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PURPOSE We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model. METHODS Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high). RESULTS The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001). CONCLUSION This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.

PURPOSE: Germline testing for men with prostate cancer (PCa) poses numerous implementation barriers. Alternative models of care delivery are emerging, but implementation outcomes are understudied. We evaluated implementation outcomes of a hybrid oncologist– and genetic counselor–delivered model called the genetic testing station (GTS) created to streamline testing and increase access. METHODS: A prospective, single-institution, cohort study of men with PCa referred to the GTS from October 14, 2019, to October 14, 2021, was conducted. Using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, we described patients referred to GTS (Reach), the association of GTS with germline testing completion rates within 60 days of a new oncology appointment in a pre- versus post-GTS multivariable logistic regression (Effectiveness), Adoption, Implementation, and Maintenance. Because GTS transitioned from an on-site to remote service during the COVID-19 pandemic, we also compared outcomes for embedded versus remote GTS. RESULTS: Overall, 713 patients were referred to and eligible for GTS, and 592 (83%) patients completed germline testing. Seventy-six (13%) patients had ≥ 1 pathogenic variant. Post-GTS was independently associated with higher odds of completing testing within 60 days than pre-GTS (odds ratio, 8.97; 95% CI, 2.71 to 29.75; P < .001). Black race was independently associated with lower odds of testing completion compared with White race (odds ratio, 0.35; 95% CI, 0.13 to 0.96; P = .042). There was no difference in test completion rates or patient-reported decisional conflict for embedded versus remote GTS. GTS has been adopted by 31 oncology providers across four clinics, and implementation fidelity was high with low patient loss to follow-up, but staffing costs are a sustainability concern. CONCLUSION: GTS is a feasible, effective model for high-volume germline testing in men with PCa, both in person and using telehealth. GTS does not eliminate racial disparities in germline testing access.

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life–extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. Significance: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.

Health-related quality of life (HRQoL) among patients with localized prostate cancer (PC) on active surveillance (AS) and whether it may be improved through lifestyle-focused interventions remain underdefined.To assess longitudinal changes in HRQoL in patients who received and those who did not receive a behavioral intervention that increased vegetable intake.A secondary analysis of participants in the Men's Eating and Living (MEAL) study (Cancer and Leukemia Group 70807 [Alliance]), a randomized trial of vegetable consumption in patients on AS, was conducted.Patient-reported outcomes (PROs) included the Memorial Anxiety Scale for Prostate Cancer (MAX-PC), the Expanded Prostate Cancer Index Composite 26 (EPIC-26), and the Functional Assessment of Cancer Therapy Scale-Prostate (FACT-P). Areas under the curves (AUCs) were used to summarize serial HRQoL.PROs were completed in 87% (n = 387) of the intention-to-collect population. Baseline characteristics of patients completing HRQoL measures did not differ significantly from the entire study population or between groups. Baseline scores were high for all PROs and remained stable over 24 mo, with no significant differences from baseline at any time point. In adjusted analyses, there were no significant differences in summary AUC measures comparing control with intervention for the total MAX-PC score (p = 0.173); EPIC-26 domains of urinary incontinence (p = 0.210), urinary obstruction (p = 0.062), bowel health (p = 0.607), sexual health (p = 0.398), and vitality (p = 0.363); and total FACT-P scores (p = 0.471).Among men with localized PC on AS enrolled in a randomized trial, HRQoL was high across multiple domains at baseline, remained high during follow-up, and did not change in response to a behavioral intervention that increased vegetable intake.Patients with localized prostate cancer enrolled on active surveillance experience minimal cancer-associated anxiety, suffer low levels of cancer-associated symptoms, and perceive high physical and emotional well-being.

