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202 Background: While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use in castrate sensitive prostate cancer (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity in BRCA2 -altered patients with biochemically recurrent (BCR) prostate cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary prostate tumors. Methods: We characterized the expression of 16 PARP transcripts using a cohort of 52,266 radical prostatectomy (RP) specimens (2016-2024) undergoing Decipher prostate genomic classifier testing (Veracyte Inc). Transcriptome-wide mRNA expression data as well as baseline clinical/pathologic factors were retrieved from the Decipher GRID database (NCT02609269). Associations between high PARP expression (top 25%), baseline factors, and gene signatures were examined using logistic regression. We assessed the association between PARP expression and distant metastases in 3 retrospective cohorts (n= 545, 855, and 325). Finally, we evaluated PARP expression in our prior phase II trial (NCT03047135, n=39) of olaparib monotherapy in the setting of BCR following RP. Results: Higher mRNA levels of PARP1 , 2 , 8 and 14 showed strong associations (all P <0.001) with known adverse prognostic factors such as very-high Decipher score (>0.85), high Gleason grade (GG5) and non-organ confined disease (EPE, SVI and LNI), while higher PARP6 and 7 expression were associated with more favorable disease characteristics. High PARP1 expression was positively correlated with DNA-repair deficiency (r=0.77) and tumor immune microenvironment (r=0.62) signatures. In 3 independent retrospective cohorts of intermediate-high risk PCa patients, higher PARP1 expression was strongly associated with development of distant metastases after RP (HR 1.70, 1.81, and 1.67 respectively; all P <0.05). Finally, in our phase II trial of patients with BCR who received olaparib monotherapy, PARP1 (but not PARP2 ) expression from RP was 1.5-fold higher in samples with BRCA2 mutations (median 0.416 vs 0.276, P =0.01) and was associated with overall improved PSA progression-free survival (continuous variable, HR 0.55, P =0.01) and longer time to next systemic treatment (continuous variable, HR 0.66, P =0.02). Conclusions: High PARP1 mRNA expression, measured at RP, is associated with aggressive disease biology and greater risk of metastasis. However, high PARP1 (but not PARP2 ) levels are associated with improved response to PARP inhibition in the setting of BCR prostate cancer. Future trials testing PARP (including PARP1-selective) inhibitors in the CSPC space should consider measuring PARP1 mRNA levels in addition to BRCA1/2 mutation status. Clinical trial information: NCT02609269 , NCT03047135 .

TPS294 Background: Approval of [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, previously treated with androgen receptor pathway inhibitors and taxane-based chemotherapy, was based on the results of the Phase 3 VISION study (NCT03511664). It is important to further characterize long-term safety outcomes in 177 Lu-PSMA-617–treated patients, with particular regard to potential treatment-related risks. To this end, the long-term follow-up (LTFU) safety study (NCT05803941) has been established. Findings from the LTFU study will be crucial for assessing delayed toxicities for patients with PSMA-positive metastatic prostate cancer treated with 177 Lu-PSMA-617 globally. Methods: The LTFU study is a prospective, multi-center, non-EU post-authorization safety study. Patients who received ≥1 dose of 177 Lu-PSMA-617 within one of the prospective parent studies (Table 1) are eligible. Patients may enroll in the LTFU study after fulfilling the requirements of their corresponding parent study. The primary endpoint is the number and proportion of selected adverse events (AEs), including myelosuppression, xerostomia, renal failure, xerophthalmia, and second primary malignancies (eg, myelodysplastic syndrome or acute myeloid leukemia), other serious AEs, and changes in laboratory values. The secondary endpoint is the number and proportion of deaths. Following enrollment, patients will undergo assessments at baseline, and then every 6–8 months for up to 10 years after their first dose of 177 Lu-PSMA-617 or until death. At each visit, a review of selected treatment-related AEs (xerostomia, xerophthalmia, myelosuppression), any-cause AEs (renal toxicity, new diagnoses of second primary malignancies), and treatment-related serious AEs will be conducted. Physical and laboratory assessments, as well as details on concomitant medications and interventions, including anti-cancer therapies, will be collected. Patients may receive treatment with any medical intervention. Interim analyses are planned at 2 and 5 years post-study activation. Enrollment is ongoing (n=13). Clinical trial information: NCT05803941 . Parent studies of the long-term follow-up safety study. Trial Indication Phase N (all groups) ClinicalTrials.gov ID VISION (+sub-study) Post-taxane mCRPC 3 831 (+30) NCT03511664 PSMAfore Pre-taxane mCRPC 3 469 NCT04689828 PSMAddition mHSPC 3 1144 NCT04720157 177 Lu-PSMA-617 in patients with moderately or severely impaired, or normal renal function Post-taxane mCRPC 2 20 a NCT06004661 a Planned. mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer.

