostic factor in patients affected by bladder cancer and its presence is associated with adverse pathological features and worse survival outcomes. However, few data exists regarding the impact of histological variants in patients affected by UTUC treated with systemic therapy. Methods: PEMBROBLAD is a retrospective multicenter RW study conducted in 24 French GETUG centers. Eligible patients had advanced UC with mixed variants (UC-V) or pure non-UC (NUC). All patients received ICI as a second line treatment. We identified all patients with UTUC within the whole study cohort. The primary endpoint was overall response rate (ORR) in first-line setting; secondary endpoints included disease control rate (DCR) in first-line setting, overall response rate (ORR) in second-line setting, DCR in second-line setting and overall survival (OS). Results: Out of 139 patients (pts) in the PEMBROBLAD cohort, 32 had UTUC. Median age was 72 years (range 49-88), 69.6 % were male with ECOG PS 0/1 in 64.5% of cases. Mixed UC represented 75% (n=24) of UTUC with histological variants. The most common were squamous cell carcinoma (n=9, 37.5%), micropapillary (n=7, 29.2%), sarcomatoïd (n=3, 12.5%), neuroendocrine (n=1, 4.2%), nested (n=4, 16.7%) and adenocarcinoma (n=3, 37.5%). Non UC concerned 25% (n=8) of UTUC with histological variants, including 4 patients with squamous cell carcinoma (n=4, 50%). Fifteen pts (46.9%) was treated with Carboplatin based combination in first-line and 14 pts (43.75%) with Cisplatin based treatment. The ORR was 33.3% and DCR was 50.0%. All patients received immunotherapy in second-line setting. The ORR was 18.7% and DCR was 28.1%. Median overall survival from first-line treatment is 8.9 months (CI95%, 3.6-18.5). Serious TRAE occurred in 5 pts (16.1%). Discontinuation due to TRAEs occurred in 9.6% of pts. Thirteen pts (41.9%) had a third-line of treatment. Conclusions: Our results suggest efficacy of chemotherapy in first-line setting and ICI in pretreated advanced UC-V and NUC. No new safety concerns were identified. Survival data will be updated for the meeting.

Discordance in HER2 expression in primary and recurrent/metastatic lesions of upper tract urothelial carcinoma: A study focusing on temporal heterogeneity.

839 Background: The promising performance of HER2 antibody–drug conjugates (ADC) in clinical trials suggested that HER2-targerted therapy, particularly ADCs, may be a suitable treatment option for metastatic UTUC. However, we have observed cases where ADCs were ineffectiveness for recurrent/metastatic lesions in patients with HER2-positive primary UTUC. Thus, we conducted a retrospective study of UTUC patients to investigate the specific HER2 expression in paired primary and recurrent/metastatic lesions. Methods: Data of 290 UTUC patients who underwent radical nephroureterectomy at West China Hospital of Sichuan University from Jan 2020 and Oct 2023 without neoadjuvant treatment were retrospectively included. The HER2 expression was independently evaluated through immunohistochemistry by our professional genitourinary pathologists. HER2 2+ and HER2 3+ were considered HER2-positive whereas others were considered HER2-negative. Results: A total of 249 patients had HER2 expression evaluation of their specimens, with 92 patients (39.36%) showing HER2-positivity (IHC HER2 2+ or 3+). During rigorous follow-up, 31 patients (12.45%) developed local recurrence or distant metastasis. The majority of those patients had locally advanced UTUC (pT ≥ 3) and high grade disease. We observed discordance in HER2 expression between primary and recurrent/metastatic lesions in 22 cases (70.97%), with 9 cases (29.03%) showing an increase in HER2 expression and 13 cases (41.94%) showing a loss of HER2 expression. The conversion from HER2 negative to positive or vice versa occured in 5 cases (16.13%) and 10 cases (32.26%), respectively. Notably, all primary lesions with HER2 0 expression obtained HER2 expression in recurrent/metastatic lesions (5/5, 100%). Conclusions: Our findings highlight the discordance in HER2 expression between primary and recurrent/metastatic lesions in UTUC, underscoring the need for further investigation and potential modifications in disease management.

