209 Background: Prostate cancer (PC) progression is driven by aberrant activity of the androgen receptor (AR) or its associated ligands - androgens. Dysregulation of genes that regulate androgen production, uptake, and conversion (APUC) may impact the efficacy of hormone therapies for PC. In our recent study of primary (n=2593) or metastatic PC (n=4490) biopsies, 6 APUC genes ( HSD3B1 , HSD3B2 , CYP11A1 , CYP11B1 , CYP17A1 , CYP3A43 ) showed strong clustering in prostate adenocarcinoma. Tumors with high APUC expression (APUC-6 high) had low AR alterations/signaling activity and showed prolonged overall survival. Here we examined the genomic, transcriptomic, and immune cell-fraction compositions in APUC-6 high versus AR-high tumors. Given improved outcomes in APUC-6 high tumors, we hypothesize reduced features of tumor aggressiveness or a favorable immune milieu in these specimens. Methods: Metastatic PC samples in the SU2C/PCF dataset (n=208) were annotated as APUC-6 high or AR-high based on gene expression quartiles, with the upper quartile defining “high” status. Additional stratification was performed to ensure that no samples classified as both APUC-6 high and AR-high were included in either group. This stratified two groups of tumors (n= 41, each). Transcriptomic, genomic, and clinical features between the two groups were compared. Gene Set Enrichment Analysis was used to identify upregulated gene-expression hallmark pathways, and CIBERSORT was used to infer fractions of 22 immune cell types. Results: APUC-6 high tumors exhibited fewer AR genomic alterations, AR gene expression, and AR-V7 detection. APUC-6 high and AR-high groups harbored significant differences in mutation alteration frequencies of 4 genes: AR, EDN2, EDA2R, and OPHN1 (q < 0.05). There were no differences in the frequency of poor-prognosis mutations such as in TP53, PTEN, or RB1. APUC-6 high tumors were enriched in several hallmark inflammatory pathways and epithelial to mesenchymal transition (EMT) (NES>1.5, FDR<0.05). APUC-6 high tumors contained a higher fraction of naïve CD4 T-cells (224-fold, q = 0.0226), and also exhibited numerically higher levels of activated natural killer cells and neutrophils (1.35-fold and 2.11-fold, q = 0.081, 0.051, respectively), relative to AR-high tumors. Conclusions: APUC-6 high tumors, characterized by a favorable prognosis, are associated with upregulation of inflammatory pathways and EMT, and a distinct immune cell repertoire despite no difference in aberrations of canonical drivers of aggressiveness, such as TP53, PTEN , or RB1 status. The more inflamed tumor microenvironment observed in APUC-6 high tumors warrants further exploration of distinct clinical approaches to this distinct phenotype. Validation of these findings in larger cohorts is ongoing.

5084 Background: The androgen receptor pathway inhibitor (ARPI) enzalutamide is one of the principal treatments for metastatic hormone-naïve and castration-resistant prostate cancer (CRPC). Most patients respond to enzalutamide. However, tumors from a subset of patients exhibit extreme non-response and are primary refractory to treatment. We sought to understand the gene expression program of enzalutamide extreme non-response (ENR) and identify alternate therapeutic approaches for tumors driven by this program. Methods: We analyzed gene expression by RNA-sequencing in pre-treatment metastatic biopsies from men with CRPC treated on a prospective enzalutamide clinical trial (NCT02099864). We focused on those with ENR (progression within 3 months) vs. long-term response (progression after 24 months) and identified a gene program linked to enzalutamide ENR. We validated the utility of this program in additional patient cohorts using a multivariable analysis and in preclinical models. Results: Unsupervised clustering correctly classified ENR patients whose tumors harbored proliferative, epithelial-to-mesenchymal transition, and stemness genes sets. Using a supervised approach, we developed a gene signature to measure the ENR program. High expression of this program in CRPC patient validation cohorts was independently associated with poor tumor control with AR targeting in multivariable analysis. Conversely, high expression of the program was independently associated with benefit with docetaxel chemotherapy, suggesting the ENR program is predictive and not merely prognostic. In support of our findings, high expression of the ENR program was strongly linked to docetaxel sensitivity in a large panel of CRPC models. Finally, we identified putative regulators of the ENR program—several of which can be targeted pharmacologically with agents that are FDA-approved or in clinical trials. Conclusions: The enza ENR program we identified is independently predictive of ENR to AR targeting. However, patients whose tumors harbor this program may be good candidates for docetaxel chemotherapy or clinical trials testing agents that block putative regulators of this program.

