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To better understand veterans' decisions about germline testing, we conducted a single-site, qualitative study of 32 veterans with advanced prostate cancer. Seven days after oncologist-patient discussions about germline testing, we conducted semistructured interviews with patients to explore their decision-making process using an interview guide. Four of 14 veterans with service-connected disability benefits for prostate cancer declined germline testing for fear of losing benefits because their livelihood depended on these benefits. All 18 veterans without service-connected benefits agreed to testing. Veterans declining germline testing based on this concern can lead to suboptimal cancer care because targeted treatments that could improve their outcomes may go unrecognized. Our findings contributed to new language in the Veterans Benefits Administration Compensation and Pension Manual clarifying that genetic testing showing hereditary predisposition is insufficient to deny service-connected benefits for conditions presumed to be caused by military exposures. Clinicians should communicate this protection when counseling veterans about genetic testing., (Published by Oxford University Press 2024.)

Understanding the relationship between lesion-absorbed dose and tumor response in 177 Lu-PSMA-617 radiopharmaceutical therapies (RPTs) remains complex. We aimed to investigate whether baseline lesion-absorbed dose can predict lesion-based responses and to explore the connection between lesion-absorbed dose and prostate-specific antigen (PSA) response. Methods: In this retrospective study, we evaluated 50 patients with 335 index lesions undergoing 177 Lu-PSMA-617 RPT, who had dosimetry analysis performed on SPECT/CT at 24 h after cycles 1 and 2. First, we identified the index lesions for each patient and measured the lesion-based absorbed doses. Lesion-based response was calculated after cycle 2. Additionally, PSA50 response (a decline of 50% from baseline PSA) after cycle 2 was also calculated. The respective responses for mean and maximum absorbed doses and prostate-specific membrane antigen (PSMA) volumetric intensity product (VIP-PSMA) at cycles 1 and 2 were termed SPECT mean , SPECT maximum , and SPECT VIP-PSMA , respectively. Results: Of the 50 patients reviewed, 46% achieved a PSA50 response after cycle 2. Of the 335 index lesions, 58% were osseous, 32% were lymph nodes, and 10% were soft-tissue metastatic lesions. The SPECT lesion-based responses were higher in PSA responders than in nonresponders (SPECT mean response of 46.8% ± 26.1% vs. 26.2% ± 24.5%, P = 0.007; SPECT maximum response of 45% ± 25.1% vs. 19% ± 27.0%, P = 0.001; SPECT VIP-PSMA response of 49.2% ± 30.3% vs. 14% ± 34.7%, P = 0.0005). An association was observed between PSA response and SPECT VIP-PSMA response ( R 2 = 0.40 and P < 0.0001). A limited relationship was found between baseline absorbed dose measured with a 24-h single time point and SPECT lesion-based response ( R 2 = 0.05, P = 0.001, and R 2 = 0.03, P = 0.007, for mean and maximum absorbed doses, respectively). Conclusion: In this retrospective study, quantitative lesion-based response correlated with patient-level PSA response. We observed a limited relationship between baseline absorbed dose and lesion-based responses. Most of the variance in response remains unexplained solely by baseline absorbed dose. Establishment of a dose-response relationship in RPT with a single time point at 24 h presented some limitations., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The tumor uptake of large non-targeted nanocarriers primarily occurs through passive extravasation, known as the enhanced permeability and retention (EPR) effect. Prior studies demonstrated improved tumor uptake and retention of 4-arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging by adding prostate-specific membrane antigen (PSMA) targeting small molecule ligands. To test PSMA-targeted delivery and therapeutic efficacy, StarPEG nanodrugs with/without three copies of PSMA-targeting ligands, ACUPA, are designed and synthesized. For single-photon emission computed tomography (SPECT) imaging and therapy, each nanocarrier is labeled with 177Lu using DOTA radiometal chelator. The radiolabeled nanodrugs, [177Lu]PEG-(DOTA)1 and [177Lu]PEG-(DOTA)1(ACUPA)3, are evaluated in vitro and in vivo using PSMA+ PC3-Pip and/or PSMA- PC3-Flu cell lines, subcutaneous xenografts and disseminated metastatic models. The nanocarriers are efficiently radiolabeled with 177Lu with molar activities 10.8-15.8 MBq/nmol. Besides excellent in vitro PSMA binding affinity (kD = 51.7 nM), the targeted nanocarrier, [177Lu]PEG-(DOTA)1(ACUPA)3, demonstrated excellent in vivo SPECT imaging contrast with 21.3% ID/g PC3-Pip tumors uptake at 192 h. Single doses of 18.5 MBq [177Lu]PEG-(DOTA)1(ACUPA)3 showed complete resolution of the PC3-Pip xenografts observed up to 138 days. Along with PSMA-targeted excellent imaging contrast, these results demonstrated high treatment efficacy of [177Lu]PEG-(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis., Methods: This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC., Results: Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes., Conclusions: Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies., (© 2024 Wiley Periodicals LLC.)

