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548 Background: TNBC is associated with higher risk of recurrence and poorer survival rates than other breast cancer subtypes. For node-positive TNBC or tumors larger than 0.5 cm, chemotherapy is generally recommended. For stage I TNBC, the benefit from chemotherapy, the optimal regimen, and whether to administer it in the neoadjuvant versus adjuvant setting remain controversial. Here, we report the treatment patterns and clinical outcomes of patients with stage I TNBC treated at Mayo Clinic. Methods: Using the Mayo Clinic Tumor Registry data, we identified patients with stage I TNBC treated between 2010 and 2021. We used the pathologic tumor (T) category for patients treated with upfront surgery and the clinical T category for patients receiving neoadjuvant chemotherapy. We used the Kaplan-Meier method and log-rank test to compare recurrence-free survival (RFS) according to treatment groups, measured from the day of surgery. RFS was reported at a median follow-up of 3.9, 6.2, and 7.3 years for patients who received chemotherapy neoadjuvantly, adjuvantly, and surgery alone with no chemotherapy, respectively. Results: A total of 602 patients with Stage I TNBC were included, with a median age of 62 years. 290 (48%) underwent upfront surgery followed by adjuvant chemotherapy (pT1a: 2%, pT1b: 25%, pT1c: 74%), 127 (21%) received neoadjuvant chemotherapy followed by surgery (cT1a: 2%, cT1b: 11%, cT1c: 87%), and 185 (31%) underwent primary surgery without any chemotherapy (pT1mi/T1a: 33%, pT1b: 32%, pT1c: 35%). Most patients treated with neoadjuvant therapy received anthracycline/cyclophosphamide + taxane (70%), while most patients treated in the adjuvant setting received a non-anthracycline containing regimen (60%). The 5-year RFS was 96% (95% CI: 93-100%) for patients who received chemotherapy neoadjuvantly, 95% (95% CI: 92-98%) for those who received chemotherapy adjuvantly, and 85% (95% CI: 80-91%) for those treated with surgery alone and no chemotherapy ( P < 0.0001). 71 (56%) of the 127 patients who received neoadjuvant therapy achieved a pCR, with only 1 RFS event (at 14 months) in that group, compared to 4 RFS events among those not achieving pCR (at 12, 20, 28 and 75 months, respectively). Among patients not receiving chemotherapy (either adjuvantly or neoadjuvantly), the 5-year RFS rates were 94% for pT1mi/T1a, 92% for pT1b and 72% for pT1c (T1mi/a/b vs T1c, P = 0.009). Conclusions: In this large cohort of stage I TNBC, patients who received chemotherapy (adjuvantly or neoadjuvantly) had better 5-year RFS compared with those treated with locoregional therapy only. Among patients receiving chemotherapy, 5-year RFS was nearly identical regardless of whether chemotherapy was administered before or after surgery. Interestingly, patients undergoing upfront surgery were more likely to receive an anthracycline-sparing chemotherapy regimen.