Supplementary Figure S1: UMAP view of NEN samples across diverse anatomic sites. Samples were unbiasedly clustered based off the top 1,000 variably expressed genes across samples and annotated using (A) DLL3 expression level and (B) anatomic site of origin.

5060 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) in men with BRCA-mutated chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) vs a control arm of physician’s choice of therapy (docetaxel or androgen-receptor pathway inhibitor [ARPI] therapy: abiraterone acetate or enzalutamide) in the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study. Herein, we conducted an analysis to determine the impact of germline vs somatic mutation status on the efficacy of rucaparib. Methods: Patients were randomized 2:1 to receive rucaparib 600 mg BID or physician’s choice of docetaxel or ARPI following progression while on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Color Health did genetic testing. Treatment-emergent adverse events (TEAEs) were reported for the BRCA subgroup. Results: In the rucaparib arm, 201/270 patients had BRCA mutations, and in the physician’s choice arm, 101/135 patients had BRCA mutations. Of patients with BRCA mutations: in the rucaparib arm, 80/201 (40%) were germline and 116/201 (58%) were somatic with 5/201 (2%) BRCA mutation status unknown, while in the physician’s choice arm, 39/101 (39%) were germline and 48/101 (48%) were somatic with 14/101 (14%) BRCA mutation status unknown. rPFS was significantly improved with rucaparib treatment vs physician’s choice in both the germline and somatic mutation groups (germline: HR, 0.52 [95% CI, 0.32–0.84]; somatic: HR, 0.38 [95% CI, 0.25–0.59]). Incidence rates of TEAEs were similar overall between patients with germline and somatic BRCA mutations in both arms. Conclusions: Rucaparib improves progression-free survival for patients with mCRPC with either germline or somatic BRCA mutations with a manageable safety profile. These data support the use of rucaparib as a beneficial treatment option for patients with BRCA-mutated mCRPC with germline or somatic mutations. Clinical trial information: NCT02975934 .