Purpose: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC., Patients and Methods: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion., Results: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively)., Conclusion: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

Rationale: 225 Ac, a long-lived α-emitter with a half-life of 9.92 days, has garnered significant attention as a therapeutic radionuclide when coupled with monoclonal antibodies and other targeting vectors. Nevertheless, its clinical utility has been hampered by potential off-target toxicity, a lack of optimized chelators for 225 Ac, and limitations in radiolabeling methods. In a prior study evaluating the effectiveness of CD46-targeted radioimmunotherapy, we found great therapeutic efficacy but also significant toxicity at higher doses. To address these challenges, we have developed a radioimmunoconjugate called 225 Ac-Macropa-PEG 4 -YS5, incorporating a stable PEGylated linker to maximize tumoral uptake and increase tumor-to-background ratios. Our research demonstrates that this conjugate exhibits greater anti-tumor efficacy while minimizing toxicity in prostate cancer 22Rv1 tumors. Methods: We synthesized Macropa.NCS and Macropa-PEG 4/8 -TFP esters and prepared Macropa-PEG 0/4/8 -YS5 (with nearly ~1:1 ratio of macropa chelator to antibody YS5) as well as DOTA-YS5 conjugates. These conjugates were then radiolabeled with 225 Ac in a 2 M NH 4 OAc solution at 30 °C, followed by purification using YM30K centrifugal purification. Subsequently, we conducted biodistribution studies and evaluated antitumor activity in nude mice (nu/nu) bearing prostate 22Rv1 xenografts in both single-dose and fractionated dosing studies. Micro-PET imaging studies were performed with 134 Ce-Macropa-PEG 0/4/8 -YS5 in 22Rv1 xenografts for 7 days. Toxicity studies were also performed in healthy athymic nude mice. Results: As expected, we achieved a >95% radiochemical yield when labeling Macropa-PEG 0/4/8 -YS5 with 225 Ac, regardless of the chelator ratios (ranging from 1 to 7.76 per YS5 antibody). The isolated yield exceeded 60% after purification. Such high conversions were not observed with the DOTA-YS5 conjugate, even at a higher ratio of 8.5 chelators per antibody (RCY of 83%, an isolated yield of 40%). Biodistribution analysis at 7 days post-injection revealed higher tumor uptake for the 225 Ac-Macropa-PEG 4 -YS5 (82.82 ± 38.27 %ID/g) compared to other conjugates, namely 225 Ac-Macropa-PEG 0/8 -YS5 (38.2 ± 14.4/36.39 ± 12.4 %ID/g) and 225 Ac-DOTA-YS5 (29.35 ± 7.76 %ID/g). The PET Imaging of 134 Ce-Macropa-PEG 0/4/8 -YS5 conjugates resulted in a high tumor uptake, and tumor to background ratios. In terms of antitumor activity, 225 Ac-Macropa-PEG 4 -YS5 exhibited a substantial response, leading to prolonged survival compared to 225 Ac-DOTA-YS5, particularly when administered at 4.625 kBq doses, in single or fractionated dose regimens. Chronic toxicity studies observed mild to moderate renal toxicity at 4.625 and 9.25 kBq doses. Conclusions: Our study highlights the promise of 225 Ac-Macropa-PEG 4 -YS5 for targeted alpha particle therapy. The 225 Ac-Macropa-PEG 4 -YS5 conjugate demonstrates improved biodistribution, reduced off-target binding, and enhanced therapeutic efficacy, particularly at lower doses, compared to 225 Ac-DOTA-YS5. Incorporating theranostic 134 Ce PET imaging further enhances the versatility of macropa-PEG conjugates, offering a more effective and safer approach to cancer treatment. Overall, this methodology has a high potential for broader clinical applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody., Experimental Design: [225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity., Results: Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi., Conclusions: [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

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.

Androgen deprivation therapy (ADT) is associated with better outcomes for men with biochemical recurrence following treatment for localized prostate cancer but can predispose patients to a higher risk of cardiovascular events. Intermittent ADT is worth considering in this setting, with close monitoring of prostate-specific antigen to decide when to restart ADT after off-treatment periods., (Published by Elsevier B.V.)