6558 Background: Allogeneic stem cell transplantation (ASCT) is currently the only curative therapy in chronic myelomonocytic leukemia (CMML). Methods: A Mayo Clinic enterprise-wide database search identified 138 CMML cases who underwent ASCT. Conventional statistical methods were used for analyses. Results: 138 CMML patients (transplanted between 1995-2024) were included (median age 63 years; males 62%);104 (group A) received ASCT before and 34 (group B) after blast transformation (BT). At initial diagnosis, CMML-1/CMML-2 and dysplastic/proliferative representations were 78%/22% and 54%/46%; 31% displayed abnormal karyotype and most frequent mutations were ASXL1 (56%), TET2 (44%) and SRSF2 (38%). At time of initial diagnosis, CPSS-Mol risk categories were low (17%), intermediate-1 (11%), intermediate-2 (40%), and high (32%). Median time from diagnosis to ASCT was 11 months (range 0-201). Median overall survival (OS) from the time of initial diagnosis was 67 months (range 4-239) and from the time of ASCT 54 (range 0-212) months. Occurrence of BT before ASCT was associated lower post-transplant survival (PTS; 16 vs 95 months, P=0.01, HR 1.9, 95%CI 1.2-3.2). Bone marrow (BM) blasts, at the time of ASCT, <5%, 5-9%, and 10-19% correlated with median OS of 171, 81, and 18 months in group A (p=0.01) and 50, 25, and 13 months in group B (P=0.07), respectively. Pre-ASCT hypomethylating agent exposure was associated with lower PTS in group A (P=0.02). PTS was also adversely affected by DNMT3A and SETBP1 mutations. In group A, PTS was the longest with myeloablative busulfan-based (median not reached) and the shortest (median 22 months) with Cy-TBI-based conditioning (p=0.1). Donor type did not impact PTS: matched unrelated (63%), matched sibling (23%), mismatched unrelated (7%), or haplo-identical (7%). Post-transplant cyclophosphamide was associated with a numerically lower median PTS (22 months), compared to other forms of GVHD prophylaxis (107 months; p=0.1) and significantly higher non-relapse mortality (p=0.02). Documentation of morphologic CR at day 100 was associated with significantly longer PTS in both groups A (92%,164 vs. 18 months; p=0.01) and B (84%, 42 vs. 11 months; p=0.01). The presence of abnormal karyotype at day 100 was associated with shorter PTS in group A (p=0.01). Grade ≥3 acute and moderate to severe chronic GVHD occurred in 20% and 34%, respectively, in group A patients and in 26% and 44% in group B. GRFS at 1/3 years were 42/21% in group A and 31/16% in group B. At last follow up, 44% in group A and 65% in group B were dead. Causes of death were relapse/non-relapse related in 36/64% in group A and 39/61% in group B. Conclusions: ASCT is effective in securing long-term survival in CMML, especially when the procedure is performed prior to BT and in the setting of <5% BM blasts/promonocytes. Response assessment at day 100 was highly informative of outcome.

6554 Background: SER-155 is an investigational, oral, live biotherapeutic product (LBP) comprised of 16 bacterial strains designed to decolonize gastrointestinal (GI) pathogens, improve epithelial barrier integrity, and modulate immune responses to prevent bloodstream infections (BSI). In the placebo-controlled cohort 2 of the phase 1b study, SER-155-001 (NCT04995653), SER-155 was generally well tolerated with a safety profile similar to placebo and the incidence of BSIs, a secondary endpoint, was significantly lower after treatment with SER-155 when compared to placebo. We report exploratory analyses of biomarkers of T cell expansion relevant for immune reconstitution after HCT. Methods: Participants were randomized 1:1 to receive 4 days of oral vancomycin (for microbiome conditioning) and 10 days of SER-155 or placebo/placebo administered pre-HCT (course 1) and post-neutrophil engraftment (course 2). Primary endpoints were safety and SER-155 strain engraftment (PK). Exploratory endpoints included plasma cytokine concentrations measured by ELISA and analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry. Results: Demographics were comparable across treatment arms. 34 of 45 randomized participants were treated and received allo-HCT (SER-155, 20; placebo, 14); 28 received course 2 (SER-155, 19; placebo, 9). SER-155 strain engraftment was observed in the peri-transplant period (median 11.5 strains after course 1) and post-HCT (median 11 strains after course 2 and HCT Day 100). Significant differences and trends in cytokines of systemic inflammation and immune homeostasis were observed relative to placebo prior to HCT Day 0 and post-HCT. On HCT Day 0, both arms had similar concentrations of IL7 and IL15 (Table 1). However, after course 2, and at HCT Day 100, significantly higher concentrations of IL7 were observed in the SER-155 arm relative to placebo (p=0.02, and p=0.003, respectively). In a preliminary analysis of PBMCs from a subset of participants, a high frequency of CD4+ T cells were observed in the SER-155 arm at the same timepoints. For homeostatic cytokine IL15, no significant differences were observed between arms. Conclusions: The significantly higher concentrations of IL7 with SER-155 treatment and observed frequency of CD4+ T cells support the potential role of the GI microbiome in promoting homeostatic expansion of peripheral T cells and immune reconstitution important for successful HCT. Clinical trial information: NCT04995653 . Median plasma IL7 and IL15 (pg/mL), SER-155 vs. placebo (generalized linear model). HCT Day or event SER-155 IL7 Placebo IL7 SER-155 IL15 Placebo IL15 D0 13.8 13.0 31.9 30.4 D7 15.1 14.6 50.9 62.6 D14 12.8 15.5 56.6 69.8 Post-neutrophil engraftment 13.4 9.0 16.3 15.4 Post-course 2 7.4* 3.9 6.2 9.1 D100 7.1** 3.5 6.2 6.2 *p<0.05, **p<0.01.

