The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

Background/Objectives: This study explored whether a multimodal artificial intelligence (MMAI) model integrating digitized histopathology and clinical features can identify prostate cancer patients who may benefit from neoadjuvant hormonal therapy (NHT) and whole-pelvic radiotherapy (WPRT). Methods: This secondary analysis of NRG/RTOG 9413 included NHT-treated patients with digitized biopsy slides and clinical data who were not part of the MMAI model optimization. A previously validated MMAI model estimated long-term risk, and Fine-Gray models evaluated interactions between MMAI-derived scores and the radiation field (WPRT vs. prostate-only RT [PORT]) for biochemical failure (BF), chosen over progression-free survival because of extended follow-up and distant metastasis (DM), with subgroup analyses by predefined MMAI strata. Results: Among 81 eligible patients, the MMAI-by-treatment interaction for BF did not confirm a differential effect (p = 0.30). Therefore, subgroup findings should be interpreted as descriptive and hypothesis-generating. Nevertheless, the magnitude effect of WPRT was numerically greater in the MMAI high-risk subgroup (5-yr: 41% vs. 79%; 10-yr: 47% vs. 79%; aHR 0.35 [0.14-0.86]) than in the low-intermediate group (5-yr: 18% vs. 33%; 10-yr: 44% vs. 57%; aHR 0.66 [0.29-1.48]). Conclusions: Although no statistically significant treatment-by-MMAI interaction was demonstrated, these findings are hypothesis-generating and support further investigation of MMAI approaches for guiding WPRT in NRG/RTOG 0534, 0924, GETUG-01, and POP-RT trials.

5000 Background: Outcomes for some patients with ≥high-risk localized prostate cancer (HR-PCa) who receive radiation therapy (RT) remain poor. Current guidelines recommend intensification with abiraterone/prednisone (AAP) in select patients; however, the current guideline-defined candidate population may be suboptimal. Methods: This is a secondary analysis of available biopsy samples from NRG/RTOG 9202, 9413, 9902, and 0521. The primary objective was to determine if a specific subgroup of ≥HR-PCa patients had sufficiently poor prognoses to derive a clinically meaningful benefit from AAP intensification. The prognostic impact of the Decipher 22-gene genomic classifier (GC; Veracyte, San Diego, CA) was first evaluated for metastasis-free survival (MFS, primary), overall survival (OS), and distant metastases (DM). GC scores were analyzed using both continuous (per 0.1 GC units) and pre-specified categorical cutpoints: ≤ intermediate transcriptomic risk (IR-PCa, GC≤0.6), HR-PCa (GC:0.6-0.85), and very high risk (VHR-PCa, GC > 0.85). A tree-based model was then used to combine clinical and transcriptomic risk category. Results: This study characterized outcomes of 427 patients (64% NCCN HR-PCa; 36% NCCN VHR-PCa) with a median follow-up of 10.4 years. Continuous GC score was observed to discriminate risk when adjusted for age, PSA, grade, T-stage, and treatment received for the endpoints of MFS (HR GC :1.19 [95% CI:1.10-1.29], p < 0.001), DM (HR GC :1.31 [95% CI:1.13-1.51], p < 0.001), and OS (HR GC : 1.18 [95% CI: 1.09-1.28], p < 0.001). MFS and OS were estimated using the Kaplan-Meier method by pre-specified GC subgroup within each NCCN risk group (HR-PCa, VHR-PCa). Based on outcomes by subgroup, a novel clinico-transcriptomic risk stratification system was constructed, where patients receive 1 point for NCCN/GC HR categorization and 2 points for NCCN/GC VHR categorization. The combined risk score ≥3 subgroup had a prognosis similar to the STAMPEDE M0 control arm, whereas the combined score ≤2 subgroup had a substantially better prognosis. Utilizing this system could enhance the specificity of AAP recommendations, increasing the candidate pool eligible for AAP intensification by approximately 20% and identifying approximately 25% of NCCN VHR in whom the therapeutic ratio of AAP may be less favorable. Conclusions: This study defines a novel clinico-transcriptomic risk stratification system to augment current clinical eligibility for AAP intensification. This system may increase the population who benefit from AAP by approximately 20% and simultaneously identify approximately 25% of NCCN VHR patients who may avoid AAP intensification. Acknowledgement: We would like to acknowledge Dr. Felix Feng for his contributions in his capacity as the former GU Committee Chair.