773 Background: BCG-unresponsive High-risk non-muscle invasive bladder cancer (HRNMIBC) tumours have an ominous prognosis and require effective, tolerable treatments. Uptake remains low for FDA approved agents (including systemic pembrolizumab, nogapendekin alfa inbakicept-pmln or N-803) due to toxicity concerns. We hypothesize direct intravesical administration of a PDL1 inhibitor could be effective with less systemic toxicity. However, it is unknown whether antibodies delivered via this route can reach tumor vasculature. INVEST is a phase Ib window of opportunity study investigating the safety and preliminary activity of passive instillation and direct injection of intravesical atezolizumab into the tumour/bladder wall. Methods: Eligible participants (ECOG performance status 0-2) are awaiting radical cystectomy (RC) for any stage urothelial cell carcinoma. Participants with muscle invasive bladder cancer, must be ineligible for/ refuse cisplatin based neo-adjuvant chemotherapy. Atezolizumab (600mg or 1200mg) is administered via direct injection into the tumour/bladder or by instillation into the bladder. The 3+3 design is utilised in the dose confirmation stages where participants receive either Single or Multiple (between 3 and 6) dose(s) of treatment before RC. Efficacy signals are derived from pathological complete response at RC and progression-free survival at 2 years. Primary endpoint, Dose confirmation stage: The number of dose-limiting toxicities (DLTs) observed from first dose of trial treatment to RC. Results: Enrolment began in May 2023. 13 participants were recruited to the single dose cohorts: 11 male, and 2 female. Age (Range; 43-86); median 70y, 9 NMIBC, 4 MIBC. 7 for direct injection (4 at 600mg and 3 at 1200mg dose) and 6 for passive instillation (3 at 600mg and 3 at 1200mg). Due to technical issues (syringe size) the first direct injection participant did not receive the full 600mg and were replaced. 12 participants received trial treatment as planned. There were no DLTs; 5 participants experienced non-trial treatment related SAEs (4 infections, 2 ileus, 2 renal impairment; 7/8 events occurred post-RC and all SAEs resolved). All participants underwent planned RC within the protocol stipulated timeline. Median time from last treatment to RC was18 days. 5 of 13 participants had downstaging of tumour in cystectomy specimen. Following independent Safety Review Committee review, recruitment is now open for the dose confirmation phase (Multiple 1200mg dose) in both treatment routes. Conclusions: Single dose atezolizumab treatment at a dose of 600mg and 1200mg in passive instillation and direct injection cohorts was well tolerated. Early efficacy data is encouraging. Multiple weekly doses of 1200mg in each treatment route are now being investigated within the INVEST trial. Clinical trial information: ISRCTN15842444 .