Background: Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11 and F-18-Fluciclovine, are increasingly used to inform therapies for prostate cancer (CaP). Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic CaP has been shown to improve progression free survival (PFS) and delay androgen deprivation therapy (ADT) compared to observation. For men who subsequently develop oligorecurrent CaP, outcomes following second SBRT are unknown., Methods: A retrospective cohort study was conducted. Eligibility criteria included patients with oligometastatic (1-5 lesions) CaP detected on PSMA or Fluciclovine PET who underwent 2 consecutive SBRT courses to tracer-avid sites. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline ≥50% (PSA50), PFS after SBRT2, and ADT initiation or intensification-free survival after SBRT2. Factors potentially associated with PSA50 after SBRT2 was evaluated with multivariable logistic regression. Factors potentially associated with PFS and ADT initiation/intensification-free survival after SBRT2 were evaluated with separate multivariable Cox proportional-hazards models., Results: Twenty-five patients were identified. At SBRT2, oligorecurrence was detected on PSMA and Fluciclovine PET in 17 (68%) and 8 (32%) patients, respectively. Fifteen (60%) patients had castration-sensitive disease and 10 (40%) had castration-resistant disease. After SBRT2, 16 (64%) achieved a PSA50 response, median PFS was 11.0mo, and median ADT initiation/intensification-free survival was 23.2mo. On multivariable analysis, maximum percent change in PSA after SBRT1 (OR 0.94, 95%CI 0.88-0.99, P = 0.046) and concurrent change in systemic therapy (OR 21.61, 95%CI 1.12-417.9, P = 0.042) were associated with PSA50 responses after SBRT2. PSA50 response after SBRT1 was associated with improved PFS (HR 0.36, 95%CI 0.00-0.42, P = 0.008) and ADT initiation/intensification-free survival (HR 0.07, 95%CI 0.01-0.68, P = 0.021) after SBRT2. From SBRT1 to last follow-up (median 48 months), 7 (28%) patients remained ADT-free., Conclusions: Serial SBRT for oligometastatic CaP detected on PSMA or Fluciclovine PET is feasible and can achieve PSA declines, with or without systemic therapy. Degree of biochemical response to first SBRT warrants further study as a potential predictor of PSA response, PFS, and ADT initiation/intensification-free survival following a subsequent SBRT course. This preliminary evidence provides rationale for larger, prospective studies of this strategy., Competing Interests: Conflict of interest The authors have no competing financial interests to report in relation to the work described., (Published by Elsevier Inc.)

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., (©2022 American Association for Cancer Research.)

Purpose: To develop techniques and establish a workflow using hyperpolarized carbon-13 ( 13 C) MRI and the pyruvate-to-lactate conversion rate (k PL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies., Methods: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of k PL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T 2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with k PL  >0.02(s -1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-k PL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk., Results: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-k PL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median k PL of 0.0319 s -1 (range: 0.0198-0.0410)., Conclusions: This proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies., (© 2022 International Society for Magnetic Resonance in Medicine.)

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease., Significance: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880., (©2022 The Authors; Published by the American Association for Cancer Research.)

Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring 1 . However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete 2-12 . Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The internet is a common source of health information for patients and can be leveraged to provide patient-facing clinical trial information. This pilot study integrated an online prostate cancer clinical trial matching technology, called Trial Library (TL), in an academic medical oncology clinic from February 2019 to April 2021., Patients and Methods: This is a single-arm interventional pilot study among patients with a known prostate cancer diagnosis. Participants were given access to TL before seeing a provider. The primary and secondary study end points were the overall satisfaction with TL and the proportion of participant-initiated clinical trial discussion with providers after exposure to TL, respectively. The null hypothesis or true satisfaction rate (acceptability) was tested against a one-sided alternative and was rejected if 29 or more satisfactions were observed., Results: Among 272 patients approached, 66 provided informed consent to participate in the study. The mean age was 70.8 years (standard deviation = 7.9). The majority of participants were White (82%) and had metastases present at the time of enrollment (65%). The baseline clinical trial discussion rate ascertained via electronic medical record review was 28%. After accessing TL, a significantly larger proportion of participants (48.5%) discussed clinical trials during the clinic visit ( P = .007), half of which were patient-initiated. The majority of participants indicated that TL increased their interest in clinical trials (68.2%); however, satisfaction/extreme satisfaction with the technology was 38%., Conclusion: Access to TL resulted in a significant increase in patient-initiated discussions regarding clinical trials and an increase in interest in clinical trial participation although these data do not address if this resulted in increased accrual to clinical trials. The satisfaction rate did not meet the target to reject the null hypothesis, suggesting the need for iterative design of patient-facing health information., Competing Interests: Hala T. BornoEmployment: Collective Health, Waymark, Trial LibraryLeadership: Collective Health, Waymark, Trial LibraryStock and Other Ownership Interests: Collective Health, Waymark, Trial LibraryHonoraria: Dendreon, BMS, ConcertAI, AstraZenecaConsulting or Advisory Role: Dendreon, BMS, AstraZeneca Li ZhangConsulting or Advisory Role: Raydiant OximetryTravel, Accommodations, Expenses: Dendreon Rahul AggarwalHonoraria: Clovis OncologyConsulting or Advisory Role: Dendreon, Advanced Accelerator Applications, Clovis Oncology, Axiom Biotechnologies, AstraZeneca, Pfizer, Merck, Amgen, Jubilant Pharmaceuticals, Alessa Therapeutics, Alessa TherapeuticsResearch Funding: Zenith Epigenetics (Inst), Novartis (Inst), Xynomic Pharma (Inst), Cancer Targeted Technology (Inst), Janssen (Inst), Merck (Inst), AbbVie (Inst), Amgen (Inst), AstraZeneca (Inst), BioXCel therapeutics (Inst) Eric J. SmallStock and Other Ownership Interests: Fortis, Harpoon Therapeutics, Teon TherapeuticsHonoraria: Janssen, Johnson and JohnsonConsulting or Advisory Role: Fortis, Janssen Oncology, Teon Therapeutics, Ultragenyx Pharmaceuticals, FortisTravel, Accommodations, Expenses: JanssenOpen Payments Link: https://openpaymentsdata.cms.gov/physician/660367/summaryNo other potential conflicts of interest were reported.

