Be bold, start cold! cold formalin fixation of colorectal cancer specimens granted superior DNA and RNA quality for downstream molecular analysis.

The use of cold formalin fixation (CFF; i.e., fixating tissue samples with 4 °C precooled formalin) recently attracted further attention owing to its putative improved ability to preserve nucleic acid compared with standard room temperature formalin (SFF). In this study, we aimed to assess the effect of four formalin-based fixation protocols (SFF, CFF, delayed formalin fixation-DFF, and cold formalin hyperfixation; CFH) on both DNA and RNA quality. We collected 97 colorectal cancer (CRC) and analyzed 23 metrics of nucleic acid quantity and quality yield using a multiplatform approach by combining spectrophotometric, fluorimetric, electrophoretic, and polymerase chain reaction (PCR) assays. Following confirmation of fixation-protocol-related different effects via clustering analysis, CFF presented best metrics compared with all protocols, specifically positive coefficients of DV1000-60000, DV2/DV1, DNA λ ratio 260/230, and ABL gene expression absolute copies, and negative coefficient of DV150-1000. The SFF subgroup presented a positive coefficient of DV150-1000 and negative coefficients for DV1000-60000, DV2/DV1, RNA λ ratio 260/230, RNA QuBit concentration, DV100/200, RNA electrophoresis concentration and absolute quantity, and ABL copies. Overall, we confirmed the superior yield performances of CFF preservation for both DNA and RNA compared with the other protocols in our series of CRC samples. Pending further validations and clarification of the specific mechanisms behind these findings, our study supports the implementation of CFF in the pathology unit routine specimen management for tumor tissue molecular profiling.

The Use of Magnetic Resonance Imaging in Radiation Therapy Treatment Simulation and Planning.

Ever since its introduction as a diagnostic imaging tool the potential of magnetic resonance imaging (MRI) in radiation therapy (RT) treatment simulation and planning has been recognized. Recent technical advances have addressed many of the impediments to use of this technology and as a result have resulted in rapid and growing adoption of MRI in RT. The purpose of this article is to provide a broad review of the multiple uses of MR in the RT treatment simulation and planning process, identify several of the most used clinical scenarios in which MR is integral to the simulation and planning process, highlight existing limitations and provide multiple unmet needs thereby highlighting opportunities for the diagnostic MR imaging community to contribute and collaborate with our oncology colleagues. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 5.

Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

PURPOSE: Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. METHODS: We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. RESULTS: For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36 months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. CONCLUSION: Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

Systematic review and recommendations for re-irradiation for intraprostatic radiorecurrent prostate cancer after definitive radiation therapy.

PURPOSE: Intraprostatic recurrence (IRR) of prostate cancer after radiation therapy is increasingly identified. Our objective was to review the literature to determine the optimal workup for identifying IRR, the management options, and practical considerations for the delivery of re-irradiation as salvage local therapy. METHODS: We performed a systematic review of available publications and ongoing studies on the topics of IRR, with a focus on salvage re-irradiation. RESULTS: Work up of biochemically recurrent prostate cancer includes PSMA PET/CT and multiparametric MRI, followed by biopsy to confirm IRR. Management options include continued surveillance, palliative hormonal therapy, and salvage local therapy. Salvage local therapy can be delivered using re-irradiation with low dose rate brachytherapy, high dose rate (HDR) brachytherapy, and stereotactic body radiotherapy (SBRT), as well as non-radiation modalities, such as cryotherapy, high-intensity focused ultrasound, irreversible electroporation and radical prostatectomy. Data demonstrate that HDR brachytherapy and SBRT have similar efficacy compared to the other salvage local therapy modalities, while having more favorable side effect profiles. Recommendations for radiation therapy planning and delivery using HDR and SBRT based on the available literature are discussed. CONCLUSION: Salvage re-irradiation is safe and effective and should be considered in patients with IRR.

Impact of PSMA PET on Prostate Cancer Management.

OPINION STATEMENT: PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.

Actionable Genomic Alterations in Prostate Cancer Among Black and White United States Veterans.

Black Veterans have higher a incidence of localized and metastatic prostate cancer compared to White Veterans yet are underrepresented in reports of frequencies of somatic and germline alterations. This retrospective analysis of somatic and putative germline alterations was conducted in a large cohort of Veterans with prostate cancer (N = 835 Black, 1613 White) who underwent next generation sequencing through the VA Precision Oncology Program, which facilitates molecular testing for Veterans with metastatic cancer. No differences were observed in gene alterations for FDA approved targetable therapies (13.5% in Black Veterans vs. 15.5% in White Veterans, P = .21), nor in any potentially actionable alterations (25.5% vs. 28.7%, P =.1). Black Veterans had higher rates of BRAF (5.5% vs. 2.6%, P < .001) alterations, White Veterans TMPRSS2 fusions (27.2% vs. 11.7%, P < .0001). Putative germline alteration rates were higher in White Veterans (12.0% vs. 6.1%, P < .0001). Racial disparities in outcome are unlikely attributable to acquired somatic alterations in actionable pathways.