We present findings from town hall meetings held with ethnically diverse Black prostate cancer (CaP) survivors in 2022 and 2023. Four town halls (total participants, N = 265) focused on diagnosis, treatment, psychosocial support, and overall survivorship. Moderated by a long-term CaP survivor, each session featured a panel that included medical providers (urologic oncologists and clinical psychologists), as well as CaP survivors of American, Caribbean, and African origin and their spouses. Surveys captured demographic data, clinical information, CaP-specific details (for survivors only), and perceptions of the town halls. The meetings highlighted three interrelated themesinfluencing decision-making: access to comprehensive information, the strength of support networks, and the availability of culturally competent care. These town halls revealed important educational and support opportunities for ethnically diverse Black men with CaP, promoting informed decision-making throughout the cancer journey and improving quality of life while reducing decisional regret during survivorship.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Purpose NRG/RTOG 1115 was a phase 3 trial evaluating the addition of orteronel, a CYP17A1 inhibitor, to radiation therapy (RT) plus androgen deprivation therapy (ADT) in men with high-risk prostate cancer. Methods and Materials The study was designed to evaluate overall survival for 900 men with high-risk prostate cancer (Gleason 9-10, prostate specific antigen (PSA) > 20, or clinical stage T2 or higher with Gleason ≥ 8). Patients were randomized 1:1 to standard of care (SOC) therapy (RT plus 2 years of ADT) or SOC plus 2 years of orteronel. RT entailed image guided conventionally fractionated dose-escalated external beam RT to the prostate and pelvis to 45 Gy using intensity modulated RT with either intensity modulated RT (to 79.2 Gy) or brachytherapy boost. Health-related quality of life (HRQOL) was measured using the Expanded Prostate cancer Index Composite (EPIC), Patient-Reported Outcome Measurement Information System (PROMIS) fatigue, and EQ-5D. Accrual was halted early because of discontinuation of orteronel development and the trial redesigned to focus on a composite biochemical failure endpoint. Results There were a total of 231 eligible randomized patients. Only 29% in the orteronel arm received ≥80% of the planned dose. With median follow-up of 6.2 years, the cumulative incidence of grade 3+ adverse events was higher on orteronel than on the standard arm (P < .001; hazard ratio [HR], 2.32; 95% CI, 1.52-3.47) with 5-year estimates of 59.0% and 35.1%, respectively. No significant differences in overall survival (P = .28; HR, 0.71; 95% CI, 0.39-1.32) or biochemical failure (P = .56; HR, 0.84; 95% CI, 0.47-1.51) were observed. Use of orteronel had a transient negative impact on all prostate cancer-specific QOL domains of the EPIC, but did not increase the magnitude of decline once RT started and had minimal impact on other HRQOL measures. Conclusions The addition of orteronel to RT and ADT did not result in significant improvement in any efficacy outcomes, although information was limited by poor drug tolerance and early termination of accrual, thus limiting statistical power.