Erratum: Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update

AVENANCE real-world study of avelumab first-line (1L) maintenance treatment for advanced urothelial carcinoma (UC): Analyses in low tumor burden subgroups.

718 Background: The effectiveness and safety of avelumab 1L maintenance was confirmed in the large real-world AVENANCE study in France. In patients with advanced UC, low tumor burden is associated with a better prognosis, which may inform treatment decisions. Here, we report post hoc analyses from AVENANCE in subgroups with disease characteristics associated with low tumor burden. Methods: AVENANCE (NCT04822350) is a noninterventional ambispective study that enrolled patients with locally advanced or metastatic UC who were progression free after 1L platinum-based chemotherapy (PBC) and who had previous, ongoing, or planned avelumab 1L maintenance treatment. The primary endpoint is overall survival (OS) from the start of avelumab treatment. In post hoc analyses, OS and progression-free survival (PFS) were analyzed in subgroups who had locally advanced disease, nonvisceral metastases (excluding bone), or lymph node (LN)–only disease at the start of PBC. Results: Of patients with available data in the overall effectiveness population (N=595), 49 (8.3%) had locally advanced disease, 80 (14.7%) had nonvisceral metastases, and 61 (10.3%) had LN-only disease. At data cutoff (July 15, 2024) in the overall effectiveness population, median follow-up from start of avelumab was 33.2 months (95% CI, 31.7-34.2), median OS was 21.2 months (95% CI, 17.3-23.3), and median PFS was 5.7 months (95% CI, 5.2-6.6). In subgroups with locally advanced disease, nonvisceral metastases, or LN-only disease, median OS (95% CI) was not reached (17.4 months-not estimable [NE]), 27.2 months (16.8-NE), and not reached (19.9 months-NE), and median PFS (95% CI) was 19.8 months (9.6-NE), 9.0 months (5.8-16.1), and 13.4 months (6.9-26.5), respectively. Subsequent treatment was received by 17 patients (34.7%) with locally advanced disease (enfortumab vedotin [EV] in 3 [6.1%]), 45 patients (56.3%) with nonvisceral metastases (EV in 12 [15.0%]), and 33 patients (54.1%) with LN-only disease (EV in 8 [13.1%]). Conclusions: Subgroup analyses from AVENANCE show pronounced clinical benefits with avelumab 1L maintenance in subgroups with low tumor burden characteristics. Results are consistent with previous analyses from JAVELIN Bladder 100 and other real-world studies (eg, READY, an Italian compassionate use program) and further support the use of avelumab 1L maintenance as a standard of care in patients with advanced UC without progression after 1L PBC, including those with low tumor burden. Clinical trial information: NCT04822350 .

A multi-center phase Ib/II study of RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer (Hope-03).