537 Background: Translocation renal cell carcinoma (tRCC) is a rare renal cell carcinoma subtype found in about 1-4% of adult patients with RCC and 40% of pediatric RCC cases. Management of advanced tRCC has been guided by clear cell RCC therapy and retrospective reviews which include tRCC cohorts. Novel therapeutic strategies are needed to improve outcomes. This study assessed an individualized neoantigen vaccine with nivolumab plus cabozantinib in a patient with metastatic TFE3-tRCC. Methods: Patient was consented (IRB# 20-011945) for a single-patient investigational new drug (IND#27755). In-house neoantigen prediction bioinformatics pipeline (REAL-neo v2.0) was performed to identify and prioritize neoantigen candidates. Patient underwent lymphodepletion with cyclophosphamide followed by vaccine administration on days 1, 4, 8, 11, 20, 40, week 12, and week 20. Patient was also treated with concurrent nivolumab 480 mg every 4 weeks and cabozantinib 40 mg daily. Objective response rate (ORR) and progression-free survival (PFS) were measured. Results: Patient was diagnosed with TFE3-tRCC and underwent nephrectomy prior to developing metastatic disease. He was treated with multiple liver surgeries, ablations, and radiation therapy without systemic therapy. This controlled his disease for 7 years before he required systemic therapy with ipilimumab plus nivolumab. After 4 cycles, imaging showed progression and was started on cabozantinib which controlled his disease for 1 year. Patient was consented for the neoantigen vaccine. Cycle 1 was administered in April 2022. Three liver lesions and 1 periportal lymph node were monitored. After 4 months of therapy, imaging showed partial response with 34% decrease in sum of target lesions. In June 2023, partial response was ongoing with a 57.4% decrease. A 2 nd vaccine series was administered in June 2023 and had stable disease until progression in June 2024 when patient held his cabozantinib for at least 4 weeks. Neoantigen combination therapy achieved a progression-free survival of 26 months and was well tolerated without significant vaccine-related adverse events. Conclusions: Individualized neoantigen vaccine plus nivolumab and cabozantinib achieved a durable partial response with prolonged progression-free survival. A randomized clinical trial is warranted to further evaluate the efficacy of this combination therapy.

524 Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) play a key role in treating renal cell carcinoma and other solid organ malignancies, but TKIs cause bothersome side effects that frequently necessitate dose reductions or treatment holds. Olanzapine has been useful for palliating symptoms from classical chemotherapies and advanced cancer, but its effect on TKI-related symptoms is largely unknown. This retrospective study aimed to estimate the efficacy of olanzapine for TKI-induced nausea, vomiting, anorexia, weight loss, and insomnia. Methods: All patients prescribed olanzapine with lenvatinib, cabozantinib, axitinib, or tivozanib at Mayo Clinic between January 1, 2018, and June 30, 2024 were assessed for inclusion. For baseline symptom assessment, clinical care team notes documenting the presence or absence of symptoms and indication(s) for starting olanzapine were reviewed. For response assessment, clinical notes and patient portal messages from the first three months after starting olanzapine were evaluated for qualitative descriptions of change in symptom burden. Relevant data were extracted as direct quotations, which were reviewed by the research team and categorized as “improved,” “worsened,” “stable,” or “missing data.” Each symptom domain was analyzed independently when olanzapine was prescribed for multiple interrelated symptoms. Results: A total of 60 patients who received olanzapine for the treatment of TKI-related adverse effects were included. The most common documented indication for olanzapine was nausea without vomiting (n=35), followed by anorexia (n=25), nausea with vomiting (n=16), weight loss (n=16), and insomnia (n=11). In 32 cases (53%), olanzapine was prescribed for multiple, simultaneous symptoms. Response rates for each symptom domain are shown in the table. In addition, prior to olanzapine, 34 patients (57%) had documented weight loss. Following olanzapine, 50% (n=17) gained weight (median increase: 6.1 kg; range: 2.0 - 10.7 