Next-generation imaging (NGI) (68 Ga-prostate-specific membrane antigen (PSMA)-PET) represents a cornerstone in biochemical recurrent prostate cancer management. PSICHE is a multicentric prospective study, aimed to assess oncological outcomes of a predefined tailored imaging-guided treatment. Patients with biochemical recurrence (BCR) after surgery (prostate-specific antigen [PSA] > 0.2 ≤ 1 ng/mL) underwent staging with PSMA-PET. A predefined treatment algorithm was proposed to all patients: prostate bed salvage radiotherapy (SRT) in case of negative or positive PET within the prostate bed, stereotactic body radiotherapy (SBRT) if pelvic nodal recurrences or oligometastatic disease were detected, and androgen deprivation therapy (ADT) was proposed in widespread polymetastatic disease. Chi-square test was used to evaluate the relationship between baseline features and the rate of positive PSMA-PET/CT. One hundred and fifty-nine patients were enrolled. One hundred and seven patients had a PSMA negative/positive in the prostate bed; pelvic nodal disease or oligometastatic metastatic disease was detected in 39 and 10 patients, respectively. Three patients had a polymetastatic disease. Seventeen patients underwent observation because of prior postoperative radiotherapy (RT)/treatment refusal. Eighty-eight patients were treated with SRT, and SBRT was performed in 49 patients with pelvic or extrapelvic oligometastatic disease. Stratifying patients according to EAU criteria (low risk: PSA doubling time > 12 months and Gleason score < 8; high risk: PSA doubling time ≤ 12 months or Gleason score ≥ 8) after a median follow-up of 19 months in the overall population, median BRFS and MFS were not significantly different between the two risk subgroups (p = 0.58 and p = 0.21, respectively). Median metastasis-free and ADT-free survival were not reached. A PSMA-targeted treatment strategy led to promising results, avoiding unnecessary toxicity from ADT or standard SRT administered in unselected patients. Analysis after longer follow-up is needed to clarify survival outcomes.

PURPOSE:Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies. EXPERIMENTAL DESIGN:We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n = 60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI at baseline and 6 months after treatment, with a median follow-up of 6 years. Gene expression differences between patients with and without BCR were analyzed using pathway tools and validated in external datasets. A novel TGF-β gene signature was derived and tested across multiple cohorts (median follow-up: 5-11 years). RESULTS:TGF-β activity was significantly associated with BCR in the discovery cohort (P = 0.0081) and correlated with PTEN/TP53 alterations (P = 0.0246) and baseline multiparametric MRI tumor volume (P = 0.026). TGF-β activity also predicted metastasis-free survival (P = 0.037) and, in an independent cohort (n = 265), was prognostic for BCR-free (P = 0.05), metastasis-free (P < 0.001), and overall survival (P < 0.001). CONCLUSIONS:TGF-β activity is a dominant feature of intermediate- to unfavorable-risk prostate tumors prone to biochemical failure after EBRT with ADT and may serve as an independent prognostic biomarker beyond existing clinical criteria.

Prostate cancer(PCa) patients treated with androgen deprivation therapy(ADT) may experience major adverse cardiovascular events(MACE) [1]. Racial disparities in PCa incidence and outcomes have been noted. In contrast to older studies, three recent studies found significantly longer overall survival in Black vs. White patients: 2019 meta-analysis of nine phase III trials in men with metastatic castration-resistant PCa(CRPC) (n = 8820) [2]; 2020 registry study in men with metastatic CRPC (n = 1902) [3]; and 2023 study in men with non-metastatic CRPC (n = 12,992) [4]. Our “real-world” data study compared MACE and all-cause mortality risk for Black vs. White PCa patients. Compared to prior studies [1–4], our study encompassed a broader scope and was not exclusive to CRPC patients. Historical, longitudinal patient-level were collected from the Decision Resources Group (DRG, now Clarivate) Real World Evidence repository. The analysis included PCa patients receiving ≥1 ADT 1991–2020. Multivariable regression model accounted for baseline metastasis, BMI (<18.5 vs. ≥18.5 kg/m2), oncology vs. urology setting, antagonist vs. agonist, personal MACE history, tobacco history, baseline prostate-specific antigen (>4 vs. ≤4 ng/mL), race (White vs. Black), statin use, increasing age per year, ethnicity (non-Hispanic vs. Hispanic), increasing ADT exposure per year, diabetes, hypertension, and family MACE history. MACE risk was higher for White patients than Black (4.0% vs. 2.4% at one year after ADT initiation; 21.0% vs. 13.3% at four years). Mortality risk after ADT initiation was 1.6% and 2.6% at 1 year and 11.7% and 18.1% at 4 years for Black and White patients, respectively. Our analysis reveals a unique finding that MACE and all-cause mortality incidence were higher in White vs. Black patients. Black race is associated with lower MACE rates and improved survival for men undergoing ADT treatment. Whether selection bias, underlying biology or other factors are responsible for these differences remains unknown.

