Prostate Cancer Outcomes Research Articles

Distinct Prostate Cancer Survival Outcomes in Firefighters: A Population-Based Study.

Introduction: Survival outcomes for prostate cancer among specific occupational groups prone to regular medical check-ups vis-à-vis the general population have been understudied. For firefighters, a demographic subject to rigorous medical evaluations, possessing above-average medical expertise, and exposed to specific carcinogens of interest, prostate cancer survival in the US has never been studied. Methods: We conducted a retrospective study, utilizing data from the Florida Cancer Data System spanning 2004 to 2014, coupled with firefighter certification records from the Florida State Fire Marshal's Office. Our study cohort consisted of 1058 prostate cancer cases among firefighters as well as prostate cases for the Florida general population (n = 150,623). We compared cause-specific survival between the two using Cox regression models adjusted for demographics and clinical characteristics, including PSA levels, Gleason scores, and treatment modalities. Results: Firefighters demonstrated a higher five-year cause-specific survival rate (96.1%, 95% CI: 94.7-97.1%) than the general population (94.2%, 95%CI: 94.1-94.3%). Overall, firefighters' diagnoses were established at younger ages (median age 63 vs. 67 in the general population), exhibited a higher proportion of localized stage cancers (84.7% vs. 81.1%), and had a greater utilization of surgery (46.4% vs. 37.6%), a treatment modality with a high success rate but potential side effects. In multivariable analysis, firefighters displayed a survival advantage for localized stage (adjusted hazard ratio [aHR] = 0.53; 95%CI: 0.34-0.82). However, for regional or distant stages, firefighters aged 65 and above exhibited a higher risk of death (aHR = 1.84; 95% CI: 1.18-2.86) than the general population. Conclusion: Firefighters experience enhanced prostate cancer survival, primarily in cases diagnosed at localized stages, likely due to increased PSA testing. Nonetheless, for regional or distant stage, survival among older firefighters' lags behind that of the general population. Further investigations are warranted to unravel factors influencing the development of aggressive disease beyond PSA and Gleason scores in this population, as well as to assess the impact of a higher rate of surgical treatment on firefighters' quality of life.

Abstract 3417: Dissecting tumor microenvironment to predict clinical outcome in prostate cancer

Abstract Prostate cancer is one of the major causes of cancer death in males, and its prevalence is particularly high in developed countries such as the United States and Western Europe. However, death rates in developing and underdeveloped countries are greater, presumably, due to a lack of routine clinical check-ups, poor health awareness, inadequate screening resources, and clinical intervention. Much progress has already been made using cutting-edge technologies like whole genome sequencing, RNAseq, phosphoproteomics, and targeted transcriptomic Nanostring profiling, etc. However, understanding of the prostate tumor microenvironment as a whole in clinical samples remains very limited. Here we use the latest genomic, proteomics, and metabolomic tools not only to understand the biology of prostate cancers but also their correlation with patient demography and clinical outcome. We recruited 80 patients from both tertiary research hospitals and clinical centers in the eastern region of India. All of their demographic information is collected along with their clinical outcome. Pathological evaluation revealed only 50 patients with positive Prostate Carcinoma. We performed a detailed analysis using experimental data (from genomic, and proteomic) in a cohort of patients' routine biomarkers (PSA and PSMA), histopathology, and clinical outcome. Our data demonstrate no linear correlation of any of the individual markers or parameters like AR status, PSA, Prostate Specific Acid Phosphatase, Prostate-Specific Membrane Antigen (PSMA), Alpha-methylacyl-CoA racemase (AMACR), Mesothelin, PD-L1, and other potential genomic and proteomic alterations or any histopathological readouts. However, a clear understanding of the relationship between these multiparameter data, disease pathology, and clinical outcomes in a group of patients has been established. The heterogeneity of these individual data for tumor microenvironments will lead us to identify novel biomarkers for the clinical response of targeted drugs, accelerating personalized treatment strategies. Citation Format: Aritri Bhattacharjee, Manjusha Biswas, Amjad Husain, Asim Kr Das, Sourav Karmakar Karmakar, Tapan Mondal, Pinaki Roy, Manas Kr Mondal, Badal Kumar Sahu, Nabendu Murmu, Partho Nath, Chandra C. Ghosh, Pradip Kumar Majumder. Dissecting tumor microenvironment to predict clinical outcome in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3417.