Purpose of Review: Prostate cancer (PCa) is the most frequently diagnosed malignancy in men in developed countries and a leading cause of cancer death worldwide. Effective methods for diagnosing and staging PCa are necessary to guide treatment options in a personalized manner. The purpose of this paper is to review recent advances in molecular imaging and therapeutics and their expanding role in imaging and treating PCa., Recent Findings: Compared with conventional imaging, PSMA PET has proven more accurate at detecting PCa in patients with newly diagnosed PCa or biochemically recurrent PCa. PSMA PET can also induce management changes in patients due to its superior accuracy in detecting metastatic disease. Further research is necessary to understand the appropriate role of PSMA PET in patients with known metastatic PCa and the impact on clinical outcomes in patients who undergo treatment planning using findings from PSMA PET. We review the role of molecular imaging in primary and biochemically recurrent PCa. We find that molecular imaging is effective in detecting PCa and may lead to management changes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated., (© 2021. The Author(s).)

Background: Androgen deprivation therapy (ADT) is associated with numerous toxicities that are potentially modifiable. We sought to evaluate the impact of participation in a multidisciplinary clinic, STAND (Supportive Therapy in Androgen Deprivation) Clinic, designed to provide individualized lifestyle modification and management of ADT-related side effects., Methods: This phase II study recruited men with prostate cancer who had started ADT <6 months prior to enrollment, and in whom ADT was planned for at least 12 months following enrollment. Patients were randomized in a 1:1 ratio to either the STAND Clinic or usual care. Patients randomized to the STAND Clinic were provided monthly multidisciplinary assessment and counseling on exercise, nutrition, and symptom management for 12 months on a rotating schedule. Primary outcome was change from baseline to 12 months in percent body fat. Feasibility outcomes were also assessed by measuring percentage of completed visits. Secondary outcomes included change from baseline to 12 months in 3 domains: (1) metabolic impact and bone health, (2) quality of life (QOL), and (3) physical activity., Results: A total of 25 men were randomized to STAND clinic, and 23 were randomized to usual care. The study did not meet its accrual target of 32 men in each arm and was closed early due to lack of financial support. Overall, 91% (295 of 325) of STAND clinic visits were completed. Eighteen out of the 25 patients in STAND clinic arm (72%) completed all 12 months of STAND clinic visits, and 80% (20 of 25) completed the first 6 months. For all primary and secondary outcomes, there were no statistically significant differences between treatment arms., Conclusion: Individualized and comprehensive management of ADT toxicities in a multidisciplinary clinic was well attended by patients. However, we did not find any differences in the outcomes assessed between the intervention arm and control., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear., Experimental Design: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity., Results: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial., Conclusions: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program., (©2021 The Authors; Published by the American Association for Cancer Research.)

Cell-free DNA (cfDNA) may allow for minimally invasive identification of biologically relevant genomic alterations and genetically distinct tumor subclones. Although existing biomarkers may detect localized prostate cancer, additional strategies interrogating genomic heterogeneity are necessary for identifying and monitoring aggressive disease. In this study, we aimed to evaluate whether circulating tumor DNA can detect genomic alterations present in multiple regions of localized prostate tumor tissue., Methods: Low-pass whole-genome and targeted sequencing with a machine-learning guided 2.5-Mb targeted panel were used to identify single nucleotide variants, small insertions and deletions (indels), and copy-number alterations in cfDNA. The majority of this study focuses on the subset of 21 patients with localized disease, although 45 total individuals were evaluated, including 15 healthy controls and nine men with metastatic castration-resistant prostate cancer. Plasma cfDNA was barcoded with duplex unique molecular identifiers. For localized cases, matched tumor tissue was collected from multiple regions (one to nine samples per patient) for comparison., Results: Somatic tumor variants present in heterogeneous tumor foci from patients with localized disease were detected in cfDNA, and cfDNA mutational burden was found to track with disease severity. Somatic tissue alterations were identified in cfDNA, including nonsynonymous variants in FOXA1 , PTEN, MED12, and ATM . Detection of these overlapping variants was associated with seminal vesicle invasion ( P = .019) and with the number of variants initially found in the matched tumor tissue samples ( P = .0005)., Conclusion: Our findings demonstrate the potential of targeted cfDNA sequencing to detect somatic tissue alterations in heterogeneous, localized prostate cancer, especially in a setting where matched tumor tissue may be unavailable (ie, active surveillance or treatment monitoring)., Competing Interests: John S. Witte Stock and Other Ownership Interests: Avail Bio Expert Testimony: Pfizer, Sanofi No other potential conflicts of interest were reported.John S. Witte Stock and Other Ownership Interests: Avail Bio Expert Testimony: Pfizer, Sanofi No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR 5ng/mL  = 1.34, P = 0.027) or to being a control (OR 5ng/mL  = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR 5bp  = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.