BACKGROUND AND OBJECTIVE:Optimal management for high-risk prostate cancer is unclear. Using individual patient data from two contemporaneous North American cooperative group phase 3 randomized controlled trials (RCTs), we compared the outcomes of high-risk prostate cancer patients treated with radiotherapy-based and radical prostatectomy (RP)-based treatment strategies. METHODS:Data were collected from newly diagnosed high-risk prostate cancer patients enrolled in NRG/RTOG 0521 who received radiotherapy-based treatment (2005-2009), and those enrolled in CALGB 90203 who received surgery-based treatment (2006-2015). Patients received radiotherapy plus 24 mo of androgen deprivation therapy (ADT) ± six cycles of adjuvant docetaxel versus RP with personalized postoperative therapy ± neoadjuvant six cycles of docetaxel and 18-24 wk of ADT. The primary objective was to compare the cumulative incidence of distant metastasis considering death as a competing event using the inverse probability of treatment weighting (IPTW). KEY FINDINGS AND LIMITATIONS:Overall, 1290 patients (radiotherapy n = 557, RP n = 733) were included with similar follow-up (median 6.4 [interquartile range {IQR}: 5.6-6.9] yr and 6.4 [IQR: 4.7-8.5] yr, respectively). Patients who received surgery had generally more favorable prognostic features and were younger relative to those who received radiotherapy. After IPTW, the cumulative incidence of distant metastasis was significantly lower in patients who underwent radiotherapy-based compared with RP-based treatment (8-yr distant metastasis: 15% [95% confidence interval {CI} 9.3-21] vs 22% [95% CI 18-26]; adjusted subdistribution hazard ratio [sHR] 0.58 [95% CI 0.42-0.81]; p = 0.001). We did not find any significant difference in the incidence of deaths after distant metastasis (adjusted sHR 0.98 [95% CI 0.61-1.58]) between the two groups. CONCLUSIONS AND CLINICAL IMPLICATIONS:High-risk prostate cancer patients enrolled in RCTs had a significantly lower incidence of distant metastasis with a radiotherapy-based treatment strategy than with an RP-based treatment strategy, while the risk of deaths after distant metastasis was similar in the two groups.

PURPOSE Artificial intelligence (AI) tools could improve clinical decision making or exacerbate inequities because of bias. African American (AA) men reportedly have a worse prognosis for prostate cancer (PCa) and are underrepresented in the development genomic biomarkers. We assess the generalizability of tools developed using a multimodal AI (MMAI) deep learning system using digital histopathology and clinical data from NRG/Radiation Therapy Oncology Group PCa trials across racial subgroups. METHODS In total, 5,708 patients from five randomized phase III trials were included. Two MMAI algorithms were evaluated: (1) the distant metastasis (DM) MMAI model optimized to predict risk of DM, and (2) the PCa-specific mortality (PCSM) MMAI model optimized to focus on prediction death in the presence of DM (DDM). The prognostic performance of the MMAI algorithms was evaluated in AA and non-AA subgroups using time to DM (primary end point) and time to DDM (secondary end point). Exploratory end points included time to biochemical failure and overall survival with Fine-Gray or Cox proportional hazards models. Cumulative incidence estimates were computed for time-to-event end points and compared using Gray's test. RESULTS There were 948 (16.6%) AA patients, 4,731 non-AA patients (82.9%), and 29 (0.5%) patients with unknown or missing race status. The DM-MMAI algorithm showed a strong prognostic signal for DM in the AA (subdistribution hazard ratio [sHR], 1.2 [95% CI, 1.0 to 1.3]; P = .007) and non-AA subgroups (sHR, 1.4 [95% CI, 1.3 to 1.5]; P < .001). Similarly, the PCSM-MMAI score showed a strong prognostic signal for DDM in both AA (sHR, 1.3 [95% CI, 1.1 to 1.5]; P = .001) and non-AA subgroups (sHR, 1.5 [95% CI, 1.4 to 1.6]; P < .001), with similar distributions of risk. CONCLUSION Using cooperative group data sets with a racially diverse population, the MMAI algorithm performed well across racial subgroups without evidence of algorithmic bias.