Abstract 3602: TRAIL-NK-92 MI as a novel adoptive therapy for castration-resistant prostate cancer (CRPC): Preliminary in vitro results

Abstract Introduction: Natural killer (NK) cell tumor infiltration and higher expression of activating receptors NKp30 and NKp46 are associated with improved clinical outcomes in prostate cancer (PC). Activation of NK cells by androgen receptor inhibitors enhanced the killing of PC cell lines (Schwermann 2023). These findings support the therapeutic potential of strategies inducing NK cell activation to treat CRPC. NK cells induce apoptosis of cancer cells via TNF-related apoptosis-inducing ligand) (TRAIL) binding of death receptor 5 (DR5), which is overexpressed in PC cells. This is the first report of adoptive therapy utilizing high expression of TRAIL as a novel therapeutic strategy. Methods: We transduced NK-92-MI and CD4+ (Jurkat) cell lines with human TRAIL (pLVX-EF1alpha-TRAIL-IRES-eGFP).Transduced cells were pre-treated with simvastatin or atorvastatin (4uM) for 36h, followed by stimulation (IL-2 100 IU/ml and IL-12 100 ng/ml) for 2h. The eGFP-expressing cells were then sorted by FACS. PC (PC3, DU145, LNCaP, and 22Rv1), fibroblast (IMR-90), and brain endothelial (hCMEC/D3) cell lines were used in co-culture experiments with non-transduced and transduced NK cells and CD4+ cells. These experiments were quantified using the ImageXpress Confocal HT instrument. Viability assays were performed using Annexin-PI and flow cytometry staining for caspases 3/7. Results: Transduced NK-92 MI cells with TRAIL displayed increased surface expression of TRAIL (control[C]: 4.38%±1; TRAIL-overexpression[NK-TRAIL]: 78.54%±3.76; p<0.001). Co-culture of PC cell lines with TRAIL-NK-92 MI cells resulted in significant tumor-induced apoptosis compared to co-culture with non-transduced NK cells after 48 hours (LNCaP + NK [C]: 16.52%±5, LNCaP + NK-TRAIL: 73.19%±6; PC [C]: 14.4%±3, PC3 + NK-TRAIL: 79%±8; 22Rv1 [C]: 16.78%±1.7, 22Rv1 + NK-TRAIL: 76%±8; DU145 [C]: 13%±4, DU145 + NK-TRAIL: 59.1%±10; p<0.001). This enhanced cytotoxic function was also observed in CD4+ cells expressing high levels of TRAIL. Annexin-PI staining as well as Caspase 3 and 7 showed increased apoptosis in PC co-cultured with NK-TRAIL. Co-culture of NK-TRAIL cells did not affect the viability of the non-malignant cells (IMR-90 and hCMEC/D3) over 48h (IMR-90 + NK: 4.6%±1, IMR-90 + NK-TRAIL: 4.47±2, p=0.9; hCMEC/D3 + NK: 2.7%±0.8, hCMEC/D3 + NK-TRAIL: 2.2±0.5, p>0.99). These results align with the lower expression of DR5 on non-malignant cells compared to PC cell lines (IMR-90: 1.46%±0.5, hCMEC/D3: 1.9%±0.8, LNCaP: 92.3%±4.5). Conclusion: Transduced NK-92 MI cells with human TRAIL-induced higher levels of apoptosis of PC cell lines compared with non-transduced NK cells in co-culture experiments. The results highlight the potential of TRAIL-expressing adoptive cell therapy for CRPC. Engaging adoptive therapies with specific targets (anti-PSMA CAR) might increase the therapeutic potential of this strategy. Citation Format: Maximilian Schwermann, Praveen Srinivasan, William MacDonald, Vida Tajiknia, Andrea Schmidt, Shengliang Zhang, Lindsey Carlsen, Andrew George, Connor Purcell, Shaolei Lu, Matthew Hadfield, Anthony Mega, Benedito Carneiro, Wafik El-Deiry. TRAIL-NK-92 MI as a novel adoptive therapy for castration-resistant prostate cancer (CRPC): Preliminary in vitro results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3602.

Abstract 1548: Olfactomedin 4 deficiency promote de novo progression of prostate cancer in TRAMP mouse model