570 Background: Major histocompatibility complex class I (MHC I) plays a critical role in immune surveillance by binding peptides derived from intracellular proteins and presenting them on the cell surface for recognition by CD8+ T cells. Loss or downregulation of MHC I expression has been identified as a key mechanism of immune evasion in cancers. Here, we evaluated MHC I expression and outcomes in all subtypes of breast cancer (BC). Methods: 9,038 BC samples were analyzed via NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ), including triple-negative BC (TNBC) 3,038, HER2-positive (HER2+) 1,082, and hormone receptor-positive (HR+HER2-) 4,918. Immune cell fractions were estimated using WTS deconvolution (Quantiseq). MHC I ( HLA-A / HLA-B / HLA-C )-high (H) and -low (L) were classified by RNA expression above or below the 25th percentile. Real-world overall survival (OS) was derived from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier. NanoString IO360 was performed in 114 samples from the FinXX trial (NCT00114816). Statistical significance was assessed using chi-square, Mann-Whitney U, ANOVA, and Cox regression with multiple comparison adjustments (q<.05). Results: TNBC had higher expression of HLA-A and HLA-B (median TPM: 169 and 191) compared to HER2+ (146.6 and 170, q<0.05) and HR+HER2- (141.7 and 157.5, q<0.05). However, there was no significant difference in HLA-C expression across 3 BC subtypes. In TNBC, MHC I-H tumors had higher frequencies of PD-L1 positivity (66.2% vs. 13.1%) as well as higher infiltration of B cells (4.5% vs. 3.2%), M1 macrophages (5% vs. 1.5%), M2 macrophages (4% vs. 2.1%), Tregs (2.8% vs. 0.8%), CD8 + T cells (1.8% vs. 0%), dendritic cells (3.2% vs. 2.8%), higher T-cell inflamed score (137 vs. -144), and IFN g score (0.02 vs. -0.49) compared to MHC I-L TNBC (all q<.05). MHC I-H TNBC was associated with significant improvement in median OS (30.1 vs. 15.2 months, HR 0.55, 95% CI 0.46-0.65, p<0.0001). However, this survival difference was not observed in patients with MHC I-H vs. MHC I-L in HER2+ (HR 1.04, 95% CI 0.74-1.47, p = 0.81) and HR+HER2- (HR 0.87, 95% CI 0.75-1.02, p= 0.09) BC subtypes. We further validated the MHC I expression in the FinXX trial. Similarly, patients with MHC I-H had significant improvement in recurrence-free survival (HR 0.27, 95%CI 0.11-0.66, p = 0.002) and OS (HR 0.23, 95% CI 0.09-0.57, p = 0.0005) compared to MHC I-L. Conclusions: Our findings demonstrate that higher MHC I expression is associated with higher immune infiltration and improved outcomes in TNBC but not in HER2+ or HR+HER2- BC subtypes. These results suggest that MHC I expression plays a critical role in the tumor microenvironment of TNBC. Future studies are needed to evaluate the prognostic value and potential therapeutic target of MHC I in TNBC. Support: Breast Cancer Research Foundation, Bankhead Coley, W81XWH-18-1-0564. Clinical trial information: NCT00114816 .