Purpose: We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [ 89 Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models., Experimental Design: [ 89 Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR - , CD46 + , prostate-specific membrane antigen-negative (PSMA - )] or 22Rv1 (AR + , CD46 + , PSMA + ) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545., Results: [ 89 Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [ 89 Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [ 89 Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [ 89 Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection)., Conclusions: [ 89 Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer., (©2020 American Association for Cancer Research.)

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., (©2020 American Association for Cancer Research.)

Despite advances in prostate cancer screening and treatment, available therapy options, particularly in later stages of the disease, remain limited and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in significant variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach to identify patients whose tumors exhibit actionable targets and make more informed treatment decisions. Here we discuss how we can accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms., Competing Interests: Competing Interests Statement. J.M. reports advisory board participation for Amgen, AstraZeneca, Roche, Janssen, MSD and Clovis Oncology; research funding from AstraZeneca and Pfizer Oncology; W.A. reports consulting /advisory for Clovis, Janssen, More Health, ORIC, Daiichi Sankyo; research funding from AstraZeneca, Zenith Epigenetics, Clovis, GlaxoSmithKline, ORIC, Epizyme; travel from GlaxoSmithKline, Clovis, ORIC; and honoraria from CARET. R.R.M. received research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for Bayer, Bristol Myers Squib, Exelixis, Janssen, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion. R.A. reports advisory board participation and research funding from Merck, AstraZeneca, and Janssen; B.M. reports research funding from AstraZeneca, Janssen, Clovis, Astellas, Beigene; M.R. reports consulting: Amgen, Ambryx, Constellation; educational writing and consulting: Plexus; speaking: Bayer, Janssen; funding and clinical research support: Novartis, Astellas, Medivation, Merck; D.B.S. has consulted for/received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, BioBridge, Vivideon Therapeutics, and Illumina; E.V. reports advisory/consulting: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; travel reimbursement: Roche/Genentech; institutional patents on chromatin mutations and immunotherapy response, and methods for clinical interpretation; D.V. reports honoraria from Clovis Oncology. H.B. reports advisory/consulting from Janssen, Amgen, Astra Zeneca, Pfizer, Astellas, Sanofi Genzyme and research funding from Janssen, Abbvie Stemcentryx, Eli Lilly, Millenium, Astellas. J.V. is employed by the Prostate Cancer Clinical Trials Consortium. H.R.S., J.W.S., and A.K.M. are employed by the Prostate Cancer Foundation.

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Background: Hyperpolarized (HP) 13 C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13 C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera., Methods: Six patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13 C-pyruvate, where pyruvate-to-lactate conversion rate (k PL ) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses., Results: We observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean k PL value of 0.020 ± 0.006 (s -1 ) and 0.026 ± 0.000 (s -1 ) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high k PL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of k PL from 0.026 at baseline to 0.015 (s -1 ) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9)., Conclusions: HP 13 C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative k PL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13 C-pyruvate MRI in the setting of advanced prostate cancer.

Survivorship care for patients with prostate cancer requires careful consideration of unique disease-specific factors, including the prolonged natural disease history, the potential for competing health risks, and the consequences of long-term androgen deprivation therapy. However, current prostate cancer survivorship research is unfortunately limited by the lack of a robust supportive evidence base, variability in the definitions and measurement of survivorship outcomes, and a heavy reliance on expert opinion. As a result, the conduct of quality prostate cancer survivorship research is of increasing importance for patients, medical providers, and other key stakeholders. This manuscript harmonizes a path forward for improving prostate cancer survivorship by defining prostate cancer survivorship and survivorship research, as well as by highlighting key research priorities and cooperative mechanisms for survivorship studies within prostate cancer, with a particular focus on men with advanced disease., (Copyright © 2019. Published by Elsevier Inc.)