A myriad of organ-specific complications have been observed with COVID-19. While racial/ethnic minorities have been disproportionately burdened by this disease, our understanding of the unique risk factors for complications among a diverse population of cancer patients remains limited. This is a multi-institutional, multi-ethnic cohort study evaluating COVID-19 complications among cancer patients. Patients with an invasive cancer diagnosis and confirmed SARS-CoV-2 infection were identified from March to November 2020. Demographic and clinical data were obtained and a multivariate logistic regression was employed to evaluate the impact of demographic and clinical factors on COVID-19 complications. The study endpoints were evaluated independently and included any complication, sepsis, pulmonary complications and cardiac complications. A total of 303 patients were evaluated, of whom 48% were male, 79% had solid tumors, and 42% were Hispanic/Latinx (Hispanic). Malignant hematologic cancers were associated with a higher risk of sepsis (OR 3.93 (95% CI 1.58–9.81)). Male patients had a higher risk of sepsis (OR 4.42 (95% CI 1.63–11.96)) and cardiac complications (OR 2.02 (95% CI 1.05–3.89)). Hispanic patients had a higher odds of any complication (OR 2.31 (95% CI 1.18–4.51)) and other race was associated with a higher odds of cardiac complications (OR 2.41 (95% CI 1.01–5.73)). Clinically, fever, cough, and ≥2 co-morbidities were independently significantly associated with any complication. This analysis evaluated covariates that can significantly predict a myriad of complications among a multi-ethnic cohort of cancer patients. The conclusions drawn from this analysis elucidate a mechanistic understanding of differential illness severity from COVID-19.

Granulocytic–macrophage colony-stimulating factor (GM-CSF) is used as an adjuvant in cancer vaccine trials and has the potential to enhance antitumor efficacy with immunotherapy; however, its immunologic effects are not fully understood. Here, we report results from a phase I study of neoadjuvant GM-CSF in patients with localized prostate cancer undergoing radical prostatectomy. Patients received subcutaneous injections of GM-CSF (250 μg/m2/day) daily for 2 weeks (cohort 1; n = 6), 3 weeks (cohort 2; n = 6), or 4 weeks (cohort 3; n = 6). Treatment was well tolerated with all grade 1 or 2 adverse events. Two patients had a decline in prostate-specific antigen (PSA) of more than 50%. GM-CSF treatment increased the numbers of circulating mature myeloid dendritic cells, proliferating conventional CD4 T cells, proliferating CD8 T cells, and to a lesser magnitude FoxP3+ regulatory CD4 T cells. Although GM-CSF treatment did not augment antigen-presenting cell localization to the prostate, treatment was associated with recruitment of CD8+ T cells to the tumor. These results suggest that systemic GM-CSF can modulate T-cell infiltration in the tumor microenvironment. Cancer Immunol Res; 4(11); 948–58. ©2016 AACR.

Supplementary Table S1. Patient characteristics by cohort. Supplementary Table S2. Treatment-related toxicity. Supplementary Table S3. Individual clinical response of patients treated with ipilimumab at {greater than or equal to} 3mg/kg/dose. Supplementary Table S4. Comparison of absolute counts of T cell subsets between LTS and STS.

Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) blockade can induce tumor regression and improved survival in cancer patients. This treatment can enhance adaptive immune responses without an exogenous vaccine, but the immunologic biomarkers associated with improved clinical outcome in cancer patients are not fully established. A phase Ib trial in patients with metastatic, castration-resistant prostate cancer was performed combining ipilimumab with sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were followed clinically for response and overall survival, and for immunomodulation of circulating T cells. PSA declines of ≥50% and radiographic responses were observed at doses of ≥3 mg/kg/dose. Timing of clinical responses could be either immediate or delayed. Durable responses were also observed off treatment. A subset of patients experienced long-term survival with or without objective clinical responses. The relationship between T-cell phenotype in peripheral blood and overall survival was examined retrospectively. We found that the treatment induced an increase in the levels of CD4+ effector T (Teff) cells, regulatory T cells, PD-1+ CD4 Teff cells, and PD-1+ CD8 T cells. However, these increased levels were not associated with overall survival. Instead, low pretreatment baseline levels of PD-1+ CD4 Teff cells were found to correlate with longer overall survival. Furthermore, baseline levels of PD-1+ CD4 Teff cells from patients with shorter overall survival were higher than from cancer-free male control subjects. These results suggest that preexisting expression of immunologic checkpoint marker PD-1 on CD4 Teff cells may help identify patients that may benefit from ipilimumab treatment. Cancer Immunol Res; 3(9); 1008–16. ©2015 AACR.

Supplementary Table 2. Clinical Characteristics of the Evaluable Paired Biopsy Cohort

Supplementary Figure S1. Patient baseline characteristics.