LUNAR: a randomized Phase 2 study of 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (clinical trial protocol).

OBJECTIVE: To assess the efficacy of 177 Lu-PNT2002, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in combination with stereotactic body radiotherapy (SBRT) to all sites of metastasis, vs SBRT alone, in men with oligorecurrent metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: The 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR) trial is an open-label, randomized, stratified, two-arm, single-centre, Phase 2 trial to compare the efficacy and safety of neoadjuvant 177 Lu-PNT2002 plus SBRT vs SBRT alone in men with oligorecurrent mHSPC. Key eligibility criteria include one to five lesions identified on a PSMA positron emission tomography (PET)/computed tomography (CT) scan centrally reviewed by a board-certified nuclear medicine physician. Key exclusion criteria include castrate-resistant disease, de novo oligometastatic disease and receipt of androgen deprivation therapy (ADT) within 6 months of trial enrolment. The trial aims to enrol 100 patients who will be centrally randomized to one of the two treatment arms, in a 1:1 ratio. Patients in the control arm receive SBRT to all sites of disease. Patients in the experimental arm receive two cycles of neoadjuvant 177 Lu-PNT2002 (6.8 GBq) 6-8 weeks apart, followed by an interval PSMA PET/CT in 4-6 weeks and dose-adapted SBRT to all sites of disease 1-2 weeks later. The primary endpoint is progression-free survival. Secondary endpoints are radiographic and prostate-specific antigen-based progression, acute and late physician-scored toxicity, patient-reported quality of life, ADT-free survival, time to progression, overall survival, locoregional control, and duration of response. Enrolment in the study commenced in September 2022. RESULTS AND CONCLUSIONS: The addition of 177 Lu-PNT2002 to metastasis-directed therapy alone may potentially further forestall disease progression. The results of this Phase 2 trial will determine, for the first time in a randomized fashion, the added benefit of 177 Lu-PNT2002 to SBRT in patients with oligorecurrent mHSPC.

Multimodality Therapies for Localized Prostate Cancer.

PURPOSE OF REVIEW: Multimodality therapy including radical prostatectomy, radiation therapy, and hormone therapy are frequently deployed in the management of localized prostate cancer. We sought to perform a critical appraisal of the most contemporary literature focusing on the multimodality management of localized prostate cancer. RECENT FINDINGS: Men who are ideal candidates for multimodality therapy include those with unfavorable intermediate-risk disease, high-risk disease, and very high-risk disease. Enhancements in both systemic agents (including second-generation antiandrogens) as well as localized therapies (such as stereotactic body radiotherapy and brachytherapy) are refining the optimal balance between the use of systemic and local therapies for localized prostate cancer. Genomic predictors are emerging as critical tools for more precisely allocating treatment intensification with multimodality therapies as well as treatment de-intensification. Close collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based multimodality therapies when clearly indicated and for supporting shared decision-making in areas where the evidence is mixed.

Selecting the optimal radiation modality in prostate cancer.

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. Classic clinical trials have established the basic tenets of treatment approaches, and emerging data have generated new potential avenues of treatment that optimize the therapeutic ratio by increasing prostate cancer tumor control while minimizing treatment-related toxicity. In the definitive setting, the selection of the optimal radiation therapy approach depends largely on the appropriate up-front risk stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. Hormonal therapy should be selectively deployed based on prognostic information derived from the National Comprehensive Cancer Network risk group and biologic tumor aggressiveness informed by genomic classifiers. Moreover, treatment intensification and target volume delineation are increasingly informed by molecular imaging and multiparametric magnetic resonance imaging. Herein, we perform a critical appraisal of the literature focusing on the optimal selection of radiation therapy modality for localized prostate cancer. Collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based radiation therapies when clearly indicated and for supporting shared decision-making when the evidence is incomplete.

Methods for restoration of ki67 antigenicity in aged paraffin tissue blocks.

Pathology archives are a treasure trove of paraffin embedded tissue spanning many years and covering a wide variety of tissues and diseases. The possibility of using old archival formalin fixed paraffin embedded (FFPE) tissues for diagnostic updates and research projects is a widespread need and it requires archives of stable, well-preserved samples. Immunohistochemistry performed on old archival paraffin blocks may give unreliable results, in particular for some antigens, such as Ki67. In consideration of this phenomenon, our aim is to comprehensively test and identify methods which may be used to obtain Ki67 immunohistochemical reactions of good quality from old archival FFPE blocks. Various methods were tested in order to evaluate their possible efficacy in increasing Ki67 immunointensity in a collection of 40-year-old, archival blocks including re-embedding, with deeper sectioning of tissue from the block and increasing heat-based pretreatment times (20 cases) and re-processing (20 cases). All reactions were performed using an automated immunostainer and Ki67 stained immunosections compared using a visual colour-based scale (the first immunostained section was considered as baseline). The combination of deep sectioning (1000 µM) and prolonged heat-based pretreatment (64 min) markedly increased immunoreactivity for Ki67. Re-embedding and reprocessing did not have a significant effect. Large tissue samples showed heterogeneity of Ki67 immunoexpression between the periphery of the sample and the central area. In conclusion, the study defines a useful protocol to increase antigen retrieval applicable to dated archival tissues.

