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Within the traditional 3-tier NCCN low, intermediate, or high-risk categorization for prostate cancer, it is recognized that heterogeneity can exist within each stratum. We explored clinical factors associated with disease outcome for men with high-risk prostate cancer treated with primary radiation therapy (RT). Of 742 men with prostate cancer treated with primary RT with curative intent between 2005-2021, 282 had NCCN high-risk disease and comprised the study group. The median age was 68, and 66% of the cohort was black. Median PSA was 19 (IQR 9-38), 56% had T2b disease or greater, and Gleason score was 6/7/8/9/10 in 4%/26%/35%/32%/2%, respectively. The median RT dose was 78 Gy; 18 (6%) had brachytherapy boost. Androgen deprivation therapy (ADT) was given in 94% for a median 28 mo. Potential prognostic variables were tested on univariate and multivariable (MVA) analysis for freedom from biochemical failure (FFBF), distant metastasis (FFDM), and cause specific survival (CSS). The number of "high risk factors" including PSA>20, cT3a+ stage, and Gleason 8+ were assessed, as well as "very high-risk disease" including cT3b stage, multiple high-risk factors, and primary Gleason pattern 5 disease. Median follow-up was 53 mo. In men with low, favorable intermediate, unfavorable intermediate, high, and very high-risk disease, the 5-y FFBF was 91/94/90/83/72, 5-y FFDM was 100/98/98/89/80, and 10-y CSS was 100/100/96/98/89 (all p<0.01). The 136 men with "very high risk" disease had inferior FFBF and FFDM compared to the other 146 men with "standard" high-risk disease (p<0.01). The number of NCCN high risk factors was 1, 2, or 3 in 157 (56%), 84 (30%), and 41 (15%) men, and was associated with 5-y FFBF (83%, 80%, 45%) and 5-y FFDM (89%, 84%, 69%, respectively, all p<0.01). 49 men had PSA>20 as the only high risk factor; this cohort had a median age 67, 88% black, 86% Gleason 7, and received a median dose of 78 Gy with ADT in 86% for a median 12 mo. Compared to others with high risk disease, men with PSA>20 as the sole risk factor had improved 5-y FFBF (94% vs 74%, p = 0.05) and FFDM (97% vs 82%, p = 0.02), similar to outcomes for intermediate risk disease. Meanwhile, men with Gleason 9-10 disease had inferior 5-y FFBF (68% vs 82%, p = 0.01) and FFDM (78% vs 89%, p < 0.01). MVA models in high-risk men revealed that Gleason score and T2b stage were associated with FFBF and FFDM (both p < 0.05 in separate models), while PSA was not (p > 0.6). In men treated with primary RT, men with "very high risk" disease including multiple high-risk factors had a poorer disease outcome. Using number of risk factors appears appropriate to stratify risk for clinical decisions, but PSA may offer the weakest prognostic value of any high-risk factor. Select men with PSA > 20 and cT1-2, Gleason 6-7 disease may warrant consideration of less aggressive therapy than RT with long-term ADT. [ABSTRACT FROM AUTHOR]

The FORMULA-509 trial randomized patients receiving salvage radiation between 6 months of GnRH agonist plus bicalutamide or 6 months of GnRH agonist plus AAP/Apa. Here we evaluate factors associated with testosterone recovery after trial treatment and the impact of testosterone recovery on patient-reported HRQoL. Testosterone was evaluated prior to treatment, at 3 months, at 6 months (end of systemic treatment), and at least every six months after treatment. Validated Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire was administered at baseline, end of treatment, and 1 year after completion of treatment. A change of 4 or more was considered a clinically meaningful change in the hormonal function domain. Log-rank test compared testosterone recovery between treatment groups. Wilcoxon rank sum and chi-square compared characteristics between those who did and did not recover testosterone. Multivariate logistic regression evaluated factors associated with lack of testosterone recovery. Chi-square evaluated frequency of clinically meaningful change in hormonal function. Three hundred forty-five patients were randomized (172 bicalutamide; 173 AAP/Apa). Median follow-up was 34 (6-53) months. There was no difference in testosterone recovery (>190 ng/dL) between treatment groups (p = 0.10). 