795 Background: To evaluate the safety and efficacy of RC48-ADC, a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab, a PD-1 antibody, as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced muscle-invasive bladder cancer (MIBC). The study design has been presented at 2022 ESMO Asia meeting, and preliminary results will be reported this time. Methods: This is a Ib/II, multi-center, open-label, single-arm study (ChiECRCT20210564). Patients with pathological and imaging diagnosed cT2-4bN0-3M0-1a HER2 positive (Immunohistochemistry status 3+ or 2+ or 1+) MIBC. Of them, 6 patients are enrolled in the dose-escalation phase, and 45 patients enter into phase II study. RC48-ADC is given every 2 weeks with a maximum dose of 120mg intravenously, and tislelizumab is given every three weeks at the dose of 200mg intravenously. Patients without disease progression will receive radical cystectomy or bladder-sparing therapies based on individual risk profiles and preferences. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (pCR) and safety. Results: Inclusion has been closed, with a total of 51 patients successfully enrolled, consisting of 7 females and 44 males. The median age was 70 ± 10.16 years. Among the participants, 3 patients were HER2(1+), 26 patients were HER2(2+), and 22 patients were HER2(3+). The median follow-up duration was 12.8 ± 1.81 months. A total of 46 patients underwent primary efficacy evaluation after neoadjuvant treatment: 26 patients cCR, 14 patients partial response (PR), 2 patients stable disease (SD), and 4 patients disease progression. The cCR rate was 56.52%, and the disease control rate (DCR) was 91.30%. Of the 51 patients, 36 opted for radiotherapy as bladder-sparing therapy, resulting in 1 patient achieving Tis and 35 achieving T0 after radiotherapy. Three patients have passed away so far, and the 18-month survival rate was 100%. Regarding safety, 7 patients experienced immune-related adverse events, including grade 2 myositis, grade 1 elevated transaminase, and grade 1 hyperthyroidism, which led to an interruption of tislelizumab treatment. Additionally, 10 patients experienced RC48-ADC-related toxicities, including grade 1 elevated transaminase, grade 2 erythema, and grade 2 paresthesia. Two treatment-related interruptions occurred. Conclusions: The novel neoadjuvant combination of RC48-ADC and tislelizumab demonstrated promising downstaging efficacy in patients with HER2-positive locally advanced MIBC and provides an opportunity for radiotherapy-based bladder-sparing treatment. The toxicities observed were manageable, and the long-term efficacy of bladder preservation will be confirmed in the final analysis. Clinical trial information: ChiECRCT20210564.

Prospective real world data evaluation of clinical outcomes in metastatic hormone sensitive prostate cancer (MHSPC) patients treated as part of triplet therapy with darolutamide: UK multicenter RECOMMEND study.

89 Background: Darolutamide has authorisation for treatment of metastatic hormone sensitive prostate cancer (MHSPC) in combination with docetaxel chemotherapy and androgen deprivation therapy (triplet therapy) based on ARASENS trial results. The RECOMMEND study is a prospective real-world evaluation (RWE) of clinical outcomes in patients with MHSPC treated with this regimen in the UK. Methods: 318 patients were enrolled from 21 UK centres over 20 months from November 2022. Data cut-off was 14 August 2024. Disease characteristics were evaluated. Descriptive statistics have been used for patient demographics and PSA changes with treatment were analysed. Results: Patients on the study had a median age of 67 (range 38-84) years. Majority of the patients were de novo metastatic (91.2%). 68.2% have a Gleason score ≥8. 76 patients (23.9%) had next generation imaging (NGI) at diagnosis. Performance score was 0 (62.7%) or 1 (37.3%). The distribution of metastases (%) were: bone (84.9), nodal (60.4), lung (12.6) and liver (2.5). The median PSA level was 134 (range 1 to 5628) ng/mL at diagnosis. At the end of docetaxel chemotherapy median PSA was 0.35 ng/mL. PSA response see in the 226 patients who had completed 6 cycles of docetaxel chemotherapy at the data cut-off, PSA 50 was seen in 87.6% (198/226) and PSA 90 in 53.2%. PSA responses in those who only completed 4/5 cycles of docetaxel (n=14) did not significantly differ compared to those who completed all 6 cycles (PSA 50 p=0.445 and PSA 90 p-0.664). At 6 months from darolutamide initiation, quality of life (QoL) data is currently available for 173 patients, of these 88.4% reported either stable or improved QoL and 11.6% had a decline in QoL at the end of chemotherapy. Conclusions: The tolerability and efficacy profile of treatment with ADT+Darolutamide+Docetaxel in MHSPC in the RECOmMEnD study is similar to that reported in the ARASENS trial. The QoL data available for 173 patients to date reports either stable or improved QoL at 6 months for 88.4% cases. This provides important prospective RWE data, enabling patients and clinical teams to make informed choices in this setting.