Non gastro-esophageal reflux disease related esophagitis: an overview with a histologic diagnostic approach.

Several pathological conditions, other than gastro-esophageal reflux disease and its complications, can affect the esophagus. While some of these can present with unspecific lesions (i.e. ulcers and epithelial damage) and require clinico-pathological correlation for diagnosis (i.e. drug-induced esophagitis and corrosive esophagitis) other conditions show distinctive histological lesions which enable the pathologist to reach the diagnosis (i.e. some specific infectious esophagites and Crohn's disease). In this context eosinophilic esophagitis is the condition which has been increasingly studied in the last two decades, while lymphocytic esophagitis, a relatively new entity, still represents an enigma. This overview will focus on and describe histologic lesions which allow pathologists to differentiate between these conditions.

Hypofractionated whole breast radiotherapy in breast conservation for early-stage breast cancer: a systematic review and meta-analysis of randomized trials.

PURPOSE: Breast conservation therapy (BCT) for early-stage breast cancer involves lumpectomy followed by whole breast radiotherapy, which can involve either standard fractionation (SRT) or accelerated fractionation (ART). This systematic review and meta-analysis was performed to determine whether any benefit exists for ART or SRT. MATERIALS AND METHODS: We searched MEDLINE (1966-2014), all seven databases of the Cochrane Library (1968-2014), EMBASE (1974-2014), clinicaltrials.gov, ISRCTN, WHO ICTRP, and meeting abstracts in the Web of Science Core Collection (1900-2014). RCTs comparing SRT to ART among women undergoing BCT with stage T1-T2 and/or N1 breast cancer or carcinoma in situ were included. Follow-up was 30 days for acute toxicity, or three years for disease control and late toxicity. RESULTS: 13 trials with 8189 participants were included. No differences were observed in local failure (n = 7 trials; RR 0.97; 95% CI 0.78-1.19, I 2 = 0%), locoregional failure, (n = 8 trials; RR 0.86; 95% CI 0.63-1.16, I 2 = 0%), or survival (n = 4 trials; RR 1.00; 95% CI 0.85-1.17, I 2 = 0%). ART was associated with significantly less acute toxicity (n = 5 trials; RR 0.36; 95% CI 0.21-0.62, I 2 = 20%), but no difference in late cosmesis (RR 0.95; 95% CI 0.81-1.12, I 2 = 54%). CONCLUSIONS: ART use does not reduce disease control or worsen long-term cosmetic outcome, and may decrease the risk of acute radiation toxicity as compared to SRT.

Biodegradable and gas barrier polylactic acid/star-shaped polycaprolactone blend films functionalized with a bio-sourced polyelectrolyte coating.

This work aims at improving and disclosing new properties of films based on polylactic acid (PLA) and a star-shaped polycaprolactone (PCL). Indeed, previous works demonstrated that the presence of ad-hoc synthesized PCL, characterized by low molecular weight and carboxyl end groups (coded as PCL-COOH), improves the elongation at break of the films compared to that of neat PLA and increases their functionality. To further improve the properties of the system, alternating layers of chitosan (CH) and DNA were deposited on the surface applying a Layer-by-Layer (LbL) technique. This method was chosen because it allows the properties of the system to be modified without affecting the specific features of the bulk. In addition, the LbL technique is easily scalable and environmentally friendly because it is based on the use of an aqueous solution of two biomaterials, namely DNA and CH, which are not only derived from renewable sources but are also biocompatible and biodegradable. IR measurements on model silicon substrates subjected to the same treatment as the films, pointed out a linear growth of the proposed LbL assembly. Indeed, FE-SEM measurements highlighted the deposition of a uniform coating. The presence of the CH/DNA assembly reduced the oxygen permeability under both dry and humid (50% R.H.) conditions when compared to the uncoated film. In addition, the coating had no relevant effect on the hydrolytic and enzymatic degradation of the system, so that the biodegradability of the film was maintained.

MRI-Guided Radiotherapy for Prostate Cancer: Seeing is Believing.

