A 67-year-old man with rising PSA and palpable prostate lesion underwent prostate MRI, which showed a large PI-RADS 5 lesion confirmed on biopsy as Gleason score 9 (4+5), grade group 5, prostate cancer. 18 F-DCFPyL PET/CT scan for initial stage showed no significant PSMA avidity in the prostate lesion. 18 F-fluciclovine was obtained for off-label disease staging and management guidance. The high Gleason score prostate lesion showed intense 18 F-fluciclovine avidity. High expression of amino acid transporters and low PSMA expression was confirmed by immunohistochemistry. This case showcases a non-PSMA-avid primary prostate cancer with intense 18 F-fluciclovine, demonstrating the potential of 18 F-fluciclovine PET/CT as an off-label alternative in the uncommon primary prostate cancer without significant PSMA expression.

INTRODUCTION:Ablative therapy (AT) procedures are an emerging first-line treatment of newly diagnosed localized prostate cancer. We studied the trend in utilization and total healthcare and patient-incurred cost of first-line AT in the United States, as well as the receipt of salvage therapies after AT, using two insurance claims-based databases. METHODS:We used the Merative MarketScan Commercial (CCAE) and Medicare (MDCR) Databases to identify men with non-metastatic prostate cancer treated with either cryotherapy, laser ablation, or high-intensity focused ultrasound between 2009 and 2022. Multivariable logistic regression was used to measure the association of covariates with receipt of each treatment. Year-to-year utilization between 2009 and 2021 was compared using Spearman's rank correlation test. Median inflation-adjusted total healthcare expenditures and patient out-of-pocket payments within 12 months of AT were calculated. Receipt of salvage therapies after AT was studied using cumulative incidence curves. RESULTS:We identified 2200 men in CCAE and 3205 men in MDCR treated with AT between 2009 and 2022. In CCAE, 1.96 per 100,000 enrollees were treated with AT in 2009, and 1.51 per 100,000 enrollees were treated with AT in 2021 (P = .064). In MDCR, 31.36 per 100,000 enrollees were treated with AT in 2009, and 15.81 per 100,000 enrollees were treated in 2021 (P = .078). In CCAE, median total and patient costs were $24,506 and $1811, respectively. In MDCR, median total and patient costs were $22,094 and $1098, respectively. The 5-year rate of any salvage therapy was 24.5% in the CCAE and 22.3% in the MDCR. Androgen deprivation therapy (ADT) was the most frequently utilized salvage treatment in both the CCAE (33.0%) and MDCR (59.3%). CONCLUSION:There was a similar utilization of AT across the study period. Over 20% patients received additional therapy, most frequently ADT, within 5 years of AT.

Purpose: We evaluated changes in radiation therapy target volume and acute toxicity using Ga-68-prostate specific membrane antigen (PSMA) versus F-18-fluciclovine positron emission tomography (PET)/computed tomography in postprostatectomy patients with biochemical recurrence. We hypothesized that both fluciclovine and PSMA-guided radiation therapy would (1) significantly change pre-PET radiation therapy volumes and (2) show similar toxicity. Methods and Materials: We performed an institutional review board-approved, randomized trial comparing fluciclovine (Arm 1) and PSMA (Arm 2)-guided postprostatectomy radiation therapy in patients with detectable prostate-specific antigen after prostatectomy. Treatment volumes were rigidly defined based on PET, and simultaneous integrated boosts to PET uptake in the prostate bed (70.2-76.0 Gy) or pelvis (54.0-56.0 Gy) were allowed. Clinical target volumes (CTVs) included: prostate bed (CTVPB); pelvic lymph nodes (CTVPLV); and volumetric constraints for bladder(-CTV) and rectum. Acute genitourinary and gastrointestinal (GI) toxicity (per Common Terminology Criteria for Adverse Events v5.0) was assessed <90 days from treatment. Results: In total, 140 patients were enrolled with 70 randomized to each arm; 11 Arm 1 and 10 Arm 2 patients did not receive radiation on study and were excluded. Fluciclovine and PSMA incorporation increased both CTVPB and CTVPLV (P < .01). More fluciclovine patients received prostate bed boosts (45 of 59 patients vs 26 of 60 patients; P < .01), but there was no difference in proportion receiving pelvic nodal boosts (10 of 15 patients vs 9of 16 patients, fluciclovine vs PSMA; P = .97). Dose constraints were met for most patients. Rates of grade 2 genitourinary (17.0% vs 6.7%, fluciclovine vs PSMA; P = .15) and GI (5.1% vs 1.7%, fluciclovine vs PSMA; P = .47) toxicity were low, with no grade 3+ events. Higher rectal and bladder dose metrics correlated with GI toxicity (P < .05), but use of simultaneous integrated boosts was not associated with acute toxicity. Conclusions: Although both PSMA and fluciclovine use modestly increased target volumes, significantly more fluciclovine patients received prostate bed boosts. Planning directives were met for most patients, and acute toxicity was mild in both Arms. Analysis of biochemical control, late toxicity, and patient-reported outcomes are forthcoming.