246 Background: Serum androgen levels are prognostic in mCRPC and genetic variation in androgen metabolism may drive these effects. OATPs, encoded by genes of the solute carrier organic anion (SLCO) family, govern the uptake of steroids. We hypothesize variation in androgen uptake may drive differential outcomes on ARPI therapy. A secondary analysis was the contribution of race to prevalence and outcome with the variants. Methods: A031201 was a randomized phase 3 trial in progressive mCRPC by Prostate Cancer Working Group 2 (PCWG2) criteria. Patients (pts) were randomized 1:1 to enzalutamide (ENZ) or ENZ plus abiraterone (AAP) at standard doses. Castrating therapy was maintained. The primary endpoint was overall survival (OS). Secondary endpoint was radiographic-free survival (rPFS). Germline DNA was genotyped for SLCO2B1 in 772 men from A031201 using a validated melting assay. 458 ENZ/AAP). Race is self-reported. Proportional hazards model was used to determine if variants predict OS/rPFS. Results: Two SLCO2B1 variants were analyzed (rs12422149 – GG (82% prevalence) vs AA allele (2% prevalence), and rs1789693 AA (prevalence 43%) vs TT allele (prevalence 13%). 105 (11%) Black patients were genotyped for rs1789693, prevalence of AA was 9%, with median rPFS 67 mos, OS of 67 mos; 50% had TT, median rPFS 16 mos (HR = 3.25 (95% CI 1.16-9.12) OS was 23 mos (hazard ratio for death 2.60 95% CI1.01-6.68). Hazard ratios for homo and heterozygotes are shown (Table). Conclusions: In black men, variations in OATP may contribute to differences in outcome when treated with ARPI therapy. Further study of these interactions with other factors is warranted. Clinical trial information: NCT01949337 . Outcome by genotype. Genotype Median in Months (95% CI) Hazard Ratio (95% CI) SLCO2B1_rs1789693 OS Black (n = 102)AA 67 (52, -) (n = 9)AT 36 (27, 53) (n = 42)TT 23 (20,42) (n = 51) Referent (ref)AT vs. AA 2.02 (0.78,5.26)TT vs. AA 2.60 (1.01, 6.68) White (n = 772; 5 undetermined (und))AA 35 (32-37) (n = 322)AT 36 (22, 39) (n = 346)TT 31 (27,43) (n = 99) RefAT vs. AA 1.01 (0.85,1.21)TT vs. AA 0.99(0.75-1.30) rPFS Black (n = 102)AA 67 (31, NR) (n = 9)AT 23 (17, 39) (n = 42)TT 16 (13,26) (n = 51) RefAT vs. AA 2.84 (1.00,8.07)TT vs. AA 3.25 (1.16, 9.12) White (n = 772; 5 und)AA 23 (20, 27) (n = 322)AT 23 (20, 25) (n = 346)TT 26 (17, 34) (n = 99) RefAT vs. AA 1.02 (0.86,1.21)TT vs. AA 0.85 (0.65, 1.12) SLCO2B1_rs12422149 OS Black (n = 102; 1 und)GG 36 (26,52) (n = 74)AG 26 (21, NR) (n = 27)AA NR (n = 0) RefAG vs GG 0.96 (0.56, 1.66)AA vs GG NE White (n = 772; 3 und)GG 34 (32,37) (n = 630)AG 36 (32, 44) (n = 125)AA 42 (25,NR) (n = 14) RefAG vs. GG 0.91 (0.72, 1.66)AA vs. GG 0.70 (0.35-1.41) rPFS Black (n = 102; 1 und)GG 23 (17,39) (n = 74)AG 20 (13, NR) (n = 27)AA NR (n = 0) RefAG vs GG 1.04 (0.61, 1.78) AA vs GG NE White (n = 772; 3 und)GG 23 (20,25) (n = 630)AG 22 (18, 26) (n = 125)AA 34 (14,NR) (n = 14) RefAG vs GG 1.07 (0.86, 1.3) AA vs. GG 0.63 (0.32,1.27) NR=not reached; NE= Not estimable.

AR activities and NEPC signatures in ATM- and BRCA2- mutated tumors.

Demographics of NEN samples by anatomic site

Correlates of DLL3 expression with immune repertoire, alternative targets, and non-neuroendocrine cancers. A, Radar plots displaying differences in immune infiltrates between DLL3-high and -low NENs. B, Ridgeline plots comparing the expression density of DLL3 and alternative precision targets in NENs and site-matched ADCs. C, Violin plots, bar plots, and heatmap displaying expression of DLL3, percent DLL3-high, and hazard ratio, respectively, across 47 cancer types. Dotted line depicts threshold for DLL3-high status. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

BACKGROUND AND OBJECTIVE:The rs4680 single-nucleotide polymorphism (SNP) of the COMT gene leads to a reduction in dopamine clearance, resulting in better mood and a decrease in symptoms in noncancer populations, but its influence on quality of life (QOL) during cancer treatment is undefined. We hypothesized that in comparison to wildtype (WT) COMT, the rs4680 SNP is associated with better QOL among men with metastatic hormone-sensitive prostate cancer receiving androgen deprivation therapy ± docetaxel (ADT ± D). METHODS:In this post hoc analysis, we tested the association between COMT rs4680 status and Functional Assessment of Cancer Therapy-Prostate (overall QOL), Functional Assessment of Chronic Illness Therapy-Fatigue, and Brief Pain Inventory scores at baseline and at 3, 6, 9, and 12 mo using Fisher's exact test and the Wilcoxon rank-sum test. Blood samples for genotyping were collected before treatment initiation. KEY FINDINGS AND LIMITATIONS:COMT SNP data were available for 550/790 men. Across the overall cohort, 3-mo pain severity was lower for rs4680 versus WT COMT (0.5 vs 1.25; p = 0.04). In the ADT arm, rs4680 versus WT COMT was associated with better overall QOL at 6 mo (128.9 vs 118.5; p = 0.04), less pain at 3 mo (no pain: 70.4% vs 41.5%; p = 0.01), and less pain interference at 3 mo (no interference: 76% vs 51.3%; p = 0.03), 6 mo (75% vs 48.7%; p = 0.02), and 9 mo (83.3% vs 52%; p = 0.02), with similar fatigue scores. Patients in the ADT + D arm had similar QOL regardless of COMT status. CONCLUSIONS AND CLINICAL IMPLICATIONS:Patients with the COMT rs4680 SNP experienced less pain and better global QOL after starting ADT alone. This is the first study to show that inherited genetic traits may influence treatment tolerability in men with prostate cancer.