TPS5130 Background: Patients with prostate cancer and deleterious HRRa have poorer prognosis but derive benefit from poly (ADP-ribose) polymerase (PARP) inhibition. However, prevalence of HRRa and response to PARP inhibition are less well defined in racial/ethnic minorities. We designed the HARMONY trial to evaluate the efficacy of N/AA/P in HL and NHB patients with mHSPC and deleterious HRRa. Methods: This multicenter, open label, phase II study is open through the Hoosier Cancer Research Network in the United States. The trial enrolls patients who self-identify as HL or NHB and have mHSPC with HRRa including BRCA 1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L. Eligible patients will have hormone sensitive, treatment naïve or minimally treated prostate cancer (i.e., bicalutamide ≤ 45 days, androgen deprivation therapy [ADT] ± AA plus P ≤ 45 days allowed). Prostate cancer variants, other therapy in mHSPC setting, or symptomatic brain metastases are exclusionary. Enrolled patients will receive 24 weeks (w) of ADT plus N/AA dual action tablet (DAT) plus P, followed by an adaptive approach based on prostate specific antigen (PSA) response. Subjects in Arm A (PSA > 4.0 ng/mL at 24 w) can continue ADT/N/AA/P for max 2 years or stop N and escalate therapy to ADT/AA/P plus 6 cycles of docetaxel followed by standard of care (SOC) therapy. Subjects in Arm B (PSA ≤ 4.0 ng/mL at 24 w) will continue ADT/N/AA/P for a total of 12 months. At 12 months in Arm B, subjects with PSA ≥ 0.2 ng/mL will continue ADT/N/AA/P for max 2 years, and subjects achieving PSA < 0.2 ng/mL have the option to continue ADT/N/AA/P for max 2 years or discontinue all therapy with the option to start SOC treatment at disease progression. PSA decline to < 0.2 ng/mL at 24w (primary endpoint) will be evaluated for each racial/ethnicity group against a historic rate of 50%. Thirty patients per racial/ethnic cohort will give 80% power at 0.1 significance to determine noninferiority with a no-inferiority margin of 0.185. Estimating 5% drop out, 64 patients will be enrolled (n=32 HL and n=32 NHB). Key secondary/exploratory endpoints include PSA reduction ≥ 90%, overall response rate, PSA/radiographic progression free survival, overall survival, time to subsequent anti-cancer therapy, quality of life and safety. Key genomic correlatives will be evaluated. ClinicalTrials.gov: NCT06392841. Study support of drug and funding: Janssen Scientific Affairs LLC. Clinical trial information: NCT06392841 .

e17064 Background: Analyses of clinical trials data suggest thatBlack men have equal or even improved overall survival (OS) with certain treatments for mCRPC compared with other races. Moreover, retrospective analysis of the PROCEED registry indicated that Black men who received Sip-T, an autologous cellular immunotherapy, had longer survival compared with other men with mCRPC. The Abi Race and PANTHER clinical trials prospectively assessed the effect of ARPIs on clinical outcomes among Black and White patient (pt) cohorts, and included pts who had received Sip-T either prior to or during study. We combined data from Abi Race and PANTHER to investigate associations between OS, Sip-T and race. Methods: Data from the Abi Race (N=100) and PANTHER (N=93) studies were retrospectively pooled for this analysis. Propensity scores for Sip-T treatment were calculated based on Karnofsky performance status, race, Gleason score, and study. Kaplan-Meier estimates for OS, with and without inverse propensity score weighting, were generated and stratified by Sip-T use. This analysis was stratified by race to examine whether the relationship between Sip-T use and OS differed by race. Results: Of the 93 Black pts and 100 White patients included from both studies, 123 patients did not receive Sip-T, while 70 patients did (60 before study, 10 on study). Pts who received Sip-T had a median OS (mOS) of 44 months (95% Confidence Interval (CI) 39, NR) compared to 36 months (95% CI 31, 48) for those who did not. Weighted by propensity scores, Black men who received Sip-T had a mOS of 72 months (95% CI 43, NR), while those who did not had a mOS of 38 months (95% CI 30, NR). Among White men, patients who received Sip-T had a mOS of 39 months (95% CI 30, NR), while those who did not had a mOS of 32 months (95% CI 29, 48) (see Table). Conclusions: Our findings from an investigator-led retrospective analysis independent of sponsors provide independent clinical trial support of prior retrospective findings that suggest Black men with mCRPC who receive Sip-T may have a greater OS than White men. While our analysis controlled for factors that may influence the use of Sip-T, it is limited by potential unmeasured confounders or timing of Sip-T. Further, adequately powered prospective trials specifically evaluating outcomes with Sip-T by race in earlier clinical settings are needed. Drug support and funding for Abi Race and PANTHER were provided by Janssen Scientific Affairs, LLC. Death counts and median overall survival (mOS) in months by race and Sipuleucel-T use. Black Men White Men Sipuleucel-T use Deaths / Total N No 36 / 64 38 / 59 Yes 12 / 29 24 / 41 Unweighted mOS (95% CI) No 36 (29, NR) 32 (29, 48) Yes 72 (43, NR) 39 (31, NR) Weighted mOS (95% CI) No 38 (30, NR) 32 (29, 48) Yes 72 (43, NR) 39 (30, NR) NR = not reached, mOS = median overall survival, CI = confidence interval.