Background PET with gallium 68 (68Ga) prostate-specific membrane antigen (PSMA)-11 and fluorine 18 (18F) fluciclovine has influenced salvage radiation therapy (sRT) planning in postprostatectomy biochemical recurrence. Purpose To assess the comparative impact of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT on sRT changes in postprostatectomy biochemical recurrence. Materials and Methods In this secondary analysis of a prospective randomized controlled trial, men with detectable prostate-specific antigen (PSA) levels after prostatectomy were randomly assigned to undergo 18F-fluciclovine PET/CT (arm A) or 68Ga-PSMA-11 PET/CT (arm B) between May 2019 and May 2023. The Clopper-Pearson binomial method was used to evaluate decision changes on whether to offer radiation therapy (RT) and to which field (with or without boost) between the pre- and post-PET time points in each arm, and to compare decision changes between the arms. Results A total of 140 eligible participants (age range, 47-83 years) were randomly assigned 1:1 to arm A (mean age, 63 years ± 8 [SD]; median pre-RT PSA level, 0.27 ng/mL) or to arm B (mean age, 65 years ± 8; median pre-RT PSA, 0.35 ng/mL). Six participants (five in the 18F-fluciclovine group and one in the 68Ga-PSMA-11 group) withdrew from the trial before undergoing PET/CT. Overall sRT decision changes occurred in 19 of 65 participants (29%) in arm A (P < .001) and 29 of 69 participants (42%) in arm B (P < .001), but there was no evidence of a difference between arms (P = .12). Among participants for whom the final decision was to offer them sRT, treatment field (and/or boost) changes occurred in 43 of 60 participants (72%) in arm A (P < .001) and 33 of 61 participants (54%) in arm B (P < .001) and were more likely with 18F-fluciclovine PET/CT than with 68Ga-PSMA-11 PET/CT (P = .046). Conclusion In postprostatectomy biochemical recurrence, the use of 18F-fluciclovine and 68Ga-PSMA-11 for PET/CT-guided sRT planning resulted in substantial treatment decision changes, but there was no difference in the likelihood of a decision change between the two radiotracers. Treatment field (and/or boost) changes were more likely with 18F-fluciclovine PET/CT than with 68Ga-PSMA-11 PET/CT. Clinical trial registration no. NCT03762759 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Iravani in this issue.