Supplementary Figure S2: Correlations between expression of DLL3, ASCL1, and NEUROD1 across select NEN sites. Scatterplots displaying the expression of DLL3 vs ASCL1 (top) and DLL3 vs NEUROD1 (bottom) across NEN sites. Expression is depicted as log(TPM + 0.001). Spearman correlations and corresponding p-values are shown for each site.

Background/Objectives: The germline polymorphism in the HSD3B1 gene (c.1100 C) results in adrenal-permissive (CC) or adrenal-restrictive (AA) functions of the protein product by regulating the production of high-affinity ligands that activate androgen signaling. Prior studies have indicated that the CC genotype is associated with worse response to hormonal therapies in prostate cancer (PC) patients. Methods: To characterize the impact of germline HSD3B1 variants on somatic tumor features, we examined 6550 primary and metastatic PCs from the Caris Life Sciences database, in which the genomic and transcriptomic landscapes were acquired via paired whole-exome/whole-transcriptome sequencing. Results: The overall prevalence of the HSD3B1 AA genotype (restrictive–homozygous) was 48.8%, AC (permissive–heterozygous) was 32.8%, and CC (permissive–homozygous) was 14.9%. There was enrichment of the CC genotype in these PC patients as compared to prior reports that examined non-cancerous populations. However, the rates of the CC genotype varied between metastatic site and by race. Compared to the AA genotype, tumors harboring the CC genotype did not demonstrate increased AR alterations, nor higher expression of AR, FOXA1, HOXB13, or AR signaling signatures. We instead found significant changes in immune-associated hallmark pathways, immune cell fractions, and biomarkers that inform the use of immune therapies (TMB-high, MSI-high). Further, the CC and AA genotypes exhibited notable differences in the expression of immunoglobulins, MHC class I/II molecules, and cell surface targets. The differences in expression by HSD3B1 genotype were especially notable in lung and liver metastases. Conclusions: Our study indicates that in prostate cancers, HSD3B1 germline c.1100 allele status may not directly influence tumor-intrinsic genomics but is associated with novel functions beyond androgen signaling.

ABSTRACT:Neuroendocrine neoplasms (NEN) encompass a diverse set of malignancies with limited precision therapy options. Recently, therapies targeting DLL3 have shown clinical efficacy in aggressive NENs, including small cell lung cancers and neuroendocrine prostate cancers. Given the continued development and expansion of DLL3-targeted therapies, we sought to characterize the expression of DLL3 and identify its clinical and molecular correlates across diverse neuroendocrine and non-neuroendocrine cancers. Here, we interrogated paired DNA and RNA-sequencing from 1,589 NENs across 29 sites, as well as 203,252 tumors across 47 cancer types. We found that high transcriptomic levels of DLL3 correlated with more aggressive histologic and mutational patterns in NENs, with adverse survival outcomes being reflected in NENs originating from the lung, pancreas, stomach, and small bowel. The heterogeneity in DLL3 expression across NENs was largely explained by site of origin, with lung, prostate, and bladder NENs exhibiting relatively high levels of DLL3, whereas gastroenteropancreatic NENs displayed relatively low expression levels. Although the therapeutic targeting of DLL3 may be less applicable for gastroenteropancreatic NENs, we did find an upregulation of alternative targets such as SEZ6, CELSR3, and SSTR2 in these settings. Lastly, expanding our investigation into non-neuroendocrine cancers, we detected an enrichment of DLL3 in both low-grade and high-grade gliomas, Merkel cell carcinomas, medulloblastomas, and melanomas, with such enrichment being associated with prolonged overall survival in gliomas, but worse overall survival in melanomas. Altogether, we demonstrate that DLL3 represents an attractive target for subsets of neuroendocrine and non-neuroendocrine cancers and uncover opportunities for future therapeutic strategies. SIGNIFICANCE:DLL3-targeted therapies have recently shown robust clinical efficacy in aggressive neuroendocrine cancers, positioning them to fulfill a great unmet need in these settings. Here, we examine the clinical and biological correlates of DLL3 expression in both neuroendocrine and non-neuroendocrine cancers. Our findings may stimulate the development and application of DLL3-targeted therapies, as well as other precision therapies, in neuroendocrine cancers and beyond.