Background: Previous studies indicate that the benefit of short-term androgen deprivation therapy (ADT) with radiotherapy (RT) for prostate cancer depends on competing risks. Objective: To determine whether a quantitative method to stratify patients by risk for competing events (omega score) could identify subgroups that selectively benefit from ADT. Design, setting, and participants: An ancillary analysis of NRG/RTOG 9408 phase 3 trial (NCT00002597) involving 1945 prostate cancer patients was conducted. Intervention: Short-term ADT. Outcome measurements and statistical analysis: We applied generalised competing event regression models incorporating age, performance status, comorbidity, T category, Gleason score (GS), and prostate -specific antigen (PSA), to stratify patients according to relative hazards for primary cancer -related events (distant metastasis or prostate cancer death) versus competing noncancer mortality. We tested interactions between ADT and subgroups defined by standard risk criteria versus relative risk (RR) using the omega score.

BackgroundDaily IGRT images show day-to-day anatomical variations in patients undergoing fractionated prostate radiotherapy. This is of particular importance in particle beam treatments.PurposeTo develop a digital phantom series showing variation in pelvic anatomy for evaluating treatment planning and IGRT procedures in particle radiotherapy.MethodsA pelvic phantom series was developed from the planning MRI and kVCT (planning CT) images along with six of the daily serial MVCT images taken of a single patient treated with a full bladder on a Tomotherapy unit. The selected patient had clearly visible yet unexceptional internal anatomy variation. Prostate, urethra, bladder, rectum, bowel, bowel gas, bone and soft tissue were contoured and a single Hounsfield Unit was assigned to each region. Treatment plans developed on the kVCT for photon, proton and carbon beams were recalculated on each phantom to demonstrate a clinical application of the series. Proton plans were developed with and without robust optimization.ResultsLimited to axial slices with prostate, the bladder volume varied from 6 to 46 cm3, the rectal volume (excluding gas) from 22 to 52 cm3, and rectal gas volume from zero to 18 cm3. The water equivalent path length to the prostate varied by up to 1.5 cm . The variations resulted in larger changes in the RBE-weighted Dose Volume Histograms of the non-robust proton plan and the carbon plan compared to the robust proton plan, the latter similar to the photon plan. The prostate coverage (V100%) decreased by an average of 18% in the carbon plan, 16% in the non-robust proton plan, 1.8% in the robust proton plan, and 4.4% in the photon plan. The volume of rectum receiving 75% of the prescription dose (V75%) increased by an average of 3.7 cm3, 4.7 cm3, 1.9 cm3, and 0.6 cm3 in those four plans, respectively.ConclusionsThe digital pelvic phantom series provides for quantitative investigation of IGRT procedures and new methods for improving accuracy in particle therapy and may be used in cross-institutional comparisons for clinical trial quality assurance.