The advent of MRI guided radiotherapy (MRIgRT) offers enormous promise in the treatment of prostate cancer. The MR-linac offers men the opportunity to receive daily MR imaging to guide and influence their radiotherapy treatment. This review focuses on the advantages that MRIgRT potentially offers as well as any potential disadvantages to MRIgRT that may have been recognized thus far. Ongoing clinical trials evaluating this novel treatment platform for the treatment of prostate cancer are also discussed.

MRI-Guided Radiation Therapy-An Emerging and Disruptive Process of Care: Healthcare Economic and Policy Considerations.

MRI-guided radiation therapy (MRgRT) is an emerging, innovative technology that provides opportunities to transform and improve the current clinical care process in radiation oncology. As with many new technologies in radiation oncology, careful evaluation from a healthcare economic and policy perspective is required for its successful implementation. In this review article, we describe the current evidence surrounding MRgRT, framing it within the context of value within the healthcare system. Additionally, we highlight areas in which MRgRT may disrupt the current process of care, and discuss the evidence thresholds and timeline required for the widespread adoption of this promising technology.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer (SATURN): Primary Endpoint Results from a Phase 2 Clinical Trial.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA) <0.05 ng/ml 6 mo after testosterone recovery (≥150 ng/dl), with the study powered to detect an improvement from 1% to 12%. We enrolled 28 men between March 2021 and June 2022. Median follow-up was 20 mo (interquartile range 16-22). Twenty-six patients (93%) completed SBRT with 6 mo of hormone therapy, of whom six discontinued at least one ARPI; two patients withdrew prematurely. At 6 mo after testosterone recovery, PSA was maintained at <0.05 ng/ml in 13/26 patients (50%, 95% confidence interval 32-67%). Rates of grade 2 and 3 AAT toxicity were 21% and 21%. The results confirm that addition of metastasis-directed SBRT to highly potent systemic therapy can maintain low PSA after testosterone recovery, although further studies are needed to clarify the optimal systemic therapy regimen. PATIENT SUMMARY: We tested a combination of intensified hormone therapy (called androgen annihilation therapy) and radiotherapy targeted at metastases in men with recurrence of metastatic prostate cancer. We found that half of patients were recurrence-free 6 months after their testosterone level recovered, and that less than a quarter of patients experienced a severe drug-related side effect. Overall, this appears to be an effective therapy with acceptable side effects. This trial is registered on ClinicalTrials.gov as NCT03902951.

Prostate-Specific Membrane Antigen PET/CT-Guided, Metastasis-Directed Radiotherapy for Oligometastatic Castration-Resistant Prostate Cancer.

Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy, androgen receptor pathway inhibitors, chemotherapy, and radiopharmaceuticals, all of which have associated toxicity. Prostate-specific membrane antigen (PSMA) PET/CT allows for higher sensitivity in detecting metastatic disease than is possible with conventional imaging. We hypothesized that PSMA PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastases. Methods: We retrospectively screened 5 prospective PSMA PET/CT studies for patients with mCRPC who had up to 5 sites of oligorecurrent or oligoprogressive disease on PSMA PET/CT and subsequently received definitive-intent, metastasis-directed radiotherapy to all new or progressing sites with concurrent androgen deprivation therapy. Progression-free survival, freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Biochemical response was defined as at least a 50% decrease in prostate-specific antigen 6 mo after the start of treatment. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 5. Results: Twenty-four patients met the inclusion criteria with a median follow-up of 33.8 mo (interquartile range, 27.6-45.1 mo). Between October 2017 and April 2023, 11 patients (45.8%) had 1 treated site, 10 patients (41.7%) had 2, and 3 patients (12.5%) had 3. Five sites were prostate or prostate bed, 15 were nodal, 19 were osseous, and 1 was visceral. Seventeen patients (70.8%) continued their preexisting systemic therapy, whereas 7 (29.2%) started a new systemic therapy. Median progression-free survival was 16.4 mo (95% CI, 9.8-23.0 mo). The biochemical response rate was 66.7%. Median freedom from a new line of systemic therapy was 29.0 mo (95% CI, 7.6-50.4 mo). Median OS was not reached. The 2- and 4-y OS rates were 91.1% (95% CI, 79.3%-100%) and 68.8% (95% CI, 45.1%-92.5%), respectively. Grade 2 and grade 3 or higher toxicity rates were 4.2% and 0%, respectively. Conclusion: PSMA PET/CT-guided, metastasis-directed radiotherapy appears to offer durable disease control with low toxicity rates for oligometastatic castration-resistant prostate cancer. Further prospective studies are needed to compare metastasis-directed radiotherapy with systemic therapy versus systemic therapy alone and PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

Oncogenic Alterations, Race, and Survival in US Veterans with Metastatic Prostate Cancer Undergoing Somatic Tumor Next Generation Sequencing.

Purpose: National guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans. Patients and Methods: This retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival. Results: 5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations in SPOP (OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]). Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes including TP53 were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]). Conclusion: In the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.