52.6% [95% CI = 42.7-58.0] of patients recovered testosterone 6 months after treatment (bicalutamide: 51.2%; AAP/Apa 54.0%); 74.5% [69.8-79.2] 12 months (70.5%; 78.6%); 81.9% [77.7-86.1] 18 months (77.7%; 86.2%); and 88.8% [85.4-92.3] 30 months after treatment (85.8%; 91.9%). On univariate analysis, older age (median 67 vs 63 years; p<0.01), lower baseline testosterone (median 274 vs 379 ng/dL; p<0.01) and higher PSA at enrollment (median 0.3 vs 0.2; p = 0.02) were associated with lack of testosterone recovery 1 year after treatment. Race, Gleason score, and treatment arm were not associated with testosterone recovery. On multivariate analysis, age at enrollment, baseline testosterone, and PSA at enrollment remained significant (all p <0.05). In the subset of patients who completed EPIC-26 1 year after treatment (n = 219), those patients who did not have testosterone recovery were more likely to report a clinically meaningful decline in hormonal function relative to baseline than those who did achieve testosterone recovery, but it was not statistically significant (59% vs. 43% reporting clinically meaningful functional decline, p = 0.06). The addition of AAP/Apa did not lengthen time to testosterone recovery. Older men or those with lower baseline testosterone or higher PSA prior to treatment were less likely to recover testosterone 1 year after treatment. Patients who did not have testosterone recovery at 1 year were more likely to report decline in hormonal function. [ABSTRACT FROM AUTHOR]

Prior studies have demonstrated antiplatelet/anticoagulant (AP/AC) medications to be associated with improved biochemical outcomes and cause-specific survival in men with prostate cancer treated with radiation therapy (RT). We explored this association and the proposed link to platelet count in a large, single-institution database. One thousand men with localized prostate cancer received definitive RT from 1989-2018, including 860 RT alone, 83 brachytherapy alone, and 57 in combination. Median age was 68 y. NCCN risk category was 28/41/31% for low/intermediate/high risk, respectively. Median dose was 76 Gy/38 fx, and 52% received androgen deprivation therapy (ADT). Medication use at consultation including AP (n = 410, e.g. aspirin, clopidogrel) and AC (n = 65, e.g. warfarin) medications and platelet count within 6 mo of RT start were retrospectively recorded. The effects of AC/AP medications and platelet counts were analyzed with respect to freedom from biochemical failure (FFBF, nadir+2), distant metastasis (FFDM), and cause-specific survival (CSS) on univariate (UVA) and multivariate analysis (MVA). Median follow-up was 78 mo. 7-y FFBF was 88%, 82%, 71%, and 69% for NCCN low, favorable intermediate, unfavorable intermediate, and high-risk disease (p<0.01). On UVA, AC/AP use was associated with increased FFBF (7-y, 82% vs 75%, p = 0.02), FFDM (p = 0.02), and CSS (p<0.01). Relationships were also observed between the lowest quartile (<181) platelet count and FFBF (5-y 81% vs 70%, p<0.01) but not FFDM (p = 0.07), or CSS (p = 0.84). MVA models including AP/AC use, platelet count < 181, PSA (continuous), Gleason score (6, 7, or 8+), T2b stage, and ADT, showed an association with disease outcomes for low platelet count (FFBF HR = 1.7, p<0.01, FFDM HR = 1.61, p = 0.04) and AP/AC use (CSS HR = 0.40, p = 0.02). The potential interaction between AP/AC use and low platelets was further explored by analyzing FFBF, FFDM, and CSS in separate subgroups. The association between low platelets with inferior FFBF was observed in AP/AC non-users (p<0.01) but not in AP/AC users (p = 0.54), and in men not receiving ADT (p<0.01) rather than in men on ADT (p = 0.31). MVA in AP/AC non-users including covariates as above demonstrated a lower FFBF for low platelets (HR: 2.09, p = 0.0001). Low platelet count and AP/AC use demonstrated associations with FFBF, FFDM, and CSS on either UVA or MVA in prostate cancer patients receiving RT. The negative prognostic association of low platelet count was strongest in AP/AC non-users. The potential interaction between AP/AC and low platelet count should be further verified and investigated for possible mechanisms, as it may present an opportunity to offer therapeutic benefits in select men. [ABSTRACT FROM AUTHOR]