155 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study of rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) in patients with chemotherapy-naive mCRPC and BRCA1/2 (BRCA) vs the control arm of physician’s choice of DTX or ARPI (abiraterone acetate [ABI] or enzalutamide [ENZ]) demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS, primary efficacy endpoint) vs physician’s choice. Here, we report final OS and safety results from TRITON3. Methods: Patients with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI, or ENZ (control). OS was a key secondary endpoint tested initially in the BRCA subgroup, followed by the intent-to-treat (ITT) population in an ordered step-down multiple-comparisons procedure. Crossover from placebo to rucaparib was allowed after radiographic progression was confirmed by independent radiology review. Results: As of March 1, 2024 (final analysis data cutoff),patients with BRCA (N = 302) and ATM (N = 103) alterations were randomized (ITT, N = 405). After an overall median follow-up of 44.0 months, median OS in the BRCA subgroup in the rucaparib arm was 23.2 months vs 21.2 months for the physician’s choice control arm (HR, 0.91 [95% CI, 0.68–1.20]; P = 0.5044; Table). Hierarchical testing did not continue due to lack of statistical significance. No OS benefit was observed in the ITT population or ATM subgroup (Table). Median duration of treatment in rucaparib and physician’s choice arms was 8.3 and 5.1 months, respectively. The most frequent any-grade treatment emergent adverse event (TEAE) in the rucaparib (n = 270) and physician’s choice (n = 130) arms was asthenia/fatigue (61.5% and 63.1%, respectively). The most frequent grade ≥3 TEAE was anemia (23.7%) with rucaparib, and asthenia/fatigue (9.2%) with physician’s choice. Of the 135 patients in the physician’s choice arm, 77 patients had radiographic progression and 70 crossed over to rucaparib. Conclusions: Rucaparib remains the only PARPi to show improved rPFS vs a DTX-containing control arm and has a similar OS even when most patients cross over to rucaparib. Safety was consistent with prior reports. These data support rucaparib as a treatment option for patients with BRCA-mutated mCRPC. Clinical trial information: NCT02975934 . Median OS at final analysis. Group Rucaparib, n Physician's choice, n Rucaparib, months Physician's choice, months HR (95% CI) a BRCA 201 101 23.2 21.2 0.91 (0.68–1.20) ITT 270 135 22.8 21.7 0.99 (0.78–1.26) ATM 69 34 18.4 22.1 1.21 (0.77–1.90) a Calculated by stratified Cox proportional hazard model.

Expression patterns of DLL3 across NENs. A, Violin plots displaying expression of DLL3 in NENs and ADCs originating from the lung or prostate. B, Violin plots displaying expression of DLL3 in lung NENs by histologic grade. Bar plots above show proportion of histologic grade that was defined as DLL3-high. LNEC, large cell neuroendocrine carcinoma; SNEC, small cell neuroendocrine carcinoma. C, Differences in genetic alterations between DLL3-high and -low NENs, as well as breakdown of samples with concurrent mutations or wildtype status in TP53 and RB1 by DLL3-high or -low NENs. D, Circular bar plot displaying proportion of DLL3-high samples by NEN anatomic site with sample sizes shown in parentheses. Bar color represents median DLL3 expression for the site. E, Heatmap displaying relative expression of DLL3, ASCL1, and NEUROD1 in DLL3-high and -low NENs from the lung, prostate, bladder, stomach, pancreas, and small bowel. F, Forest plot showing association between DLL3 expression level and real-world overall survival. Dotted line represents the hazard ratio of 1.0. *, q < 0.05; **, q < 0.01; ***, q < 0.001.