e17035 Background: 177 Lu-PSMA-617 was approved in March 2022 for patients with mCRPC pretreated with an androgen receptor pathway inhibitor (ARPI) and a taxane. There are limited data on the effectiveness of treatments post- 177 Lu-PSMA-617. The aim of this study was to describe prostate-specific antigen (PSA) responses among patients with mCRPC receiving a guideline-recommended therapy as the next therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis, comprised of patient-level electronic health record and claims data that represent the US advanced prostate cancer population in the community, academic, urology, and medical oncology settings. Patients with mCRPC who received any guideline-recommended therapy at least 14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024 were included. Guideline-recommended therapies included abiraterone, enzalutamide, darolutamide, apalutamide, cabazitaxel, docetaxel, pembrolizumab, sipuleucel-T, niraparib, olaparib, talazoparib, rucaparib, and radium-223. Patients’ PSA values while on 177 Lu-PSMA-617 treatment were compared with their PSA values during the subsequent therapy course. Proportions of patients achieving reductions in PSA levels ≥50% (PSA50) and ≥80% (PSA80) were estimated. All analyses were descriptive. Results: A total of 152 patients receiving any subsequent guideline-recommended therapy after 177 Lu-PSMA-617 were identified. Mean age was 72.1 years. Most patients received an ARPI (n=93, 61.2%) – abiraterone (n=38), enzalutamide (n=37), darolutamide (n=10), or apalutamide (n=8) – as their subsequent therapy. Of patients who received a taxane (n=42, 27.6%), 24 received cabazitaxel and 18 received docetaxel. Median time to initiation of subsequent therapy was 206 days (interquartile range [IQR] 101–301 days) from 177 Lu-PSMA-617 initiation and 44 days (IQR 17–119 days) from 177 Lu-PSMA-617 discontinuation. Overall, among patients with sufficient information for PSA evaluation (n=30), 46.7% achieved PSA50 and 40.0% PSA80 post- 177 Lu-PSMA-617. Among patients receiving an ARPI, PSA50 was observed in 11/18 (61.1%) and PSA80 in 10/18 (55.6%). Among patients receiving a taxane, PSA50 and PSA80 were seen in 3/12 (25.0%) and 2/12 (16.7%), respectively. Conclusions: In this real-world analysis, the majority of patients who received guideline-recommended therapies after 177 Lu-PSMA-617 achieved at least a PSA50 response, suggesting that 177 Lu-PSMA-617 treatment does not preclude response to other subsequent therapies.