Agents targeting prostate-specific membrane antigen (PSMA) comprise a rapidly emerging class of radiopharmaceuticals for diagnostic imaging of prostate cancer. Unlike most other PSMA agents with a urea backbone, CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA. We conducted a first-in-humans phase I study of CTT1057 in patients with localized and metastatic prostate cancer. Methods: Two patient cohorts were recruited. Cohort A patients had biopsy-proven localized prostate cancer preceding radical prostatectomy, and cohort B patients had metastatic castration-resistant prostate cancer. Cohort A patients were imaged at multiple time points after intravenous injection with 362 ± 8 MBq of CTT1057 to evaluate the kinetics of CTT1057 and estimate radiation dose profiles. Mean organ-absorbed doses and effective doses were calculated. CTT1057 uptake in the prostate gland and regional lymph nodes was correlated with pathology, PSMA staining, and the results of conventional imaging. In cohort B, patients were imaged 60-120 min after injection of CTT1057. PET images were assessed for overall image quality, and areas of abnormal uptake were contrasted with conventional imaging. Results: In cohort A ( n = 5), the average total effective dose was 0.023 mSv/MBq. The kidneys exhibited the highest absorbed dose, 0.067 mGy/MBq. The absorbed dose of the salivary glands was 0.015 mGy/MBq. For cohort B ( n = 15), CTT1057 PET detected 97 metastatic lesions, and 44 of 56 bone metastases detected on CTT1057 PET (78.5%) were also detectable on bone scanning. Eight of 32 lymph nodes positive on CTT1057 PET (25%) were enlarged by size criteria on CT. Conclusion: CTT1057 is a promising novel phosphoramidate PSMA-targeting 18 F-labeled PET radiopharmaceutical that demonstrates similar biodistribution to urea-based PSMA-targeted agents, with lower exposure to the kidneys and salivary glands. Metastatic lesions are detected with higher sensitivity on CTT1057 imaging than on conventional imaging. Further prospective studies with CTT1057 are warranted to elucidate its role in cancer imaging., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 ( 13 C) applications., Methods: Initial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1- 13 C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.8 K. Following injection of the HP substrate, pyruvate, lactate, and bicarbonate (for brain studies) were sequentially excited with a singleband spectral-spatial RF pulse and signal was rapidly encoded with a single-shot echo planar readout on a slice-by-slice basis. Data were acquired dynamically with a temporal resolution of 2 s for prostate studies and 3 s for brain studies., Results: High pyruvate signal was seen throughout the prostate and brain, with conversion to lactate being shown across studies, whereas bicarbonate production was also detected in the brain. No Nyquist ghost artifacts or obvious geometric distortion from the echo planar readout were observed. The average error in center frequency was 1.2 ± 17.0 and 4.5 ± 1.4 Hz for prostate and brain studies, respectively, below the threshold for spatial shift because of bulk off-resonance., Conclusion: This study demonstrated the feasibility of symmetric EPI to acquire HP 13 C metabolite maps in a clinical setting. As an advance over prior single-slice dynamic or single time point volumetric spectroscopic imaging approaches, this metabolite-specific EPI acquisition provided robust whole-organ coverage for brain and prostate studies while retaining high SNR, spatial resolution, and dynamic temporal resolution., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: Patients with biochemically recurrent prostate cancer and short prostate-specific antigen doubling time (PSADT) are at risk for metastasis yet may wish to avoid androgen deprivation therapy. Itraconazole may have antitumor activity without affecting circulating androgen levels. We therefore evaluated itraconazole as a potentially noncastrating treatment approach in biochemically recurrent prostate cancer., Patients and Methods: Patients with biochemically recurrent prostate cancer and PSADT ≤ 15 months, with serum testosterone > 150 ng/dL, were prospectively enrolled. The primary end point was the proportion of patients who experienced ≥ 50% decline from baseline in serum prostate-specific antigen (PSA) by week 12., Results: Twenty-one patients were enrolled. The median (range) age, baseline PSA, and PSADT at study entry was 72 (49-76) years, 7.6 (1.5-45.5) ng/mL, and 5.7 (1.2-13.0) months, respectively. Among 19 patients with evaluable data, 1 patient (5%) had a > 50% PSA decline. Nine patients (47%) experienced any PSA decline (mean decline 25.0%, range 2%-60%) by week 12. Among 10 patients without a PSA decline, the on-treatment versus pretreatment PSADT was not significantly longer (median 6.8 vs. 4.3 months, P = .17). There was no significant change from baseline to week 12 in serum testosterone (median change = 32.4%, P = .21) or androstenedione (median change = -8.3%, P = .85). The most common adverse events were edema (52%), fatigue (38%), hypertension (24%), and hypokalemia (24%)., Conclusion: Itraconazole modulates serum PSA levels without lowering serum testosterone. However, the magnitude of effect is modest, and treatment carries risk of toxicities associated with mineralocorticoid excess., (Copyright © 2018 Elsevier Inc. All rights reserved.)

MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1- 13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, k PL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in k PL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B 1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate k PL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless k PL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1- 13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1- 13 C]pyruvate parameters (SNR, k PL , bolus characteristics) in the human prostate., (© 2018 John Wiley & Sons, Ltd.)

Purpose: The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1- 13 C]pyruvate to [1- 13 C]lactate with whole gland coverage at high spatial and temporal resolution., Methods: A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1- 13 C]pyruvate. 3D dynamic 13 C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm 3 , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time., Results: Through preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13 C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1- 13 C]pyruvate to [1- 13 C]lactate in a biopsy-proven prostate cancer patient with full gland coverage., Conclusion: The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure k PL , the kinetic rate constant of [1- 13 C]pyruvate to [1- 13 C]lactate conversion., (© 2018 International Society for Magnetic Resonance in Medicine.)