5083 Background: Blood-based predictive biomarkers of sensitivity to 177 Lu-PSMA-617 are lacking, and may facilitate clinical decisions. Here, we studied whether integrated PSMA protein detection in circulating tumor cells (CTCs) and extracellular vesicles (EVs) is associated with outcomes in patients receiving 177 Lu-PSMA therapy. Methods: We enrolled 100 metastatic castrate-resistant prostate cancer (mCRPC) pts who were candidates for 177 Lu-PSMA into a prospective biomarker trial. Blood samples were collected for CTC and EV analysis at baseline, at the time of response, and at progression. Baseline characteristics included serum PSA, alkaline phosphatase (ALP), hemoglobin, albumin, and radiographic tumor burden. PSMA+ CTCs were enumerated using an AI-empowered holographic imaging platform combined with in-flow protein marker analysis (Astrin Biosciences, St. Paul, MN); PSMA protein was quantified in plasma EVs using shotgun proteomics via mass spectrometry (Arafa et al., Cancers 2024; 16: 4261). We assessed the impact of PSMA+ CTCs and EV-derived PSMA protein on PSA 50 responses, PFS, and OS. Multivariable Cox regressions were used to adjust for baseline PSA, ALP, and hemoglobin. Exploratory analyses of other EV-derived proteins were also conducted. Results: Of 100 enrolled pts, 47% had Gleason sum 9-10, 62% had >10 bone mets, 12% had visceral mets, 72% had received ≥3 prior systemic therapies, and median PSA was 57 (range 1.5–5,000) ng/mL. High PSMA+ CTC counts (> median) were associated with shorter overall survival (OS) (HR 2.71, 95%CI 1.18–6.21, p=0.02). PSA 50 response rates were similar for those with high and low PSMA+ CTC counts (39% vs 42%, p=0.8). Shotgun proteomics from plasma EV samples identified >11 000 unique proteins, of which 12% represented the cell surfaceome. EV-PSMA protein correlated with baseline PSA, ALP, and tumor burden (all p<0.05). High EV-PSMA protein (> median) was associated with worse OS (1.81, 95%CI 0.97–3.35, p=0.06). PSA 50 response rates were similar for those with high and low EV-PSMA protein (48% vs 42%, p=0.5). After multivariate adjustment, nonsignificant trends for shorter OS persisted for pts with high PSMA+ CTCs (HR 1.71, 95%CI 0.72–4.05) and high EV-PSMA levels (HR 1.49, 95%CI 0.78–2.84). Worse OS was also observed in pts with high EV levels of B7-H3 (HR 2.85, 95%CI 1.58–5.14, p=0.002), Trop-2 (HR 2.23, 95%CI 1.22–4.05, p=0.008), and STEAP1 (HR 1.69, 95%CI 0.93–3.06, p=0.08) proteins. Conclusions: In mCRPC pts receiving 177 Lu-PSMA, high PSMA+ CTC counts and high EV-derived PSMA levels portended poor survival. PSMA protein may be a novel blood-based biomarker of 177 Lu-PSMA sensitivity, facilitating treatment decisions, with relevance for other PSMA-targeting strategies. The robust detection and prognostic impact of additional cell-surface proteins ( e.g. B7-H3, Trop-2, STEAP1) may fuel the development of alternative novel therapeutics.