Androgen receptor activity in biopsy specimens at initial diagnosis of prostate cancer and correlation with outcomes and treatment response.

409 Background: Androgen receptor activity (AR-A) has been described after radical prostatectomy (RP) and metastatic castration-sensitive prostate cancer (mCSPC). In RP specimens low AR-A is associated with basal subtypes, decreased DNA repair and increased immune activity. In mCSPC, low AR-A is associated with poor overall survival (OS) and time to progression to CRPC. However, AR-A has not been well characterized in localized disease at initial diagnosis. Here we sought to assess AR-A signatures in biopsy samples from patients across the prostate cancer risk continuum and assess correlations between AR-A and outcomes. Methods: We analyzed 150,162 biopsy samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, Inc. San Diego, CA). Transcriptome-wide expression data and clinical factors were retrieved from the Decipher GRID (NCT02609269). Patients with low and high AR-A expression as defined by Spratt et al 2019 were compared using Chi-square tests. Clinical and pathologic outcomes for specific cohorts in the overall sample population were analyzed using Cox regression. Results: Overall, 11,752 (7.8%) patients had low AR-A expression. 9.8% of patients > 70 years of age had low AR-A compared to 7.6% of patients <70 (p<0.0001). Low AR-A was enriched in samples with poor prognostic clinical factors such as very high Decipher (p<0.0001), Grade Group (GG) 5 (p<0.0001) and very high NCCN risk (p<0.0001). The same differences were present when looking only at patients with a PSA <4 ng/mL. Like in RP samples, AR-A expression in biopsy samples positively correlated with intact DNA repair and negatively correlated with basal subtypes, PORTOS and immune infiltration scores (all p<0.001). Low AR-A was prognostic of poor clinical outcomes across 4 independent retrospective cohorts. In cohort 1, intermediate risk disease (n=647), low AR-A correlated with adverse pathology at time of RP (p <0.05). In cohort 2, intermediate risk disease treated with radiation therapy (RT) (n=121), low AR-A correlated with biochemical failure (p<0.05). In cohort 3, high risk disease (n=405), low AR-A correlated with decreased OS (p<0.05) in all patients and metastasis (p<0.05) after RT and androgen deprivation therapy (ADT). Finally, in cohort 4, high risk disease treated with RT+ADT (n=100), low AR-A correlated with metastasis (p<0.01). Conclusions: Overall, in a large cohort of biopsy specimens, low AR-A was associated with increased age, very high Decipher score, very high NCCN risk, and GG5 disease. Subpopulation analyses suggest that low AR-A portends a poor prognosis. Given that patients with low AR-A had decreased DNA repair activity and increased PORTOS scores, clinicians should consider post-operative RT and novel clinical trials with PARP inhibitors for these patients.

Global spatiotemporal trends in prostate cancer burden and its socioeconomic disparities: An observational study from 1990 to 2021.