Although initially responsive to androgen signaling inhibitors (ASIs), metastatic castration-resistant prostate cancer (mCRPC) inevitably develops and is incurable. In addition to adenocarcinoma (adeno), neuroendocrine prostate cancer (NEPC) emerges to confer ASI resistance. We have previously combined laser capture microdissection and phage antibody display library selection on human cancer specimens and identified novel internalizing antibodies binding to tumor cells residing in their tissue microenvironment. We identified the target antigen for one of these antibodies as CD46, a multifunctional protein that is best known for negatively regulating the innate immune system. CD46 is overexpressed in primary tumor tissue and CRPC (localized and metastatic; adeno and NEPC), but expressed at low levels on normal tissues except for placental trophoblasts and prostate epithelium. Abiraterone- and enzalutamide-treated mCRPC cells upregulate cell surface CD46 expression. Genomic analysis showed that the CD46 gene is gained in 45% abiraterone-resistant mCRPC patients. We conjugated a tubulin inhibitor to our macropinocytosing anti-CD46 antibody and showed that the resulting antibody-drug conjugate (ADC) potently and selectively kills both adeno and NEPC cell lines in vitro (sub-nM EC50) but not normal cells. CD46 ADC regressed and eliminated an mCRPC cell line xenograft in vivo in both subcutaneous and intrafemoral models. Exploratory toxicology studies of the CD46 ADC in non-human primates demonstrated an acceptable safety profile. Thus, CD46 is an excellent target for antibody-based therapy development, which has potential to be applicable to both adenocarcinoma and neuroendocrine types of mCRPC that are resistant to current treatment.

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging is a highly sensitive tool for the detection of prostate cancer metastases. However, the effect of primary and secondary androgen deprivation therapy (ADT) on PSMA PET uptake has not been described., Objective: To prospectively evaluate changes in 68 Ga-PSMA-11 PET uptake on initiation of androgen receptor (AR)-targeted therapy., Design, Setting, and Participants: Prospective single-institution study of patients with metastatic castration-sensitive (n=4) and castration-resistant prostate cancer (n=4) starting treatment with ADT and enzalutamide, respectively, who underwent serial 68 Ga-PSMA-11 PET imaging before and after treatment initiation., Outcome Measurements and Statistical Analysis: The percentage change in 68 Ga-PSMA-11 PET uptake from baseline was descriptively reported and graphically represented., Results and Limitations: Early increases in PSMA PET tracer uptake in at least one metastatic lesion were observed in six out of seven patients who achieved subsequent prostate-specific antigen declines of >50% from baseline. Overall, 22 of 45 metastatic lesions (49%) exhibited early increases in PSMA uptake that were indicative of a flare effect rather than disease progression. Considerable intra- and interpatient heterogeneity was observed in the temporal pattern of PSMA uptake on treatment initiation. Study limitations include the sample size, the variable timing for scan acquisition, and limited long-term follow up., Conclusions: Tumor flare in PSMA PET tracer uptake in the absence of disease progression is variably observed on initiation of AR-targeted treatment. Further studies are needed to delineate the factors controlling PSMA expression to optimize the diagnostic yield., Patient Summary: Flares of increased prostate-specific membrane antigen (PSMA) tracer uptake on positron emission tomography scans are variably observed following initiation of hormone therapy for prostate cancer and do not necessarily represent disease progression. There was considerable variability in PSMA expression between patients, and further studies are needed to understand the factors controlling PSMA expression., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The purpose of this prospective study was to estimate the effect of 68 Ga-labeled prostate-specific membrane antigen (PSMA)-11 PET on the intended management of patients with biochemically recurrent prostate cancer. Methods: Pre- and postimaging surveys were filled out by the referring providers for patients with biochemical recurrence who were imaged using 68 Ga-PSMA-11 PET. The inclusion criterion for this study was a prostate-specific antigen (PSA) doubling time of less than 12 mo after initial treatment (NCT02611882). Of the 150 consecutive patients imaged, 126 surveys were completed (84% response rate). The responses were categorized as major change, minor change, no change, or unknown change. Results: There were 103 patients (82%) with disease detected on 68 Ga-PSMA-11 PET. On the basis of the survey results, there were 67 patients (53.2%) with major changes in management and 8 patients (6.4%) with minor changes. The proportion of cases resulting in a change in management did not significantly differ by baseline PSA level. In patients with PSA levels below 0.2 ng/dL, 7 of 12 patients had disease detected on 68 Ga-PSMA-11 PET, 5 of whom had a major change in management. Conclusion: 68 Ga-PSMA-11 PET resulted in a major change in management in 53% of patients with biochemical recurrence. Further studies are warranted to investigate whether PSMA-based management strategies result in improved outcomes for patients., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

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 68 Ga-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 68 Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68 Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68 Ga-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 68 Ga-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 68 Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68 Ga-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 ., (©2017 American Association for Cancer Research.)

Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance. Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR. See related commentary by Domchek, p. 937 See related article by Kondrashova et al., p. 984 See related article by Goodall et al., p. 1006 This article is highlighted in the In This Issue feature, p. 920 ., (©2017 American Association for Cancer Research.)

Purpose: The management of advanced or recurrent prostate cancer is limited in part by the lack of effective imaging agents. Metabolic changes in prostate cancer have previously been exploited for imaging, culminating in the recent US FDA approval of [ 11 C]choline for the detection of subclinical recurrent disease after definitive local therapy. Despite this milestone, production of [ 11 C]choline requires an on-site cyclotron, limiting the scope of medical centers at which this scan can be offered. In this pilot study, we tested whether prostate cancer could be imaged with positron emission tomography (PET) using [ 68 Ga]citrate, a radiotracer that targets iron metabolism but is produced without a cyclotron., Procedures: Eight patients with castrate-resistant prostate cancer were enrolled in this single-center feasibility study. All patients had evidence of metastatic disease by standard of care imaging [X-ray computed tomography (CT), bone scan, or magnetic resonance imaging (MRI)] prior to PET with [ 68 Ga]citrate. Patients were intravenously injected with increasing doses of [ 68 Ga]citrate (136.9 to a maximum of 259 MBq). Uptake time was steadily increased from 1 h to approximately 3.5 h for the final 4 patients, and all patients were imaged with a PET/MRI. Qualitative and semi-quantitative (maximum standardized uptake value (SUV max )) assessment of the metastatic lesions was performed and compared to the standard of care imaging., Results: At 1- and 2-h imaging times post injection, there were no detectable lesions with [ 68 Ga]citrate PET. At 3- to 4-h uptake time, there were a total of 71 [ 68 Ga]citrate-positive lesions (67 osseous, 1 liver, and 3 lymph node). Of these, 65 lesions were visible on the standard of care imaging (CT and/or bone scan). One PET-avid osseous vertebral body metastasis was not apparent on either CT or bone scan. Twenty-five lesions were not PET-avid but seen on CT and bone scan (17 bone, 6 lymph node, 1 pleural, and 1 liver). The average of the maximum SUVs for bone or soft tissue metastases for patients treated at higher doses and uptake time was statistically higher than the corresponding parameter in normal liver, muscle, and bone. Visually obvious blood pool activity was observed even 3-4 h post injection, suggesting that further optimization of the [ 68 Ga]citrate imaging protocol is required to maximize signal-to-background ratios., Conclusions: Our preliminary results support that PET with [ 68 Ga]citrate may be a novel tool for imaging prostate cancer. Future studies are needed to determine the optimal imaging protocol, the clinical significance of [ 68 Ga]citrate uptake, and its role in therapeutic decisions.

Background: Androgen deprivation therapy (ADT) remains the cornerstone of primary systemic treatment for men with metastatic disease and is a commonly applied therapy in the biochemically relapsed setting. Despite the high response rate with ADT, resistance is universal. Furthermore, over the past decade, there has been a growing appreciation for the significant short-term and long-term toxicities of continuous ADT (CADT). The rationale to develop alternative androgen receptor (AR) targeting strategies that seek to minimize or eliminate the need for upfront castration therapy is 2-fold-(1) delay the emergence of AR-independent disease, potentially improving long-term disease outcomes and (2) mitigate the short-term and long-term side effects of CADT, improving quality of life and potentially lessening comorbidities related to ADT including osteoporosis, diabetes, and potentially cardiovascular disease. The 2 most rigorously studied alternatives to CADT include intermittent ADT and peripheral androgen blockade with the use of first-generation or second-generation AR antagonists. Both intermittent ADT and peripheral androgen blockade have been evaluated in the biochemically relapsed and metastatic setting in multiple phase 2 and 3 studies., Aim: In the current review, we aim to discuss the data from these studies, as well as the emerging noncastrating strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

After prolonged androgen deprivation therapy, a subset of castrate-resistant prostate cancer patients will develop neuroendocrine prostate cancer (NEPC) associated with resistance to further hormonal therapy and frequent visceral metastases. Imaging the presence of somatostatin receptors on the cancer cell surface may provide a readily available, noninvasive means to distinguish adenocarcinoma from NEPC. This distinction is important for therapeutic decision making and may open the door for developing novel radionuclide targets for the treatment of this aggressive subtype of prostate cancer. We describe a case of NEPC successfully imaged using In-labeled octreotide.

Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy.

Considerable developments in prostate cancer in 2013 have emerged from the imaging field. Hyperpolarized 13C-MRI can monitor metabolic activity to identify high-grade disease and treatment response, and novel PET radiotracers might identify distinct subsets of patients with advanced disease. These examples highlight the progress made at all stages of care.