e17030 Background: The broad therapeutic arsenal for mCRPC, with overlapping indications, makes selecting the optimal treatment sequence challenging in clinical practice. The aim of this study was to evaluate the prostate-specific antigen (PSA) responses and overall survival (OS) among patients with mCRPC receiving 177 Lu-PSMA-617 based on prior ARPI and taxane treatment exposure. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a harmonized dataset of advanced prostate cancer patients in the US from diverse clinical settings. Patients with mCRPC who had received ≥1 dose of 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024, after prior treatment with ≥1 ARPI and ≥1 taxane, were included. To assess PSA response, the baseline PSA value obtained within 90 days before starting 177 Lu-PSMA-617 was compared with the on-treatment PSA value obtained ≥28 days after 177 Lu-PSMA-617 initiation. The number of patients achieving PSA reductions ≥50% (PSA50) and ≥80% (PSA80) were estimated, with patients classified into two cohorts based on prior ARPI and taxane exposure: (1) prompt cohort: after only 1 ARPI and 1 taxane, and (2) deferred cohort: >1 ARPI and/or >1 taxane. Patient characteristics and treatment patterns were evaluated descriptively. OS from 177 Lu-PSMA-617 initiation was estimated using Kaplan–Meier methodology. Results: A total of 431 patients were included: 177 patients in the prompt cohort and 254 patients in the deferred cohort. Of patients in the deferred cohort, 185 (72.8%) received ≥1 ARPI and 1 taxane, 32 (12.6%) received 1 ARPI and ≥1 taxane, and 37 (14.6%) received ≥1 ARPI and ≥1 taxane. Median (interquartile range) age was 73 (67–78) years and most demographic characteristics were balanced between groups. Patients in the deferred cohort had higher median PSA levels at baseline (63.1 ng/mL vs 25.2 ng/mL). PSA50 was observed in 18/33 (55%) patients in the prompt cohort vs 28/66 (42%) in the deferred cohort. PSA80 was observed in 13/33 (39%) patients in the prompt cohort vs 21/66 (31%) in the deferred cohort. Across both cohorts, median OS was 18.0 months (95% confidence interval [CI]: 15.1 months–not reached [NR]). Median OS was NR in patients in the prompt cohort vs 15.1 months in patients in the deferred cohort (95% CI: 11.6 months–NR). Conclusions: In this large real-world study, prompt initiation of 177 Lu-PSMA-617 (after only 1 ARPI and 1 taxane) showed superior clinical outcomes versus deferred initiation of 177 Lu-PSMA-617. Patients were more likely to achieve a PSA reduction ≥50% and ≥80% and had longer OS with prompt initiation of 177 Lu-PSMA-617. These results may help to guide treatment sequencing in clinical practice.

6538 Background: TP53 mutated ( TP53 mt ) high-risk myeloid neoplasm (HR-MN) confers a dismal prognosis in the contemporary era with only a subset of eligible patients (pts) able to achieve long-term remission with allogeneic stem cell transplantation (allo-HCT). Owing to poor outcomes, many physicians believe it is futile to treat older pts with disease-directed therapy, since curative intent allo-HCT cannot be offered. We sought to describe the outcomes of older pts with TP53 mt HR-MN receiving disease directed treatment. Methods: We conducted a multicenter observational study in collaboration with 11 U.S. academic centers under the COMMAND consortium. We reviewed the data of 451 older (≥ 60 years [yrs]) TP53 mt HR-MN (n= 282 acute myeloid leukemia [AML], n= 91 MDS transformed AML, n= 50 myeloproliferative neoplasm blast phase (MPN-BP) and n= 28 high-risk myelodysplastic syndromes [HR-MDS]) pts to analyze their outcome with disease directed treatment. Results: The median age was 70 yrs (range [R],60-90) and 58% were male. Proportions of pts with age ≥ 70 yrs were 47.5%. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was available in 68% (n= 306) of pts; 10.5%, 49%, 32% and 8.5% had ECOG-PS 0-3, respectively. The median bone marrow (BM) blast % was 32 (R, 5-99) and TP53 variant allele frequency (VAF) was 45% (R, 2-97). The proportion of pts with multi-hit (MH) TP53 mt and complex cytogenetics (CG) was 83% and 82%, respectively. 43 %, 31%, 20% and 6% received hypomethylating agent (HMA) + venetoclax, intensive chemotherapy, HMA and other low-intensity therapy, respectively. The complete remission rate with or without count recovery (CR/CRi) amongst evaluable patients (n= 356) was 37%. The median duration of response was 6.7 months (mo) (R, 5.9-7.5). Amongst 56 (12%) pts who underwent allo-HCT, the median overall survival (mOS) from time of allo-HCT was 21.9 mo. The mOS among pts ≥ 70 yrs was 6.5 mo. The mOS in mo was better in HR-MDS (16.4), compared to de novo AML (6.5), MDS transformed AML (7.1) and MPN-BP (5.27), p= 0.003. We conducted multivariable analysis for OS using baseline variables that were significant/ showed trend towards significance, on univariate analysis ( p <0.1). HR-MDS (HR; 0.43, 95% CI: 0.23-0.82, p= 0.01), CR/CRi (HR; 0.55, 95% CI: 0.39-0.77, p= <0.001) and allo-HCT (HR; 0.28, 95% CI: 0.16-0.47, p= <0.001) positively impacted OS. Whereas age ≥ 70 yrs showed trends towards inferior OS (HR; 1.31, 95% CI: 0.95-1.80, p=0.09). Complex CG (HR; 1.63, 95% CI: 0.83-3.21, p =0.15) and MH TP53 mut (HR; 1.30, 95% CI: 0.67-2.52, p= 0.42) did not retain significance for OS. Conclusions: Our multi-center study suggests that disease directed treatment in older TP53 mt HR-MN leads to modest response rates with short durations of response in the absence of allo-HCT. 12% of pts were able to receive allo-HCT with improvement in OS close to 2 yrs. The decision to treat this poor risk gp of pts should be based on individual pt characteristics and desires.