Supplementary Table S1. Baseline demographics and disease characteristics in patients with mCRPC from the phase III sipuleucel-T trials included in the eosinophil analysis and the overall pooled population. Supplementary Figure S1. Overview of the study designs of three phase III clinical trials from which data were pooled for this retrospective analysis. Supplementary Figure S2. Changes in eosinophil counts for sipuleucel-T-treated patients with or without an elevated eosinophil count in randomized phase III trials, versus the control group. Supplementary Figure S3. Association of immune response with change in eosinophil counts for sipuleucel-T-treated patients in randomized phase III trials.

Supplementary Table 1. Clinical Characteristics of the Whole Genome Sequencing Cohort

Supplemental Figure 1: Biodistribution data reflecting the accumulation of 68Ga-citrate over time in the tissues of male nu/nu mice bearing PC3 xenografts. Peak radiotracer uptake was observed at 4 hours post injection. Supplemental Figure 2: Biodistribution data reflecting the accumulation of 68Ga-citrate at 4 hours post injection in the tissues of male nu/nu mice bearing 22Rv1 xenografts. Supplemental Figure 3: Biodistribution data collected 4 hours post injection of 68Ga-citrate in male nu/nu mice bearing subcutaneous PC3 xenografts, and 48 hours post injection of 89Zr-Tf in male nu/nu mice with subcutaneous PC3 xenografts. Supplemental Figure 4. BET inhibitors suppress MYC and transferrin uptake in MYC positive prostate cancer cell lines. Supplemental Figure 5: Biodistribution data collected 4 hours post injection of 68Ga-Tf in male nu/nu mice bearing subcutaneous PC3 or 22Rv1 xenografts. Mice were treated with vehicle, (+)-JQ1 (25 mg/kg, BID), or iBET (50 mg/kg, daily oral gavage) for 5 days prior to radiotracer injection. Supplemental Figure 6: Representative PET data collected 4 hours post injection of 68Ga-citrate or 48 hours post injection of 89Zr-Tf in male nu/nu mice bearing subcutaneous 22Rv1 xenografts. Supplemental Figure 7: Paired PET imaging plus CT-guided biopsy of tracer-avid liver metastasis in patient-003 with mCRPC. Supplemental Figure 8: H&E staining of the PDX tissue isolated from the liver metastasis of patient-003 shows morphological features consistent with the liver biopsy. Supplemental Figure 9. Biodistribution data acquired 4 hours post injection of 68Ga-citrate shows the accumulation of the radiotracer in the PDX tissue and selected normal mouse tissues. Supplemental Table 1. A summary of the tumor:blood and tumor: muscle ratios for 68Ga-citrate Supplemental Table 2. A summary of the patient characteristics in this study. Supplemental Table 3. A summary of the test/re-test data for 68Ga-citrate in normal tissues. Data are presented as SUVmax. Supplementary Table 4. A summary of the histological subclassifications for the prostate cancer biopsies acquired during this study.

Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary.Implications:The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC.Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221–9. ©2017 AACR.

Supplementary Table S1: Patient 1 reversion alleles. Supplementary Table 2: DNA read identifiers supporting reversion alleles. Supplementary Table S3: Gene targets of the SeqCap library used for cfDNA sequencing. Supplementary Figure S1: Frequent loss of heterozygosity in Patient 1's tumor DNA. Supplementary Figure S2: A single copy of chromosome 13 at the BRCA2 locus is present in Patient 1's tumor DNA. Supplementary Figure S3: Mutation signature three is present in patient 1's solid tumor. Supplementary Figure S4: A single copy of chromosome 13 at the BRCA2 locus is present in Patient 2's tumor DNA. Supplementary Figure S5: Patient 2's DNA coverage depth at residue 259. Supplementary Figure S6: Nucleotide and inferred protein sequences for patient 2's reversion alleles. Supplementary Figure S7: Reversion indels were significantly longer than the background distribution of indels. Supplementary Methods.

Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer–specific survival [HR, 0.713; 95% confidence interval (CI), 0.525–0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563–1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials. Cancer Immunol Res; 2(10); 988–99. ©2014 AACR.

Supplemental Tables 1-7

Supplementary Table S5 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Supplementary Table 2

Figure S1 shows that copy number alterations of well-described prostate cancer tumor suppressor genes are not different between enzalutamide-naïve and -resistant tumors.