kg), 26% (n=9) stabilized their weight (±1 kg), and 24% (n=8) continued to lose weight. Clinicians utilized a TKI dose reduction within one week of olanzapine initiation in 5 cases (8.3%), and 3 of these patients could resume the higher dose of TKI after starting olanzapine. Only 4 patients (7%) discontinued olanzapine within 3 months due to perceived side effects. Conclusions: Olanzapine appears to be effective in treating TKI-induced nausea, vomiting, anorexia, insomnia, and weight loss. Prospective randomized placebo-controlled studies are needed to confirm these findings. Improvedn (%) Worsened n (%) Stablen (%) Missing Datan (%) Nausea without emesis 32 (84) 3 (8) 1 (3) 2 (5) Nausea with emesis 13 (93) 0 (0) 0 (0) 1 (7) Anorexia 26 (74) 2 (6) 4 (11) 3 (9) Insomnia 11 (85) 0 (0) 2 (15) 0 (0)

520 Background: The annual incidence of renal cancer is 0.02% among the general United States population. End stage renal disease (ESRD) and exposure to dialysis are thought to be the primary drivers of increased risk of renal cancer in renal transplant patients rather than immunosuppression. This has been evidenced by how the incidence of RCC in heart transplant recipients is no different than the normal population. In this study, we aim to characterize RCC incidence among kidney transplant patients (usually exposed to ESRD/dialysis) versus other solid organ transplant patients (usually unexposed to ESRD/dialysis). Methods: We used CPT codes to search for patients who had received a solid organ transplant (kidney, liver, heart, lung, pancreas) at all Mayo Clinic sites from 1/1/2018 to 1/1/2024. Within this cohort, we identified those who had been diagnosed with kidney cancer after initiating dialysis or receiving a transplant, and retrospectively extracted data related to demographics, cancer diagnosis, and transplant details. Results: We identified 10873 patients who had received a solid organ transplant (Table 1). Of these, 178 (1.76%) were diagnosed with kidney cancer after either starting dialysis or receiving a transplant. These 178 patients were of median age 56 years at time of cancer diagnosis (STD 12), 71% male, 70% white, 20% black, 4.5% Asian, 2.8% American Native. Of 5792 patients who had received a kidney transplant (with or without another solid organ transplant), 172 (2.97%) were diagnosed with kidney cancer after having started dialysis or receiving a kidney transplant. Of these 172, 156 (91%) were exposed to dialysis (107 primarily hemodialysis and 48 peritoneal). Of 4392 patients who had received a solid organ transplant other than kidney (liver, heart, lung, and/or pancreas), 6 (0.14%) were diagnosed with kidney cancer after having received a kidney transplant. Of these 6, none underwent dialysis. Conclusions: Patients with kidney transplants are at increased risk of kidney cancer compared to patients with non-kidney solid organ transplants (2.97% vs 0.14%). This supports prior evidence showing ESRD plays a significant role in the pathogenesis of kidney cancer. Patients who received solid organ transplants at Mayo Clinic from 2018-2024 and were subsequently diagnosed with kidney cancer. n % With RCC after TXP 178 1.7587% Cancer Diagnosis after Kidney HD/TXP 172 2.9696% Cancer Diagnosis after Other TXP 6 0.1386% Patients who received solid organ transplants at Mayo Clinic from 2018-2024 n % Unique Patients 10121 100% Kidney Transplant 5792 57.23% Alone 5088 50.27% &Liver 332 3.28% &Heart 119 1.18% &Lung 8 0.08% &Pancreas 245 2.42% Non-kidney Transplant (Liver, Heart, Lung, or Pancreas) 4329 42.77% TXP: Transplant, HD: Hemodialysis.

745 Background: The combination of EV-P therapy has recently been approved as first-line (1L) therapy for patients with LA/mUC based on the results of the EV-302 trial. Herein, we report the updated results from a cohort of patients with LA/mUC who received EV-P in real world clinical setting. Methods: This retrospective study included patients with LA/mUC (07/2022-08/2024) at the Mayo Clinic who completed at least one cycle of EV-P. The best overall response (BOR) was evaluated using radiographic imaging and was adjudicated as complete response (CR), partial response (PR), stable disease (SD), mixed response (MR), or progressive disease (PD). The median progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death, was estimated using the Kaplan-Meier method. Patients who