TPS5127 Background: Androgen deprivation therapy (ADT) ± androgen receptor pathway inhibitor therapy is a primary treatment for metastatic hormone-sensitive prostate cancer, but is noncurative and has significant toxicities when used long-term. In patients with OMPC for whom delaying ADT is appropriate, metastasis-directed therapy such as stereotactic body radiation therapy (SBRT) has been shown to provide local disease control. However, many patients do not experience a complete prostate-specific antigen (PSA) response and develop poly-metastatic disease. [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with demonstrated efficacy and a manageable safety profile in patients with PSMA-positive metastatic castration-resistant prostate cancer in the VISION and PSMAfore trials. PSMA-DC (NCT05939414) is an ongoing, international, randomized phase 3 trial to evaluate the efficacy of 177 Lu-PSMA-617 versus observation after SBRT in delaying castration and disease progression in patients with PSMA-positive OMPC. Methods: Eligible patients have histologically confirmed prostate cancer, biochemical recurrence post-definitive treatment, OMPC with ≤ 5 PSMA-positive metastatic lesions including ≥ 1 distant metastasis on PSMA PET/CT scans (all must be amenable to SBRT), PSA doubling time < 10 months and non-castration testosterone levels (> 100 ng/dL). Exclusion criteria include distant metastasis by conventional imaging (CI; CT/MRI and bone scans) at screening, prior ADT (except adjuvant ADT completed > 12 months before randomization), or other systemic therapy for metastatic prostate cancer. Patients (N = ~450) will be randomized 2:1 to 177 Lu-PSMA-617 or observation and will receive SBRT to all metastatic lesions within 14 days, completed within 3 weeks. Patients will then receive either intravenous 177 Lu-PSMA-617 (7.4 GBq/6 weeks; 4 cycles), starting 7–21 days after SBRT, or undergo observation only. Additional SBRT for new lesions is allowed. ADT is allowed after a metastasis-free survival (MFS) event by CI confirmed by blinded independent review committee (BIRC). Safety follow-up will occur 42 days after the last 177 Lu-PSMA-617 dose and at the week 24 visit for the observational arm. Long-term follow-up for the 177 Lu-PSMA-617 arm will include safety assessments every ~32 weeks. The primary endpoint is MFS by CI as assessed by BIRC using RECIST v1.1, or death. To provide 90% power to detect a hazard ratio of 0.6, 187 MFS events are required. The key secondary endpoint is time to next hormonal therapy. Additional secondary endpoints include time to PSA progression, radiographic progression-free survival, symptomatic progression, patient-reported health-related quality of life, overall survival and safety. Shore et al. PSMA-delay castration (DC): an open-label, multicenter, randomized phase 3 study of [ 177 Lu]Lu-PSMA-617 versus observation in patients with metachronous PSMA-positive oligometastatic prostate cancer (OMPC). J Urol 2025;213 (5S2_suppl):e28. https://www.auajournals.org/doi/10.1097/01.JU.0001110444.53548.eb . Reused with permission; ©American Urological Association, 2025. This abstract previously presented at 2025 AUA Annual Meeting. Clinical trial information: NCT05939414 .