Figure S2 shows a heatmap illustrating copy number alteration of the 124 protein-coding genes in individual samples.

Purpose:Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response.Experimental Design:Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.Results:We found that all epithelial tumors demonstrated similar gene expression–based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity in vitro to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel.Conclusions:This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.

Supplementary Table 4. Univariate analysis examining association between baseline clinico-pathological factors and PSA response in patients switched onto enzalutamide after collection of circulating cell-free DNA (n = 39)

Supplementary Figure 3. CONSORT diagram with patient disposition.

1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

Supplementary Data from Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance)

Purpose:Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC).Experimental Design:Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation–specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes.Results:SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1.Conclusions:We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.

Supplementary materials and Methods, Tables ST1-13. Table ST1: Baseline clinical characteristics of patients in IMPACT Table ST2: Baseline clinical characteristics of patients in ProACT. Table ST3: Increase in levels of IgG against candidate antigens at weeks 2 and 22 in IMPACT as measured with ProtoArray Table ST4: Protein reagents used in Luminex xMAP assays. Table ST5: Overlap of the number of patients who were IgG responders to different antigens at week 10 after treatment in the sipuleucel-T arm of IMPACT. Table ST6: Evaluation of IgG responses to candidate antigens at week 12 in ProACT using Luminex xMAP. Table ST7: Association of post-treatment changes in serum levels of IgG at week 10 with OS in the sipuleucel-T arm of IMPACT. Table ST8: Comparison of OS in sipuleucel-T-treated IgG responders and IgG non-responders at week 10 with that in control patients in IMPACT. Table ST9: Evaluation of IgG responses against candidate antigens at weeks 2 and 22 in IMPACT using Luminex xMAP. Table ST10: Assessment of IgG responses against candidate antigens at weeks 4 and 20 in ProACT using Luminex xMAP. Table ST11: Overlap of the number of sipuleucel-T-treated patients who were IgG responders to antigens across the post-treatment time points in IMPACT Table ST12: Association of changes in serum IgG levels with OS at week 2 or 22 in the sipuleucel-T arm of IMPACT. Table ST13: Comparison of OS in sipuleucel-T-treated IgG responders and IgG non-responders with that in control patients at weeks 2 and 22 in IMPACT.

Supplementary Figure 1. Comparison of AR, MYC, CCND1 and CCNE1 copy number status in 5 patients with matched circulating cell-free DNA and tumor biopsies subjected to array comparative genomic hybridization

Purpose:Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale.Experimental Design:We utilized data from the Cancer Cell Line Encyclopedia (N = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N = 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort.Results:RBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic loss) was associated with promoter hypermethylation (P = 0.008) and gene body hypomethylation (P = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (P < 0.00001), overall (P = 0.0004), and disease-specific (P < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (P = 0.03) and of shorter overall survival in mCRPC (P = 0.004) independently of the number of DNA alterations in RB1.Conclusions:Our study provides the first validated tool to assess RB1 biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption.See related commentary by Choudhury and Beltran, p. 4199

Supplementary Figure from A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

Supplementary Table 1. Genome copy number calls for all patients.

Purpose:In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation.Patients and Methods:In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis.Results:In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; P < 0.0001 for both), any AR aberration with PFS2 (1.74; P = 0.024), and TP53 or BRCA2 inactivation with OS (2.06; P = 0.003; or 3.1; P < 0.0001).Conclusions:Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.

Supplementary Figure S3 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Supplementary Table from CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease

Baseline characteristics of patients in STAMP and STRIDE trials stratified by lower, middle, and upper tertiles of CTL activity

Supplementary Figures S1-S9

Supplementary Figure S2 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Supplementary Dataset S1 shows the list of copy number gain genes.

Supplementary Data from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Supplementary Figures 1-8 with legends

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life–extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype.Significance:The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.

Genes differentially expressed in RB1 loss tumors with two or more RB1 mutations

Supplementary Figure S4 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Supplementary Table S2 S4 S6 S7 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

FigureS3

Supplementary Table from A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

Supplementary Figure 2. Schematic showing how sipuleucel-T is designed to activate a patient's immune system by ex vivo cellular activation during manufacture and subsequent in vivo immune response.