Circadian rhythms regulate cellular mechanisms related to radiation response, including cell death and repair. We explored whether time of day was associated with disease outcome and recovery in a large cohort of men treated with radiation therapy (RT) for prostate cancer. This retrospective study included 336 men treated with curative intent with external beam RT between 2010 and 2019. The median age was 69 years, 69% were black, median PSA was 11.3, and 40% had Gleason 8+. Median dose was 78 Gy/39 fractions; 27% received concurrent hormonal therapy. Average treatment time was calculated according to the average time of each patient's daily treatments. For analysis, average time of treatment was separated into quartiles and by median, based on distribution. Disease outcomes including freedom from biochemical failure (FFBF) and distant metastasis (FFDM), RTOG and CTC gastrointestinal (GI) and genitourinary (GU) toxicity, and patient reported quality of life (QOL, EPIC-26) were analyzed on univariate and multivariable analysis (MVA). Median follow-up was 55 months. The median average treatment time was 10:47AM (IQR = 9:12AM - 12:42PM, range = 6:37AM-5:12PM). There were no imbalances in NCCN risk category or race across treatment times. There were no overall differences observed in FFBF or FFDM by treatment time. However, on subset analysis by race, white men treated in the first half of the day had better FFBF (89% vs 67%, p = 0.0139) and FFDM (93% vs 72%, p = 0.0268) than those treated in the second; this difference was not observed for black men. The crude rate of BF in white men by quartile of average treatment time was 5%, 10%, 28%, and 32%, respectively (p = 0.04), whereas it was 14%, 17%, 18%, and 21% in black men (p = 0.81). On MVA, treatment time was not associated with FFBF or FFDM when included in a model with NCCN risk category, or a model including NCCN risk category and race. On an MVA of white men only, treatment time was associated with FFBF (HR = 2.8, p = 0.06) in a model also including risk category (p = 0.21); a model for FFDM indicated an association for risk category (p<0.01) but not treatment time (p = 0.18). No significant differences were observed for grade 2-3+ toxicity and treatment time. A trend for worse grade 2+ GU toxicity (by median time, p = 0.2) and grade 3+ GU toxicity (median, p = 0.1) were observed for later treatment times. There were trends (p<0.2) observed in QOL for the urinary incontinence (quartile 4, p = 0.16), urinary obstruction (quartile 3, p = 0.09), and sexual function (median, p = 0.16) for later treatment time, with stronger associations for white race than black race. In this exploratory analysis, treatment time of prostate RT may be associated with disease outcome depending on race, and later treatment time was weakly associated with GU toxicity and QOL. Further study is warranted to confirm these findings and understand the causality of these relationships. [ABSTRACT FROM AUTHOR]

Salvage radiotherapy (RT) after prostatectomy is common, but data for long term patient-reported outcomes (PROs) are limited. We report on the largest cohort to date assessing quality of life (QOL) outcomes with 5 years of median follow-up. PROs for men undergoing salvage intensity modulated RT following post-prostatectomy biochemical failure at a single institution were prospectively collected using the Expanded Prostate Cancer Index Composite (EPIC-26). Declines in QOL were deemed significant if they exceeded the minimally important difference (MID), defined as 7.5, 6, 5, and 11 for the urinary incontinence (UI), urinary obstruction/irritation (UO), bowel function (BF), and sexual function (SF) domains, respectively. Physician-reported genitourinary (GU) and gastrointestinal (GI) toxicities were recorded prospectively with CTCAE v3.0. Univariable and multivariable (MVA) general estimating equation and Fine-Gray models assessed the association between clinical factors and QOL or adverse events. Between 2007 and 2019, there were 317 men were treated to a median dose of 68.4 Gy to the prostate bed with 72% receiving a median dose of 50.4 Gy to the pelvic nodes and 72% receiving hormone therapy. Median follow-up was 64 months. Table 1 shows median QOL scores over time. At 5 years, rates of QOL decline exceeding MID for UI, UO, BF, and SF were 32%, 27%, 30%, and 17%, respectively. Of men