Abstract Prostate cancer is the most diagnosed solid tumor and the second leading cause of cancer-related death in American men. Olfactomedin (OLFM4) plays tumor suppressor roles and is associated with the initiation, growth, and clinical outcome of human prostate cancer. Olfm4-null mouse sporadically developed prostate epithelial neoplasia through up-regulated hedgehog signaling pathways. In this study, we have generated Olfm4+/+/GFP/TRAMP and Olfm4−/−/TRAMP mouse models to investigate Olfm4 gene biological functions underlying prostate cancer de novo progression. We have observed that Olfm4−/−/TRAMP mice developed more advanced prostate cancer at 47.6% (20/42) compared to Olfm4+/+/TRAMP at 11.9 % (5/42) and had poor survival compared to Olfm4+/+/TRAMP mice (P<0.01). Histopathological and immunofluorescent staining revealed that tumor tissues containing more heterogeneous cells such as Ar+/Ck8+ epithelial or Syn+ neuroendocrinal cells or Vim+/Ck8+ epithelium mesenchymal transition cells in the primary tumors obtained from Olfm4−/−/TRAMP mouse. We found more tumor angiogenesis and metastases into lymph nodes, liver, lung, kidney, and soft tissues in Olfm4−/−/TRAMP mice. The accumulations of the dendritic cell population in primary tumor and lung metastasis tumors were detected. The primary tumor was sensitive to androgen deprivation therapy by using castration with both Olfm4+/+/GFP/TRAMP and Olfm4−/−/TRAMP mice. However, castration-resisted EMT tumor cells or expressing neuroendocrine marker cells regrew after castration 7-8 months in both Olfm4+/+/GFP/TRAMP and Olfm4−/−/TRAMP mice. Furthermore, we tested JQ1, a BET bromodomain inhibitor, as an epigenetic targeted therapy reagent and found that JQ1 significantly inhibited tumor cell growth of Olfm4−/−/TRAMP mouse tumor in the organoids culture. Taken together, we have provided novel evidence that Olfm4 plays a tumor-suppressing role during prostate cancer de novo progression. Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kyung Chin, Griffin P. Rodgers. Olfactomedin 4 deficiency promote de novo progression of prostate cancer in TRAMP mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1548.

Abstract 471: Attenuation of circulating miR-17-5p, miR-20b-5p, and miR-106a-5p in low-risk prostate cancer patients following proton therapy

Abstract Introduction: Liquid biopsies offer a novel approach to diagnose, predict cancer outcomes, and monitor treatment response by analyzing tumor-derived substances. Circulating cell-free microRNAs (miRNAs) show clinical promise as biomarkers within prostate cancer (PCa) and have been implicated with PCa prognosis and outcomes. However, their potential for monitoring and assessing radiotherapy (RT) treatment response remains understudied. Understanding miRNA expression changes during RT is crucial, as they impact RT efficacy by directly affecting genes and proteins within RT-response pathways. Aim: This study aimed to profile the expression of three oncogenes, miR-17-5p, miR-20b-5p, and miR-106a-5p and to determine their association with PCa risk groups in patients receiving proton therapy (PT). Patients and Methods: Plasma was obtained from the University of Florida Health Proton Therapy Institute Outcomes Tracking Protocol biobank. Plasma was collected from men diagnosed with localized PCa without metastatic disease at three time points: prior to PT (PRE-PT), at 4 weeks following the start of PT (4WKSPD1), and at 8 weeks following the start of PT (8WKSPD1). The pilot study consisted of 38 patients, with 23 categorized as low-risk and 15 categorized as high-risk for PCa. MiRNA expression levels were evaluated using reverse transcription-polymerase chain reaction and quantified using the Livak method. Results: The study revealed a downregulation of miR-17-5p in response to PT, with median gene expression levels decreasing from 0.73 at PRE-PT to 0.587 at 8WKSPD1. Low-risk PCa patients also showed distinct miRNA expression changes with all three miRNAs (miR-17-5p, miR-20b-5p, and miR-106a-5p) downregulated from 0.953, 1.037, and 1.010 at PRE-PT to 0.398, 0.216, and 0.298 at 8WKSPD1, respectively. Statistical analysis using a Kruskal-Wallis test followed by a Dunn's post-hoc test identified significant differences (p=0.035) specifically between PRE-PT and 8WKSPD1 for miR-17-5p. Conclusion: The study revealed that PT led to a time-dependent reduction in miRNA levels, indicating a higher responsiveness in low-risk compared to high-risk PCa patients. This differential response highlights miR-17-5p, miR-20b-5p, and miR-106a-5p as potential PT response biomarkers, with clinical implications for personalizing PCa treatment. These results underscore the necessity for further validation of these miRNAs to maximize their clinical utility. Citation Format: Johnny Velasquez, Curtis Bryant, Nancy Mendenhall, Luisel Ricks-Santi. Attenuation of circulating miR-17-5p, miR-20b-5p, and miR-106a-5p in low-risk prostate cancer patients following proton therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 471.

Abstract 2565: Vitamin D deficiency and outcomes in prostate cancer patients: A real-world database