had not experienced disease progression by their last follow-up were censored for the PFS analysis. Results: A total of 120 patients were included; 79 (65.8%) were males, 41 (34.1%) females, 109 (91%) White, and 119 (99%) were non-Hispanic/Latino. The median age was 72 years (IQR: 65-77). Of these, only 22 (18.3%) had locally advanced disease while the remaining had mUC; 62 (51.6%) had lower tract urothelial carcinoma (LUTC), 36 (30%) had upper tract urothelial carcinoma (UTUC). The median follow-up time was 7.1 months (IQR: 4.93-9.26). In terms of BOR, 56 patients (46.6%) experienced PR, 34 (28.3%) CR, 12 (10%) PD, 7 (5.8%) MR, and 8 (6.6%) experienced SD. 3 (2.5%) patients were not evaluable. The BOR across subgroups, LA and mUC, including LUTC and UTUC, is summarized in the table. Among the responders, the median number of treatment cycles to first response was 3 (IQR: 2.25–4). Within the follow-up, 28 patients (23.3%) experienced eventual radiographic disease progression; death was observed in 25 patients (20.8%). The median PFS was 12.7 months (95% CI: 9.8-NE), and OS was 25.1 months (16.3-NE). Conclusions: In real world setting, the combination of EV-P in LA/mUC demonstrated clinical efficacy compatible with the findings from the EV-302 trial. Our results showed comparable efficacy with EV-P in both UTUC and LUTC, highlighting it's broad therapeutic potential. However, clinical data at longer follow-up is required to fully evaluate overall survival and the durability of response. mUC LA Overall LUTC UTUC Total patients 98 62 36 22 BOR CR 23 (23.4%) 13 (20.9%) 10 (28.5%) 11 (50%) PR 49 (52.6%) 31 (50%) 18 (50%) 7 (31.8%) SD 6 (6.4%) 2 (3.2%) 4 (11.4%) 2 (9.0%) PD 10 (10.7%) 9 (15.5%) 1 (2.8%) 2 (9.0%) MR 7 (7.5%) 5 (8.6%) 2 (5.7%) 0 (0%)

727 Background: Despite the availability of targeted therapies like erdafitinib for pts with aUC with susceptible genomic alterations, the rate of NGS testing remains low at 32% in the United States (Hage Chehade...Swami, JAMA Network Open, 2024). Furthermore, limited data exist regarding the timing of NGS testing in relation to the time of death. Herein, we sought to assess the rates of NGS testing at the end of life in pts with aUC in a real-world patient population. Methods: A de-identified nationwide Flatiron Health electronic health record (EHR)-derived database was used to extract patient-level data. Inclusion criteria: pts who received NGS testing (blood/tissue) and who had a date of death recorded. The analytic cohort included pts diagnosed with aUC between 1/1/2011 and 11/14/2022 who received first NGS testing results between 5/3/2012 and 12/21/2022. The time difference between each pt’s first NGS result delivered and death was calculated, and thereafter, pts were categorized into 3 categories: pts receiving results > 3 months (mo) before death, within 3 mo of death, or after death. The frequency and percentages of the 3 categories were reported, as well as by year of death. The percentages in each category were compared between 2019 (year of erdafitinib approval) and 2022 (last year in dataset) to evaluate changes in NGS testing trend. Results: Among 12,157 pts with aUC in the dataset, 1,637 had both a recorded date of death and underwent NGS testing, and were eligible and included in final analysis. The median age was 72 (IQR 66 – 79). The majority were male (73%), White non-Hispanic (76%), and treated in community practice (86%). 68.2% received NGS results > 3 mo before death (n = 1,117), 28.3% received results within 3 mo of death (n = 464), and 3.4% of NGS results were reported after death (n = 56). In pts who died in 2019 versus 2022, the percentage of pts receiving NGS results > 3 mo before death increased from 61% to 75%, while the percentage of pts receiving results within 3 months decreased from 33% to 22%, and the percentage of NGS results reported after death declined from 5.2 to 2.7%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting. Conclusions: Our findings suggest that a sizeable number of pts with aUC (∼ 32%) received their first NGS testing results towards the end of life, highlighting the need to integrate genomic testing earlier during the course of the disease to optimize benefit with targeted therapies. These results could inform clinical practice and therapeutic decisions in the clinic. CHC, YJ: Equal contribution; US, NA: Senior authors.