whose QOL decline exceeded MID, 35%, 49%, 54%, and 40% had subsequent improvement in UI, UO, BF, and SF scores, respectively, and no longer exceeded MID at last follow-up. The cumulative incidences of grade 2+ GU and GI toxicity at 5 years were 30% and 7%, respectively. Incontinence was the most common GU toxicity (26%). Rates of grade 3+ GU and GI toxicity were 5% and 2%, respectively. Of men experiencing grade 2+ GU toxicity, 40% recovered at last follow-up. On MVA, race, hormone therapy duration, age, and volume of bladder or rectum receiving 65-75 Gy were significantly associated with change in EPIC UI, UO, BF, and SF domain scores. Rectal volume receiving 75 Gy, RT prescription dose, and anticoagulation use were significantly associated with grade 2+ GU and GI toxicity. Post-prostatectomy RT was well-tolerated through 5 years. Of patients experiencing QOL decline or CTCAE toxicity, nearly half recovered by last follow-up. Bladder and rectum dose were significantly associated with patient- and physician-reported toxicity. [ABSTRACT FROM AUTHOR]

This prospective study was designed to evaluate the safety and preliminary efficacy of stereotactic body radiotherapy (SBRT) for oligometastatic renal cell carcinoma (RCC). It was hypothesized that SBRT would offer excellent local control with minimal severe toxicity, and potentially delay the need to initiate systemic therapy. Patients with oligometastatic RCC (1-5 lesions ≤ 6cm, ≤ 3 brain metastases addressed prior to enrollment, no therapies in prior month) were treated with SBRT to all metastatic sites (40-50 Gy/5 fractions). The primary endpoint was the rate of grade 4+ adverse events (AEs) per CTCAE v4.0; the trial would test the null hypothesis of a 5% toxicity rate using a sequential toxicity monitoring schema (n = 25). Secondary endpoints included local failure of treated lesions (LF), distant progression outside of the treated sites (DM), and progression-free survival (PFS). Exploratory endpoints included time to subsequent systemic therapy and metastasis-directed therapy. Overall survival (OS) and PFS were analyzed via the Kaplan-Meier method and other time-to-event endpoints were analyzed as cumulative incidence with death as a competing risk. Fifteen patients (median age 50 years, 33% female, all with resected primary tumors, 40% prior systemic therapy, 27% prior metastasis-directed therapy) received SBRT to 23 lesions (median 1 lesion, range = 1-4; median BED 10 of 100 Gy; 43% lung, 35% abdomen, 17% bone, 4% head and neck). The trial was closed early due to slow accrual. With median follow-up of 4.8 years, there were no grade 3+ AEs and no late grade 2+ AEs attributable to SBRT. Five (33%) patients experienced 7 acute grade 2 AEs (nausea [n = 2], vomiting, pneumonitis, numbness/tingling, back pain, and fatigue). Outcomes are presented in the Table below. LF occurred in one lesion (4.3% crude LF across lesions) in one patient; the dominant pattern of failure was distant. The cumulative incidence of subsequent systemic therapy was only 40% and 54% at 2- and 5-years, respectively. Additional ablative metastasis-directed therapy was utilized in roughly half of the patients, at a median time of 2.1 years. Metastasis-directed SBRT for oligometastatic RCC is safe and associated with excellent local control. This prospective study adds to emerging data that SBRT may delay additional systemic therapy with a minimal risk of severe toxicity. A subset of patients with more favorable disease biology may benefit from additional local interventions, such as SBRT or surgery. [ABSTRACT FROM AUTHOR]

Stereotactic Ablative Body Radiotherapy (SABR) is an effective treatment for localized renal cell carcinoma (RCC). However, the role of primary site SABR for locally recurrent or metastatic RCC has not been established. Here, we report the outcomes of primary SABR across a heterogeneous cohort of localized, recurrent, and metastatic RCC patients treated at our institution. All RCC patients treated with SABR in 1-5 fractions to the kidney or to the nephrectomy bed at our institution were included for analysis. Patients were deemed either medically inoperable or high risk for dialysis due to poor baseline renal function. Local control (LC), overall survival (OS), and freedom from distant failure (FFDF) were estimated