325 Background: Prostate cancer is the second most common cancer in men globally, posing significant health challenges. Conflicting findings on its global burden and trends necessitate updated analyses. This study provides recent estimates of prostate cancer's global, regional, and national burden from 1990 to 2021, analyzes temporal trends, and offers epidemiological insights for clinicians, researchers, and policymakers. Methods: We analyzed data from the Global Burden of Disease Study 2021 on prostate cancer cases, deaths, and disability-adjusted life years (DALYs) from 1990 to 2021, including age-standardized rates (ASRs) for incidence, mortality, and DALYs. Trend analyses utilized average annual percent change (AAPC) calculations and joinpoint regression models. Age-period-cohort analysis assessed the effects of age, period, and cohort on incidence and mortality trends. Pearson correlation evaluated associations between ASRs and the Socio-demographic Index (SDI) to explore socioeconomic impacts. Results: From 1990 to 2021, global prostate cancer cases, deaths, and DALYs increased, reflecting aging populations. The age-standardized incidence rate (ASIR) showed a slight global increase (AAPC = 0.15, 95% CI: 0.05–0.25), while the age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) decreased (ASMR AAPC = -0.83, 95% CI: -0.92 to -0.74; ASDR AAPC = -0.75, 95% CI: -0.82 to -0.68), indicating improved survival. High-SDI regions had decreasing ASMR and ASDR despite high ASIRs due to better detection and treatment. Low-SDI regions saw increases in ASIR, ASMR, and ASDR, with the highest mortality and DALY rates, indicating rising burden and potential healthcare access issues. Joinpoint regression showed initial increases then decreases in ASIR, ASMR, and ASDR, with regional differences in timing. Age-period-cohort analysis revealed age effects with rising incidence and mortality risks, declining incidence risk in the oldest age groups. Period effects showed incidence risk increasing until 2011–2017, then declining; mortality risk decreased over time. Cohort effects showed stable then increasing incidence risk in younger cohorts, while mortality risk decreased across cohorts, reflecting healthcare improvements. Conclusions: The global absolute burden of prostate cancer has increased, but age-standardized mortality and DALY rates have decreased, especially in high-SDI regions due to advancements in detection and treatment. Low-SDI regions face rising incidence and mortality, highlighting growing disparities. Targeted interventions and resource allocation in low-SDI regions are needed to address the increasing burden and reduce global health inequalities.

Development of a FKSI-23: A new bespoke health-related quality of life (HRQOL) questionnaire for the advanced and adjuvant setting in renal cell carcinoma (RCC).

526 Background: Existing HRQOL measures may not fully capture the experiences of patients with localized and advanced RCC. This study aimed to develop a validated, patient-centered HRQOL metric by incorporating insights from patients, advocates, and clinical experts for both localized and advanced RCC. We previously developed a questionnaire for advanced RCC (Bergerot et al., JCO 2024). In this study, we integrate it into the FKSI-19 model and create a new questionnaire. Methods: A four-phase approach was used. Previous work in advanced RCC assessed item relevance from established HRQOL measures (FKSI-19, EORTC QLQ-C30, EQ-5D), refined through patient feedback and expert review. This phase expanded to include localized RCC in the adjuvant setting. In Phase 1, patients with localized RCC rated the the relevance of 54 items from the metastatic cohort. Phase 2 included a panel of 11 expert refining the adjuvant-specific items. Phase 3 gathered feedback from patient advocates, and Phase 4 further refined the items by harmonizing them with the FACT library for consistency across RCC stages. Results: In Phase 1, 6 of 54 items were rated as most relevant by patients with localized RCC. Phase 2 refined these further, excluding redundant items and adding 4 new questions focused on adjuvant therapy. Phase 3 led to minor revisions after advocate review, and Phase 4, the new items were harmonized with validated FACT library questions. The final adjuvant-specific questionnaire comprises 10 items, addressing concerns such as long-term side effects, surveillance anxiety, and post-surgery emotional distress. The advanced-specific version includes 13 items. Both versions deemed to be of utmost importance to patients with localized and advanced disease. These items can be used as standalone scoring options, resulting in the creation of a novel FKSI-23 metric, allowing for customized questionnaires tailored to specific clinical scenarios. Conclusions: Through collective input from patients, advocates and experts, novel items that aid in capturing the experience of RCC patients were identified and existing metrics were refined to generate separate “scoring options” for patients with localized and metastatic disease. Validation of the resulting FKSI-23 tool is underway in forthcoming studies in RCC.

Safety and efficacy of salvage lymph node dissection in prostate cancer patients with nodal recurrence after radical prostatectomy: A prospective single center phase I/II study.