Abstract Introduction: Vitamin D is essential for many bodily functions, including bone health and the prevention of osteoporosis and rickets. In recent years, the importance of vitamin D metabolism in immune system regulation and cancer prevention has been studied with increased focus. With the advent of cancer immunotherapies this has become more important. Multiple recent publications document that vitamin D deficiency is prevalent in cancer patients. This has also been observed specifically in prostate cancer patients, with a high percentage of these deficient patients being of African- American ancestry. It has been theorized that high levels of vitamin D deficiency among African American prostate cancer patients could contribute to worse cancer outcomes and increased health disparities. However, routine vitamin D testing has not been commonly performed in the oncologic community. We hypothesized that deficient levels of vitamin D could lead to inferior prostate cancer outcomes in men with a wide range of ethnic and socio-economic backgrounds. In this project we recorded vitamin D levels in prostate cancer patients at a large community oncology group and evaluated them by stage, pathologic data, survival, race/ethnicity, and other clinical features. Methods: This study is a retrospective, observational study of the data from the electronic medical records of patients with prostate cancer who received vitamin D level testing at Florida Cancer Specialists & Research Institute from 2008- 2023, throughout the state of Florida. All data used in this study will constitute secondary data, it will have been collected originally for clinical use in the general oncology practice setting. No date parameters or patient limits will be applied to this study, and all eligible patients are included. Results: 451 patients with prostate cancer had determination of vitamin D levels, out of a total of 27,772 prostate cancer patients in the database. 38% of the prostate cancer patients analyzed had low 25-OH vitamin D levels (<32 ng/ml). Patients with low vitamin D levels had an average Gleason score of 7.46. Patients with low vitamin D levels who died had an average survival of 144 months. Patients with low vitamin D levels who presented with localized disease had a 35% chance of eventually developing castrate-resistant disease. 45% of the low vitamin D group developed metastatic disease during their course of treatment. Further comparisons of vitamin D levels with pathologic data, survival/longevity, race/ethnicity, and clinical course will be evaluated and presented. Citation Format: Lowell L. Hart, James Reeves, Stacey Garofalo, William Amick. Vitamin D deficiency and outcomes in prostate cancer patients: A real-world database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2565.

Adrenal-Permissive Germline HSD3B1 Allele and Prostate Cancer Outcomes

The adrenal androgen-metabolizing 3β-hydroxysteroid dehydrogenase-1 enzyme, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary for synthesizing nontesticular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding the 3β-HSD1 protein with decreased susceptibility to degradation resulting in higher extragonadal androgen synthesis. Retrospective studies have suggested an association of the HSD3B1 adrenal-permissive homozygous genotype with androgen deprivation therapy resistance in prostate cancer. To evaluate differences in mortality outcomes by HSD3B1 genetic status among men with prostate cancer. This cohort study of patients with prostate cancer who were enrolled in the Million Veteran Program within the Veterans Health Administration (VHA) system between 2011 and 2023 collected genotyping and phenotyping information. HSD3B1 genotype status was categorized as AA (homozygous adrenal-restrictive), AC (heterozygous adrenal-restrictive), or CC (homozygous adrenal-permissive). The primary outcome of this study was prostate cancer-specific mortality (PCSM), defined as the time from diagnosis to death from prostate cancer, censored at the date of last VHA follow-up. Secondary outcomes included incidence of metastases and PCSM in predefined subgroups. Of the 5287 participants (median [IQR] age, 69 [64-74] years), 402 (7.6%) had the CC genotype, 1970 (37.3%) had the AC genotype, and 2915 (55.1%) had the AA genotype. Overall, the primary cause of death for 91 patients (1.7%) was prostate cancer. Cumulative incidence of PCSM at 5 years after prostate cancer diagnosis was higher among men with the CC genotype (4.0%; 95% CI, 1.7%-6.2%) compared with the AC genotype (2.1%; 95% CI, 1.3%-2.8%) and AA genotype (1.9%; 95% CI, 1.3%-2.4%) (P = .02). In the 619 patients who developed metastatic disease at any time, the cumulative incidence of PCSM at 5 years was higher among patients with the CC genotype (36.0%; 95% CI, 16.7%-50.8%) compared with the AC genotype (17.9%; 95% CI, 10.5%-24.7%) and AA genotype (18.5%; 95% CI, 12.0%-24.6%) (P = .01). In this cohort study of US veterans undergoing treatment for prostate cancer at the VHA, the HSD3B1 CC genotype was associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-hydroxysteroid dehydrogenase-1 and the androgen-signaling axis.

Neighborhood Deprivation, Race and Ethnicity, and Prostate Cancer Outcomes Across California Health Care Systems