In “Explanatory and Pragmatic Attitudes in Therapeutic Trials”, Schwatrz and Lelouch describe two approaches to the design of trials, “… the first “explanatory”, the second “pragmatic”. They explained “… the biologist may be interested to know whether the drugs differ in their effects … the explanatory approach”. Biologically endpoints might determine whether it was better to give androgen deprivation therapy (ADT) before or after external beam radiation (EBRT) (i.e., does the sequence of treatments matter). Alternatively, if the arms focus on a clinical endpoint, this is considered … “the pragmatic approach”. An example of a clinically relevant endpoint is overall survival (OS). A real-world example of this are the two randomized controlled trials (RCTs) evaluating the role of prophylactic whole pelvic radiotherapy (WPRT) conducted by the Radiation Therapy Oncology Group (RTOG). RTOG 9413 evaluated possible interactions between the sequence of drugs and volume irradiated, while RTOG/NRG 0924 focuses on OS. There appears to be a common pattern of “what not to do”, or “design errors” made by a number of investigators, that I call the “three sins”. I posit that the prospects for a well-designed pragmatic RCT are likely to be high if these “three sins” are avoided/minimized. The “three sins” alluded to are: 1. You can’t prove something doesn’t work by treating people who don’t need the treatment. 2. You can’t prove something does not work if the treatment is not done properly. 3. You can’t prove something does not work with an underpowered study.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Delays in the work-up and definitive management of patients with prostate cancer are common, with logistics of additional work-up after initial prostate biopsy, specialist referrals, and psychological reasons being the most common causes of delays. During the COVID-19 pandemic and the subsequent surges, timing of definitive care delivery with surgery or radiotherapy has become a topic of significant concern for patients with prostate cancer and their providers alike. In response, recommendations for the timing of definitive management of prostate cancer with radiotherapy and radical prostatectomy were published but without a detailed rationale for these recommendations. While the COVID-19 pandemic is behind us, patients are always asking the question: “When should I start radiation or undergo surgery?” In the absence of level I evidence specifically addressing this question, we will hereby present a narrative review to summarize the available data on the effect of treatment delays on oncologic outcomes for patients with localized prostate cancer from prospective and retrospective studies.

Technological advancements have firmly established radiation therapy as a cornerstone of cancer treatment. This is particularly true for prostate cancer, where radiation therapy is often employed with curative intent. These innovations have given rise to terminologies that have sparked debates and differing opinions. In this context, we explore some of these terms and address the challenges they present. Finally, we propose clarifications that we believe can guide these debates toward more constructive and meaningful discussions.

BACKGROUND:Androgen deprivation therapy (ADT) has been associated with coronary heart disease and myocardial infarction (MI) in prostate cancer patients, but controversy persists regarding its effects on cardiovascular mortality (CVM). OBJECTIVE:We assessed the long-term relationship between ADT and CVM in a prostate cancer randomized trial (NRG Oncology/Radiation Therapy Oncology Group 9202). DESIGN, SETTING, AND PARTICIPANTS:From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-T4, prostate-specific antigen <150 ng/ml) received radiotherapy with 4 mo (short-term [STADT]) versus 28 mo (longer-term [LTADT]) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Using the Fine-Gray and Cox regression models, the relationship between ADT and mortality was evaluated. RESULTS AND LIMITATIONS:With a median follow-up of 19.6 yr, LTADT was associated with improved overall survival (OS) versus STADT (adjusted hazard ratio [HR] 0.88; p = 0.03) and prostate cancer survival (subdistribution HR [sHR] 0.70, p = 0.003). Comparing LTADT with STADT, prostate cancer mortality improved by 6.0% (15.6% [95% confidence interval 13.0-18.3%] vs 21.6% [18.6-24.7%]) at 15 yr, while CVM increased by 2.2% (14.9% [12.4-17.6%] vs 12.7% [10.4-15.3%]). In multivariable analyses, LTADT was not associated with increased CVM versus STADT (sHR 1.22 [0.93-1.59]; p = 0.15). An association between LTADT and MI death was detected (sHR 1.58 [1.00-2.50]; p = 0.05), particularly in patients with prevalent cardiovascular disease (CVD; sHR 2.54 [1.16-5.58]; p = 0.02). CONCLUSIONS:With 19.6 yr of follow-up, LTADT was not significantly associated with increased CVM in men with locally advanced prostate cancer. Patients may have increased MI mortality with LTADT, particularly those with baseline CVD. Overall, there remained a prostate cancer mortality benefit and no OS detriment with LTADT. PATIENT SUMMARY:In a long-term analysis of a large randomized prostate cancer trial, radiation with 28 mo of hormone therapy did not increase the risk of cardiovascular death significantly versus 4 mo of hormone therapy. Future studies are needed for patients with pre-existing heart disease, who may have an increased risk of myocardial infarction death with longer hormone use.