using the Kaplan-Meier method. Our primary outcome was LC, which was evaluated using RECIST v1.1. Toxicities were reported according to the CTCAE v5.0. Estimated glomerular filtration rate (eGFR) was assessed at baseline and at 1-year post-SABR. Univariable and multivariable linear modeling were used to test the association of 1-year post-SABR eGFR with the following clinical and treatment-related features: age, race, Charlson comorbidity index (CCI), planning target volume, ipsilateral kidney volume, and baseline eGFR. From March 2018 to July 2023, 42 patients with RCC received primary site SABR. The median follow-up was 26 (range = 6-65) months. Median age was 73 (range = 47-93) years. Median CCI was 8 (range = 5-14). By disease extent, 28 (67%) patients had localized and 14 (33%) patients had metastatic RCC. Seven (17%) tumors were locally recurrent after prior surgery or ablation. Median tumor size was 4.5 (range = 1.8-12.9) cm. Median biologically equivalent dose using an alpha/beta ratio of 10 was 93.6 (range = 60-112.5) Gy. Two-year LC was 100%, and 3-year LC was 93.8% (95% CI = 82.6%-100%). Two-year OS was 74.7% (95% CI = 61.6%-90.7%). Among 28 patients with initially localized disease, 2-year FFDF was 96.4% (95% CI = 89.8%-100%). Ten (24%) patients experienced acute grade 1-2 GI toxicity, with no acute grade 3+ toxicities. Two (4.8%) patients developed late grade 3+ GI toxicity. Among 29 patients with an intact ipsilateral kidney who were not on dialysis pre-SABR, the median baseline eGFR was 48 (range = 22-101) mL/min/1.73 m2. At 1-year post-SABR, the median eGFR decline was 3 mL/min/1.73 m2. No patients required dialysis within 1-year post-SABR. Only baseline eGFR was significantly associated with eGFR change at 1 year with a predicted drop of 9 mL/min/1.73 m2 in 1-year eGFR for every 10 mL/min/1.73 m2 decrease in baseline eGFR (p < 0.001). This analysis demonstrates excellent LC rates across patients with localized, recurrent, and metastatic RCC treated with SABR. Treatment was well tolerated, with minimal associated eGFR decline. These findings support the efficacy and safety of primary SABR for recurrent and metastatic RCC. [ABSTRACT FROM AUTHOR]

The randomized FORMULA-509 trial demonstrated that for patients with a PSA > 0.5 after prostatectomy receiving salvage radiation and 6 months of GnRH Agonist, the addition of abiraterone acetate plus prednisone (AAP) and apalutamide (Apa) improved metastasis-free survival compared to bicalutamide. Here we present the patient-reported health-related quality of life (HRQoL) results through three years. Validated questionnaires were administered at baseline, end of treatment, and 1 and 3 years after completion of treatment. Patients completed Expanded Prostate Cancer Index Composite (EPIC)-26, PROMIS Fatigue, and Saint Louis University Mental Status Exam (SLUMS). EPIC-26 is scored from 0 to 100 with 100 indicating higher function. PROMIS Fatigue is scored using a standardized T score with higher score indicating greater fatigue. SLUMS is scored from 0 to 30 with 27 to 30 interpreted as normal, 21 to 26 as mild neurocognitive disorder and 20 or less as dementia. Scores between treatment arms were compared using the t-test. Results were interpreted using established thresholds for clinically meaningful differences (4-6 for EPIC-26 hormonal domain, 5-10 for PROMIS Fatigue). Three hundred forty-five patients were randomized (172 bicalutamide and 173 AAP/Apa). Completion rates at baseline, end of treatment, 1 year, and 3 years, were 96%, 80%, 70%, and 57% for EPIC-26; 95%, 79%, 67%, and 57% for PROMIS Fatigue; and 96%, 80%, 70%, and 34% for SLUMS. From baseline to end of treatment, both arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change -15 bicalutamide; -15 AAP/Apa) and increase in PROMIS Fatigue (median change 6 bicalutamide; 7.4 AAP/Apa). From end of treatment to 1 year after treatment patient-reported HRQoL improved to near baseline for both EPIC-26 hormonal function (bicalutamide median score baseline = 95, end = 75, 1 year = 90; AAP/Apa baseline = 95, end = 75, 1 year = 90) and fatigue (bicalutamide median score baseline = 43.1, end = 48.6, 1 year = 46.0; AAP/Apa baseline = 43.1, end = 51.0, 1 year = 46.0) with further improvement in EPIC-26 hormonal function at 3 years (bicalutamide = 95.0; AAP/Apa = 95.0) and stable fatigue at 3 years (bicalutamide = 46.0; AAP/Apa = 46.0). The cMedian SLUMS score was within normal range at baseline (27 bicalutamide; 27 AAP/Apa), end of treatment (28, 28) and 1 (27, 27) and 3 (27, 27) years after treatment. There was no difference in patient-reported hormonal function, fatigue, or mental status between treatment arms, at end of treatment (P = 0.40; P = 0.78; and P = 0.41, respectively), 1 year after treatment (P = 0.78; P = 0.89; and P = 0.76), and 3 years after treatment (P = 0.45; P = 0.95; and P = 0.86). The addition of AAP/Apa improved oncologic outcomes without causing a detectable difference in patient-reported hormonal function, fatigue, or mental status compared to bicalutamide through three years after treatment. [ABSTRACT FROM AUTHOR]

FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to a GnRH Agonist could improve outcomes compared to six months of bicalutamide plus GnRH Agonist for patients with unfavorable features receiving SRT for a detectable PSA post-RP. FORMULA-509 is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA ≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000 mg/5 mg + Apa 240 mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (>0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned and utilized two-sided p-values. Three hundred forty-five participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA >0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p = 0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p = 0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA >0.5 for PFS [HR 0.50, (95% CI 0.27-0.95), p = 0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (95% CI 0.13-0.84), p = 0.02 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa instead of bicalutamide to SRT+6 months of GnRH Agonist may improve PFS and MFS, particularly in the subgroup of patients with PSA>0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. (NCT03141671). [ABSTRACT FROM AUTHOR]

We sought to investigate whether enzalutamide (ENZA) treatment, without androgen deprivation therapy, increases freedom‐from‐PSA‐progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer post-radical prostatectomy (RP). Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double‐blind, phase II, placebo-controlled, multicenter study of SRT + placebo vs SRT + ENZA. The randomization (1:1) was stratified by center, surgical margin status (R0 vs R1), PSA prior to salvage treatment (PSA ≥0.5 vs <0.5 ng/mL), and pathologic Gleason sum (7 vs 8‐10) using a minimization algorithm. Following randomization, patients received either placebo or ENZA 160 mg PO once daily for 6 months. Following 2 months of study drug therapy, external beam radiotherapy to 66.6‐70.2 Gy was administered to the prostate bed (no pelvic nodes). The primary endpoint was FFPP. The trial design was powered for a HR 0.44 FFPP benefit with intended enrollment of 96 subjects and was closed as planned to enrollment on March 2020 short of that goal. Secondary endpoints were time to local recurrence (LR) within the radiation field, metastasis‐free survival (MFS), and safety as determined by frequency and severity of adverse events (AEs). A total of 86 patients were randomized with a median follow-up of 34 (range 0-52) months. The median pre-SRT PSA was 0.3 (range 0.06-4.6) ng/mL, 56/86 (65%) had extra-prostatic disease (pT3), 39/86 (45%) had Gleason Grade Group 4 or higher and 43/96 (50%) had positive surgical margins. Trial arms were well balanced. FFPP was significantly improved with ENZA vs placebo, for example 2-year FFPP was 87.1% vs 68.1%, respectively, and overall, with a HR 0.40 [95% confidence interval (CI), 0.17-0.92, p-value =0.026]. Subgroup analyses demonstrate differential benefit (p-value of interaction=0.031) of ENZA in men with pT3 (HR 0.19, 95%CI 0.05-0.67) vs pT2 disease (HR 1.29, 95%CI 0.34-4.81). There were insufficient secondary endpoint events for analysis. The most common adverse events were grade 1-2 fatigue (13% ENZA vs 9%) and urinary frequency (6 % ENZA vs 8%). SRT plus ENZA monotherapy for men with PSA recurrent high-risk prostate cancer following RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time. Additional molecular biomarker analyses are being pursued. [ABSTRACT FROM AUTHOR]