Non-Hispanic Black (hereafter, Black) individuals experience worse prostate cancer outcomes due to socioeconomic and racial inequities of access to care. Few studies have empirically evaluated these disparities across different health care systems. To describe the racial and ethnic and neighborhood socioeconomic status (nSES) disparities among residents of the same communities who receive prostate cancer care in the US Department of Veterans Affairs (VA) health care system vs other settings. This cohort study obtained data from the VA Central Cancer Registry for veterans with prostate cancer who received care within the VA Greater Los Angeles Healthcare System (VA cohort) and from the California Cancer Registry (CCR) for nonveterans who received care outside the VA setting (CCR cohort). The cohorts consisted of all males with incident prostate cancer who were living within the same US Census tracts. These individuals received care between 2000 and 2018 and were followed up until death from any cause or censoring on December 31, 2018. Data analyses were conducted between September 2022 and December 2023. Health care setting, self-identified race and ethnicity (SIRE), and nSES. The primary outcome was all-cause mortality (ACM). Cox proportional hazards regression models were used to estimate hazard ratios for associations of SIRE and nSES with prostate cancer outcomes in the VA and CCR cohorts. Included in the analysis were 49 461 males with prostate cancer. Of these, 1881 males were in the VA cohort (mean [SD] age, 65.3 [7.7] years; 833 Black individuals [44.3%], 694 non-Hispanic White [hereafter, White] individuals [36.9%], and 354 individuals [18.8%] of other or unknown race). A total of 47 580 individuals were in the CCR cohort (mean [SD] age, 67.0 [9.6] years; 8183 Black individuals [17.2%], 26 206 White individuals [55.1%], and 13 191 individuals [27.8%] of other or unknown race). In the VA cohort, there were no racial disparities observed for metastasis, ACM, or prostate cancer-specific mortality (PCSM). However, in the CCR cohort, the racial disparities were observed for metastasis (adjusted odds ratio [AOR], 1.36; 95% CI, 1.22-1.52), ACM (adjusted hazard ratio [AHR], 1.13; 95% CI, 1.04-1.24), and PCSM (AHR, 1.15; 95% CI, 1.05-1.25). Heterogeneity was observed for the racial disparity in ACM in the VA vs CCR cohorts (AHR, 0.90 [95% CI, 0.76-1.06] vs 1.13 [95% CI, 1.04-1.24]; P = .01). No evidence of nSES disparities was observed for any prostate cancer outcomes in the VA cohort. However, in the CCR cohort, heterogeneity was observed for nSES disparities with ACM (AHR, 0.82; 95% CI, 0.80-0.84; P = .002) and PCSM (AHR, 0.86; 95% CI, 0.82-0.89; P = .007). Results of this study suggest that racial and nSES disparities were wider among patients seeking care outside of the VA health care system. Health systems-related interventions that address access barriers may mitigate racial and socioeconomic disparities in prostate cancer.

Five-year clinical outcomes of scanning carbon-ion radiotherapy for prostate cancer.

Carbon-ion radiotherapy (CIRT) has been associated with favorable clinical outcomes in patients with prostate cancer. At our facility, all patients are treated using scanning CIRT (sCIRT). We retrospectively analyzed five-year clinical outcomes of prostate cancer treated with sCIRT to investigate treatment efficacy and toxicity. In this study, we included 253 consecutive prostate cancer patients treated with sCIRT at the Kanagawa Cancer Center from December 2015 to December 2017. The total dose of sCIRT was set at 51.6 Gy (relative biological effect) in 12 fractions over three weeks. We employed the Phoenix definition for biochemical relapse. The overall survival (OS), biochemical relapse-free (bRF) rate, and cumulative incidence of late toxicity were estimated using the Kaplan-Meier method. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. The median age of the patients was 70 years (range: 47-86 years). The median follow-up duration was 61.1 months (range: 4.1-80.3 months). Eight (3.2%), 88 (34.8%), and 157 (62.1%) patients were in the low-risk, intermediate-risk, and high-risk groups, respectively, according to the D'Amico classification system. The five-year OS and bRF were 97.5% and 93.3%, respectively. The five-year bRF rates for the low-risk, intermediate-risk, and high-risk groups were 87.5%, 93.7%, and 93.4%, respectively (p = 0.7215). The five-year cumulative incidence of Grade 2 or more late genitourinary and gastrointestinal toxicity was 7.4% and 1.2%, respectively. The results of this study show that sCIRT has a favorable therapeutic effect and low toxicity in the treatment of prostate cancer.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Applications of artificial intelligence in prostate cancer histopathology.

The diagnosis of prostate cancer (PCa) depends on the evaluation of core needle biopsies by trained pathologists. Artificial intelligence (AI) derived models have been created to address the challenges posed by pathologists' increasing workload, workforce shortages, and variability in histopathology assessment. These models with histopathological parameters integrated into sophisticated neural networks demonstrate remarkable ability to identify, grade, and predict outcomes for PCa. Though the fully autonomous diagnosis of PCa remains elusive, recently published data suggests that AI has begun to serve as an initial screening tool, an assistant in the form of a real-time interactive interface during histological analysis, and as a second read system to detect false negative diagnoses. Our article aims to describe recent advances and future opportunities for AI in PCa histopathology.

Longer time to testosterone recovery impacts favorably on outcomes for prostate cancer following androgen deprivation and radiotherapy.