716 Background: Nadofaragene firadenovec is an FDA-approved gene therapy for Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) with promising clinical trial results. However, real-world post-marketing efficacy or safety data remain lacking. We evaluated complete response rates and safety in a multisite experience. Methods: Per IRB protocol, we analyzed patients treated with nadofaragene firadenovec for BCG-unresponsive NMIBC across three Mayo Clinic sites. Outcomes included complete response (CR), high-grade recurrence-free survival (HGRFS), cystectomy-free survival (CFS), overall survival (OS), and adverse events (AEs). CR and HGRFS were reported for patients with carcinoma in situ (CIS) and patients with Ta/T1 without CIS respectively. Failure to retain was defined as any medication loss, including leakage around the catheter or early voiding. Results: Between November 2023 and October 2024, 45 patients were treated with nadofaragene firadenovec for BCG-unresponsive NMIBC. Fifteen patients with follow-up less than 6 months and one patient with extensive metastatic disease identified one week after first instillation were excluded from efficacy analysis. Our efficacy-evaluable population of 29 patients with median follow-up of 8.2 months is summarized in the Table. CR/HGRFS at 3 and 6 months was 72% and 62% respectively. CFS was 94% and OS was 100% at 6 months. Three patients experienced disease progression during follow-up: one to T1, another to T2, and a third with metastases to the abdomen and lungs. A separate patient developed a metachronous upper tract urothelial carcinoma (pT2) without bladder recurrence. Bladder spasms (62%) and failure to retain (31%) were the most common AEs. Most AEs were low-grade, although four (9%) patients had grade 3 events (fatigue, fever, and dizziness). No grade 4-5 AEs were reported. Conclusions: Early real-world data demonstrates encouraging clinical complete response rates in patients with BCG-unresponsive NMIBC and a favorable safety profile. Further investigation with larger cohorts and longer follow-up is warranted. Evaluable patients (N=29) CIS cohort (N=15) Ta/T1 only cohort (N=14) Prior pembrolizumab (N=9) Prior intravesical chemotherapy (N=16) Age, years 72 (67-77) 74 (69-77) 71 (67-77) 69 (67-78) 73 (67-81) Elixhauser Index 5 (4-6) 5 (4-7) 5 (4-6) 5 (3-5) 5 (3-6) Prior BCG instillations 12 (10-14) 12 (12-15) 11 (8-13) 12 (12-12) 12 (11-13) Prior intravesical chemotherapy among recipients 6 (6-11) 6 (6-10) 6 (6-11) 10 (7-12) 6 (6-11) Prior pembrolizumab doses among recipients 7 (4-8) 8 (7-8) 4 (4-4) 7 (4-8) 8 (5-8) Follow-up, months 8.2 (6.9-9.5) 7.6 (6.9-9.5) 8.5 (6.9-9.4) 9.1 (8.0-10.1) 8.6 (6.7-9.9) 3-month CR/HGRFS 72% [53-87] 73% [45-92] 71% [42-92] 67% [30-93] 56% [30-80] 6-month CR/HGRFS 62% [42-79] 67% [38-88] 57% [29-82] 44% [14-79] 44% [20-70] Data are median (IQR) or % [95% CI].

309 Background: Standard of care (SOC) treatment options for HR-PCa include RT with long-term androgen deprivation (LT-ADT) or RP with selective use of post-operative RT +/- androgen deprivation therapy (ADT). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. Therefore, we conducted an emulated randomized comparison of RT vs RP in HR-PCa leveraging patients enrolled in RCTs. Methods: We searched Medline for RCTs in HR-PCa with a SOC arm of an RT- or RP-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. This identified 2 trials, NRG/RTOG 0521 (RT+LT-ADT +/- 6 cycles docetaxel [doce]), and CALGB 90203 (RP +/- neoadjuvant 6 cycles doce and ADT). Due to inherent difference in the biochemical recurrence criteria after RT vs RP, we chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis (DM) as the primary endpoint, considering deaths as competing events. Death after DM was measured to create a harmonized metric of deaths likely attributed to PCa. To assess potential residual selection bias, death without DM to capture non-cancer associated deaths was analyzed. Results: Overall, 1290 patients (RT n=557, RP n=733) were included, with similar median follow-up of 6.4 years. Prior to IPTW, RP patients were significantly younger with lower baseline PSA compared to RT patients. Adjuvant (18%) and salvage therapy (44%) was used in RP cohort. Cumulative incidence of DM was significantly lower in patients who underwent RT compared to RP (8-year DM: 16% vs 23%; p=0.01; subdistribution hazard ratio [sHR] 0.48 [95%CI 0.34-0.69], p<0.001). 8-year rates of death after DM were 10% vs 8% (p=0.72) in the RP and RT patients, respectively. RT patients had significantly greater risk of death without DM (HR 2.09 [1.01-4.34], p=0.048) with early differences measured. On a cross-arm comparison, 8-year cumulative incidence of DM when comparing SOC RT+LT-ADT group versus the doce+ADT+RP group was 18% vs 21%, respectively (sHR 0.75 [0.45-1.24], p=0.26). Conclusions: HR-PCa patients enrolled on RCTs had significantly lower incidence of DM with an RT-based strategy compared to an RP-based approach. Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison (use of cooperative group RCT data, contemporaneous enrollment in the same country, patients fit enough for chemotherapy, and IPTW adjustments) there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm. Utilization of post-operative radiotherapy and ADT+Doce may mitigate differences between RP and SOC RT+LT-ADT.