92 Background: Androgen deprivation therapy (ADT) is foundational for advanced prostate cancer (PCa); luteinizing hormone-releasing hormone (LHRH) agonists and gonadotropin-releasing hormone (GnRH) antagonists are widely used. ~20% of PCa patients on LHRH analogs develop castration-resistant prostate cancer (CRPC) within 3 years. We evaluated factors associated with CRPC onset and time to CRPC onset for agonists vs. antagonist using real-world dataset. Methods: Data were collected from an EMR database purchased from Decision Resources Group. Analysis set included PCa patients who received ≥1 ADT 1991-2020 and excluded those who received both LHRH agonist and a GnRH antagonist and/or developed CRPC on the same day/before ADT initiation. CRPC onset date was defined as the earlier of 2 options: CRPC diagnosis or first CRPC therapy (standard of care treatments e.g., androgen pathway inhibitors, immunotherapy, chemotherapy, radiotherapy). Associations between CRPC and each available factor were evaluated using MV Cox regression. Time to CRPC onset was assessed for agonists vs. antagonist. Results: 41,379 patients were analyzed. Factors associated with MV HR >1.4, p<0.001 were oncology setting, metastatic disease, absence of diabetes, and no statin use (Table 1). Antagonist use had an adjusted HR of 1.4 (95% CI 1.06-1.85, p=0.02). Median time to CRPC onset after ADT initiation is 10.9 months for antagonist (n=238) vs. 17.3 months for agonists (n=5,231). Conclusions: Treatment-related (oncology setting; antagonist use) and comorbidity factors (older age, no diabetes, no statin use) were associated with CRPC onset. Oncology setting and antagonist use may reflect practice patterns in higher risk individuals. The association between diabetes and CRPC risk is under further evaluation e.g., whether antecedent diabetes therapies confer protection. Hazard ratio (95% CI) and P-value of CRPC for top 10 significant factors 1 in multivariable analysis. Multivariable (n=9,554) 2,3 Factors HR (95% CI) P-value Oncology vs Urology (Setting) 3.04 (2.56-3.59) <0.001 W vs W/o Metastasis (Baseline) 2.20 (1.58-3.05) <0.001 W/o vs W Diabetes 4 1.45 (1.22-1.73) <0.001 W/o vs W Statin 4 1.43 (1.25-1.63) <0.001 Antagonist vs Agonist 1.40 (1.06-1.85) 0.02 W/o vs W Hypertension 4 (HTN) 1.17 (1.01-1.36) 0.041 Decreasing ADT Exposure per Year 1.09 (1.05-1.13) <0.001 Increasing Age per Year (Older vs Younger) 1.02 (1.02-1.03) <0.001 1 Significant for multivariable analysis. 2 Excluded patients with CRPC on the same day/before ADT Start. 3 Excluded patients with both agonist and antagonist use; without BMI, PSA, and age data; non-white/black race; with unknown urology/oncology or with both urology/oncology setting. 4 Has taken statins/hypertension/diabetes medication or diagnosed with hypertension/diabetes disease.

DLL3-high versus -low hazard ratios across cancer.

BACKGROUND AND OBJECTIVE:Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS:Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS:Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS:The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.

HSD3B1 encodes an enzyme that catalyzes the conversion of adrenal precursors into potent sex steroids. A common germline variant (c.1100C) enhances this effect and is linked to breast cancer (BC) progression. As the HSD3B1 genotypes contribute to differences in local and adrenal steroid production, their transcriptional and phenotypic effects on cancers influenced by hormonal signaling such as BC and endometrial cancer (EC)—particularly in relation to menopausal status—remain unclear. We analyzed BC and EC sequenced from patients that received diagnostic tests in oncology clinics, and we determined the germline HSD3B1 c.1100 genotype (AA, AC, CC) from tumor DNA sequencing by using variant allele frequency, with inferred menopausal status assumed by age at molecular profiling. Whole-transcriptome RNA sequencing and gene set enrichment analysis showed that adrenal-permissive homozygous (CC) tumors in premenopausal ER + BC were enriched for hormone-related pathways, including Estrogen Response Early (NES ≈ +1.8). In premenopausal triple-negative BC, adrenal-restrictive homozygous (AA) tumors exhibited the elevated expression of immune and epithelial genes and the increased prevalence of MED12 alterations (AA 0.25% vs. CC 8%, p < 0.01). In endometrioid EC, CC tumors demonstrated the suppression of immune and proliferative pathways. Postmenopausal cases had higher progesterone receptor IHC positivity (AA 75% vs. CC 83%, p < 0.05) and numerically more frequent ESR1 copy number gains (AA 2.0% vs. CC 4.0%). Results highlight context-specific associations between germline HSD3B1 genotypes and tumor biology in BC and EC.