To evaluate the impact of sustained hypogonadism after androgen deprivation therapy (ADT) associated with radiotherapy in prostate cancer (PCa) patients with biochemical relapse-free survival (bRFS). Aretrospective cohort analysis of 213consecutive PCa patients referred for radiotherapy plus ADT was carried out. Follow-up times including time to testosterone recovery (TTR) and bRFS were calculated from the end of ADT. Univariate and multivariate Cox regression analyses predicting bRFS were used. The optimal cutoffs for TTR and duration of ADT were determined using the maximally selected rank statistics (MSRS). After amedian follow-up of 104 months, 18patients relapsed among those who had recovered testosterone levels and 9 among those who did not. Median ADT duration was 36months. The optimal cutoff for TTR was determined using MSRS. TTR >48months was significantly associated with better bRFS (logrank, p < 0.0027). Five-year bRFS was 100% for >48months vs. 85% for <48months. TTR was the only significant variable for bRFS in multivariate Cox analysis. Our data show an association between longer TTR and bRFS values among PCa patients treated with ADT.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Focal Minimally Invasive Treatment in Localized Prostate Cancer: Comprehensive Review of Different Possible Strategies.

Focal therapy is a promising, minimally invasive method for the treatment of patients with localized prostate cancer. According to the existing literature, there is growing evidence for positive functional outcomes and oncological effectiveness. The aim of this review is to evaluate the technical efficacy of three minimally invasive techniques (cryoablation, electroporation, and microwave ablation) and their impact on quality of life in patients with prostate cancer. Studies between January 2020 and July 2023 were selected using PubMed, Embase, and The Cochrane Library and analyzed following PRISMA guidelines; they have not been registered. Twenty-three studies investigating three different sources of energy to deliver focal therapy were found. Thirteen studies evaluated the performance of the cryoablation therapy, seven studies of the irreversible electroporation, and three studies of microwave ablation option. The majority of studies were retrospective cohort studies. Cryoablation showed excellent oncological outcomes for low-grade prostate cancer, whether performed on the lesion, on the hemigland, or on the entire gland, with the best results obtained for patients with intermediate risk. Irreversible electroporation showed promising oncological outcomes with no significant changes in functional outcomes. Microwave ablation showed great early functional outcomes. The oncological effectiveness of minimally invasive treatment in comparison to standard of care is still under investigation, despite encouraging results in terms of functional outcomes improvement and adverse events reduction. More comprehensive research is needed to fully understand the function of minimally invasive treatment in patients with localized PCa.

The complex interplay of modifiable risk factors affecting prostate cancer disparities in African American men.

Prostate cancer is the second most commonly diagnosed non-skin malignancy and the second leading cause of cancer death among men in the USA. However, the mortality rate of African American men aged 40-60 years is almost 2.5-fold greater than that of European American men. Despite screening and diagnostic and therapeutic advances, disparities in prostate cancer incidence and outcomes remain prevalent. The reasons that lead to this disparity in outcomes are complex and multifactorial. Established non-modifiable risk factors such as age and genetic predisposition contribute to this disparity; however, evidence suggests that modifiable risk factors (including social determinants of health, diet, steroid hormones, environment and lack of diversity in enrolment in clinical trials) are prominent contributing factors to the racial disparities observed. Disparities involved in the diagnosis, treatment and survival of African American men with prostate cancer have also been correlated with low socioeconomic status, education and lack of access to health care. The effects and complex interactions of prostate cancer modifiable risk factors are important considerations for mitigating the incidence and outcomes of this disease in African American men.

Telemedicine in urologic oncology care: Will telemedicine exacerbate disparities?

IntroductionDisparities in prostate, bladder, and kidney cancer outcomes are associated with access to care. Telemedicine can improve access but may be underutilized by certain patient populations. Our objective was to determine if the patient populations who suffer worse oncologic outcomes are the same as those who are less likely to use telemedicine. MethodsUsing an institutional database, we identified all prostate, bladder and kidney cancer encounters from March 14, 2020 to October 31, 2021 (n = 15,623; n = 4, 14; n = 3,830). Telemedicine was used in 13%, 8%, and 12% of these encounters, respectively. We performed random effects modeling analysis to examine patient and provider characteristics associated with telemedicine use. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were reported as measures of association. ResultsAmong prostate, bladder, and kidney cancer patients, Black patients had lower odds of a telemedicine encounter (OR 0.51, 95% CI 0.37–0.69; OR 0.22, 95% CI 0.07–0.70; OR 0.46, 95% CI 0.24–0.86), and patients residing in small and isolated small rural towns areas had higher odds of a telemedicine encounter (OR 1.44, 95% CI 1.09–1.91; OR 2.12, 95% CI 1.14–3.94; OR 1.89, 95% CI 1.12–3.19). Compared to providers in practice ≤5 years, providers in practice for 6 to 15 years had significantly higher odds of a telemedicine encounter for prostate and bladder cancer patients (OR 4.10, 95% CI 1.4511.58; OR 3.42, 95% CI 1.09–10.77). ConclusionThe lower rates of telemedicine use among Black patients could exacerbate pre-existing disparities in prostate, bladder, and kidney cancer outcomes.

Association of multiparametric magnetic resonance imaging findings with oncologic outcomes in non-palpable localized prostate cancer.