149 Background: Optimal management of pelvic nodal recurrence of prostate cancer after RP detected by PSMA-PET is still unclear, although a significant change in treatment due to early use of PET in the setting of BCR has been shown in multiple trials. As pelvic nodal recurrence can be seen as a “in between” state of disease before metastatic disease, metastasis directed therapy could improve oncological outcomes in the long term or at least delay the use of systemic treatment. Salvage Lymph node dissection (sLND) has been described in retrospective trials as effective with biochemical response in up to 60% of patients and long term BCR-free survival of up to 20%. Aim of this study was to prospectively evaluate safety as well as biochemical response to sLAE. Methods: In this study we prospectively included 71 patients with PET detected pelvic nodal recurrence after RP. Uptake in the prostatic fossa, previous pelvic radiation and short-term ADT were allowed. Patients with extra-pelvic metastasis, ECOG ≥2 or thromboembolic event within the last 6 months were excluded. Patients received complete bilateral open sLND. The resection margins were cranially the aortic bifurcation up to the level of the IMA, laterally the genitofemoral nerve, caudally the inguinal ligament or Cloquet's lymph node, medially the urinary bladder, and dorsally the pelvic wall. The obturator fossa was excised with exposure of the obturator nerve and removal of the presacral lymph nodes down to the periosteum. The primary endpoints of the study were safety measured by complication-rate and biochemical response to sLAE by PSA. Results: The median follow-up was 40 months. At the time of surgery median PSA was 1.20ng/ml (IQR 0.79-2.69) and the median number of positive spots on PET was 2 (IQR1-3). Overall, 30% patients showed biochemical remission defined as PSA <0.01. Within the follow up 90% (n=63) of patients experienced biochemical progression. The median time from sLND to BCR and additional treatments was 2 months (95%CI 2 – 5) and 12 months (95%CI 9 – 24) respectively. The median number of LNs removed was 39 and the most common site of relapse was the pelvis. Severe postoperative complications were rare yet did occur with 5 patients experiencing Clavien 3,4 and 5 complications of which one was a bilateral central pulmonary embolism which resulted in the death of the patient. Conclusions: Progression and additional treatments can be delayed with the use of sLAE, however long-lasting biochemical remission was rare. Certain patients with good initial PSA response were able to avoid systemic treatment. While mostly safe, severe side-effects did occur. Due to the potential complications of the surgery, it should be reserved for highly selected cases. Additional trials evaluating criteria for patient selection are important to further explore the potential benefit of sLAE. Clinical trial information: NCT02974075 .

Impact of liquid biopsies on early detection, monitoring, and prognostication in prostate cancer: A meta-analysis of emerging evidence.

32 Background: Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men worldwide. Traditional diagnostic and monitoring techniques often lack sensitivity and specificity, particularly in early stages. Liquid biopsies, which analyze circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) from blood samples, have emerged as a promising non-invasive alternative for early detection, monitoring disease progression, and prognostication in prostate cancer. Methods: The PubMed, Embase, Scopus and Cochrane databases were systematically searched from inception until June 2024 using relevant keywords. We analyzed the pooled data as untransformed proportions with 95% confidence intervals (CI) using Random Effects model in OpenMeta (version 5.3). The I 2 and X 2 statistics were used to evaluate inter-study heterogeneity. An I 2 value of >50% was considered significant heterogeneity. Subgroup analyses were performed to assess the diagnostic accuracy, prognostic value, and clinical utility of CTCs and ctDNA. Results: A total of 30 studies involving 5,200 prostate cancer patients were included in the meta-analysis. Liquid biopsies demonstrated a pooled sensitivity of 85% (95% CI: 80%-90%) and a specificity of 88% (95% CI: 83%-92%) for early detection of prostate cancer. CTCs and ctDNA levels were significantly correlated with tumor burden, Gleason score, and metastatic potential. Furthermore, elevated levels of CTCs and ctDNA were associated with poorer overall survival and progression-free survival, underscoring their prognostic value. Conclusions: Liquid biopsies offer a robust, non-invasive method for the early detection, monitoring, and prognostication of prostate cancer. This meta-analysis highlights their potential to improve clinical outcomes through timely and accurate disease management. Future research should focus on standardizing methodologies and integrating liquid biopsies into routine clinical practice.