281 Background: Multiparametric magnetic resonance imaging (mpMRI) is becoming increasingly integrated into the evaluation and medical decision making for localized prostate cancer. However, mpMRI findings have not been correlated with prostate cancer outcomes and therefore are not currently included in staging. The purpose of this study was to test the association between mpMRI detected extraprostatic extension with oncologic outcomes in patients with non-palpable prostate cancer. Methods: We used the Veterans Affairs Prostate Data Core to identify patients diagnosed with cT1N0M0 prostate cancer between 2000-2021 with an mpMRI prior to definitive treatment. We reviewed MRI reports to identify presence of extracapsular extension (MRI-T3a), seminal vesicle invasion (MRI-T3b), and adjacent organ invasion (MRI-T4). We assessed the impact of mpMRI findings on metastasis free survival with multivariable Fine-Gray competing-risks regression. Results: Overall, 3,142 veterans with cT1N0M0 prostate cancer were included. There were 1,411 (45%) Black patients. By clinical staging, 904 (29%) had low risk, 1,626 (52%) had intermediate risk, and 612 (19%) had high risk disease. The majority of patients were treated with radiation (N=2,267; 72%). There were 217 (7%) patients with MRI-T3a disease, 87 (3%) patients with MRI-T3b disease, and 26 (1%) patients with MRI-T4 disease. The median follow-up time was 5.4 years (90% CI, 1-13 years). The 5-year cumulative incidence of metastases for patients with low, intermediate, and high risk prostate cancer were 3% (95% CI, 2-4%), 7% (95% CI, 6-8%), and 15% (95% CI, 12-18%). The 5-year cumulative incidence of metastases for patients with MRI-T3a, MRI-T3b, and MRI-T4 disease were 15% (95% CI, 10-20%), 29% (95% CI, 29-39%), and 40% (95% CI, 13-66%). After controlling for age, race, risk stratification (which includes prostate specific antigen (PSA) and grade group), local therapy, and co-morbidities, the presence of MRI-T3a (HR 1.58, 95% CI 1.09-2.29, p=0.02), MRI-T3b (HR 3.38, 95% CI 2.31-4.95, p&lt;0.0001), and MRI-T4 disease (HR 4.47, 95% CI 2.32-8.62, p&lt;0.0001) were independently associated with worse metastasis free survival. Similar results were obtained with PSA and grade group as individual variables. Conclusions: Extraprostatic extension observed on mpMRI is independently prognostic of metastasis free survival in patients with non-palpable prostate cancer. mpMRI is a critical imaging modality that should be widely available for patients with prostate cancer, and studies are ongoing to define its role as a standard staging modality.

Comparison of pathologist and deep learning–based prostate cancer grading for prediction of metastatic outcomes in primary prostate cancer.

345 Background: Gleason grading is the most potent prognostic variable in primary prostate cancer, however inter-observer variability remains a major issue, particularly where subspecialty-trained pathologists are not available. Artificial intelligence algorithms for prostate cancer grading may improve health care equity by ensuring widespread access to standardized, high quality grading, however most algorithms have not been tested for performance with respect to oncologic outcomes. Here, we compared deep learning-based and pathologist-based Gleason grading for prediction of metastatic outcome in three large radical prostatectomy cohorts. Methods: Three previously published radical prostatectomy cohorts from Johns Hopkins were utilized for this study. The Natural History Cohort (n=318, PMID: 26058959) and Case-Cohort (n=231, PMID: 36006048) both utilized a case-cohort design on the outcome of metastasis, while the Race Cohort (n=335, PMID: 30851334) was designed for a grade-matched comparison of self-identified White and Black patients. For each cohort, a single representative H&amp;E-stained slide from the dominant tumor nodule was scanned and Gleason Grade Group (GG) assessed by a modified deep learning-based grading algorithm (PMID: 35233002), or by a subspecialty-trained pathologist. Harrell’s C-indices based on unadjusted Cox models for time to metastasis were compared for the pathologist- and deep learning-assigned GG in each cohort. Results: The C-index for deep learning-assigned GG in the Natural History Cohort was 0.757 (95% confidence interval [CI]: 0.703-0.811) compared to 0.748 (95% CI: 0.692-0.804) for the pathologist-assigned GG. The C-index for deep learning-assigned GG in the Case-Cohort was 0.848 (95% CI: 0.727-0.969) compared to 0.843 (95% CI: 0.722-0.964) for the pathologist-assigned GG. The C-index for deep learning-assigned GG in the Race Cohort was 0.754 (95% CI: 0.697-0.810) compared to 0.780 (95% CI: 0.717-0.844) for the pathologist-assigned GG. In a combined analysis of all three cohorts, the C-index for the deep learning-assigned GG was 0.765 (95% CI: 0.725-0.805) compared to 0.772 (95% CI: 0.730-0.814) for the pathologist-assigned grade group. In the combined cohorts, the historical pathologist-assigned GG for the entire case had a C-index of 0.796 (95% CI: 0.757-0.836). Conclusions: Deep learning and subspecialty-trained pathologist grading were highly comparable for association with metastatic outcome across three large radical prostatectomy cohorts.

A safety net for safety net hospitals: Affiliation with cancer centers and survival outcomes in patients with metastatic genitourinary cancers.

543 Background: Safety net hospitals (SNH) care for a substantial proportion of medically vulnerable populations (MVP). Addressing health disparities at a hospital level through partnerships with cancer centers is a potential strategy to improve outcomes of MVPs. We thus compared outcomes for metastatic prostate (mPCa), kidney (mKCa), and urothelial cancer (mUCC) among National Cancer Institute centers (NCI), NCI affiliated SNH (NCI-SNH), and non-affiliated SNH using the Texas Cancer Registry (TCR). Methods: The TCR has 98% case ascertainment of all cancers diagnosed in Texas. The TCR can identify each facility where a patient was diagnosed and treated, allowing detailed hospital level comparisons of outcomes. The TCR was queried from 2004-2017 for mPCa, mKCa, and mUCC. Publicly available data identified Texas NCIs. The top quartile of Disproportionate Share Hospital Index values identified SNH. SNH with established relationships to NCI were designated NCI-SNH and remainder were SNH. Non-SNH were hospitals not affiliated with NCI nor SNH. MVPs were defined as age &gt; 75, non-US natives, non-whites, and uninsured or Medicaid patients. Cox multivariable regression was used to assess overall mortality (OM). Results: Of the 1,048,464 patients in TCR, MVPs accounted for 44.7% of cases. The SNHs and NCI-SNHs accounted for 53.1% of all MVP cancer care statewide. MVPs were the majority of cases within NCI-SNH compared to other SNH or NCI (80% vs 45% vs 37.1%, p&lt;0.01). TCR identified 20,503 metastatic genitourinary (GU) cancers. For mPCa, rates of hormone therapy were similar between NCI-SNH (76.7%) and NCI (76.2%), but greater than SNH (51.5%) or non-SNH (49.7%) ( p&lt;0.01). Receipt of chemotherapy or immunotherapy was greater at NCI-SNH compared to other SNH or non-SNH for both mKCa (36.1% vs 31.1% vs 27.1%, p&lt;0.01) and mUCC (44.0% vs 36.7% vs 33.2%, p&lt;0.01). On multivariable cox analysis, equivalent OM between NCI and NCI-SNH for any metastatic GU cancer (Table). OM was worse at other SNH and non-SNH compared to NCI (Table). Conclusions: Medically vulnerable patients made up almost half of cancer care in Texas and majority were cared for at SNH. NCI-SNHs had equivalent OM to NCI and superior OM compared to other SNH. Future initiatives to improve cancer care should focus on strengthening existing relationships between NCI and SNH, and examine mechanisms to centralize care of MVPs to these facilities.[Table: see text]

Real-world effects of novel androgen receptor axis-targeted agents on oncological outcomes in non-metastatic castration-resistant prostate cancer: A multi-institutional retrospective study.

142 Background: The benefits of novel androgen receptor axis-targeted agents (ARATs) on oncological outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in real-world settings are unclear. Methods: This multi-institutional retrospective study included 178 patients with nmCRPC treated between September 2003 and August 2022. Patients were divided into two groups: those who were treated with any novel ARATs, including apalutamide, enzalutamide, darolutamide, and abiraterone acetate, during any line of nmCRPC treatment (novel ARATs group) and those who were not (control group). Multivariable Cox proportional hazards regression analyses were performed to evaluate the effects of novel ARATs on metastasis-free survival (MFS) and overall survival (OS). Results: The median age and follow-up period after nmCRPC diagnosis were 76 years and 37 months, respectively. Of the 178 patients, 122 (69%) were treated with novel ARATs after nmCRPC diagnosis. The MFS and OS in the novel ARATs group were significantly longer than those in the control group ( P &lt; 0.001 and P = 0.020, respectively). In multivariable analyses, a prostate-specific antigen doubling time (PSADT) of &lt; 3 months and novel ARATs were independently and significantly associated with MFS and OS (Table). The effects of novel ARATs on MFS were consistently observed across subgroups stratified by age (&lt; 75 years or ≥ 75 years), history of radical treatment (no or yes), biopsy Gleason score (&lt; 9 or ≥ 9), clinical stage (≤ cT3 and cN0, or cT4 or cN1), and PSADT (≥ 3 months or &lt; 3 months). Conclusions: Novel ARATs were significantly associated with improved oncological outcomes in patients with nmCRPC in a real-world setting, regardless of tumor aggressiveness. [Table: see text]