Importance:Androgen deprivation therapy (ADT) for men with prostate cancer (PCa) is associated with cardiovascular (CV) morbidity, yet the biological basis remains unclear. Recent studies have yielded conflicting results regarding the CV safety of gonadotropin-releasing hormone (GnRH) agonists vs antagonists. Objective:To test the hypothesis that ADT is associated with accelerated coronary atherosclerosis and is more prominent with a GnRH agonist compared with a GnRH antagonist. Design, Setting, and Participants:This open-label randomized clinical trial was conducted at 4 centers affiliated with a single academic institution in Atlanta, Georgia. Participants were men with nonmetastatic PCa without prior ADT exposure receiving pelvic radiotherapy with ADT of 6 months duration or longer. Patients were randomly assigned 1:1 to either the GnRH agonist leuprolide or the GnRH antagonist relugolix. Trial enrollment was completed between June 16, 2022, and March 6, 2024. Data analysis was completed between March 31, 2025, and June 23, 2025. Intervention:Pelvic radiotherapy plus either GnRH agonist leuprolide or GnRH antagonist relugolix. Main Outcomes and Measures:The primary end point was change in coronary artery total plaque volume (TPV), measured by coronary computed tomographic angiography completed at baseline and 12 months after ADT initiation. The secondary end point was change in coronary artery noncalcified plaque volume (NCPV). Other outcome measures included change in calcified plaque volume (CPV) and low-attenuation plaque volume (LAPV). Results:Of 65 men enrolled, 62 (31 in each arm) completed all study procedures for analysis. Mean (SD) age was 68.5 (8.5) years, and 35 of 62 participants (56%) were taking statins. Compared with relugolix, leuprolide was associated with a significantly greater 12-month increase in TPV (estimated difference, +68.9 mm3; 95% CI, 23.2-114.5 mm3; P = .02) and NCPV (+64.5 mm3; 95% CI, 31.6-97.3 mm3; P = .004) after adjustment for baseline plaque volume, age, and statin use. There was no significant difference in 12-month change in CPV or LAPV between patients treated with leuprolide vs relugolix. Conclusions and Relevance:In this randomized clinical trial in men with localized PCa treated with radiation plus ADT, the GnRH agonist leuprolide was associated with greater coronary plaque progression within 12 months compared with the GnRH antagonist relugolix. This change was driven by an increase in noncalcified plaque volume and may be mediating ADT-associated CV risk. Trial Registration:ClinicalTrials.gov Identifier: NCT05320406.

QuestionIs gonadotropin-releasing hormone (GnRH) receptor agonist androgen deprivation therapy (ADT) for prostate cancer associated with accelerated coronary atherosclerosis?FindingsIn a randomized clinical trial of men with prostate cancer treated with radiotherapy and concomitant ADT, the GnRH agonist leuprolide was associated with a significant increase in 12-month coronary artery total plaque volume of 68.9 mm3 and noncalcified plaque volume of 64.5 mm3 more than treatment with the GnRH antagonist relugolix.MeaningFor men with prostate cancer, GnRH agonist leuprolide results in significantly greater near-term coronary plaque progression compared with GnRH antagonist relugolix. ImportanceAndrogen deprivation therapy (ADT) for men with prostate cancer (PCa) is associated with cardiovascular (CV) morbidity, yet the biological basis remains unclear. Recent studies have yielded conflicting results regarding the CV safety of gonadotropin-releasing hormone (GnRH) agonists vs antagonists.ObjectiveTo test the hypothesis that ADT is associated with accelerated coronary atherosclerosis and is more prominent with a GnRH agonist compared with a GnRH antagonist.Design, Setting, and ParticipantsThis open-label randomized clinical trial was conducted at 4 centers affiliated with a single academic institution in Atlanta, Georgia. Participants were men with nonmetastatic PCa without prior ADT exposure receiving pelvic radiotherapy with ADT of 6 months duration or longer. Patients were randomly assigned 1:1 to either the GnRH agonist leuprolide or the GnRH antagonist relugolix. Trial enrollment was completed between June 16, 2022, and March 6, 2024. Data analysis was completed between March 31, 2025, and June 23, 2025.InterventionPelvic radiotherapy plus either GnRH agonist leuprolide or GnRH antagonist relugolix.Main Outcomes and MeasuresThe primary end point was change in coronary artery total plaque volume (TPV), measured by coronary computed tomographic angiography completed at baseline and 12 months after ADT initiation. The secondary end point was change in coronary artery noncalcified plaque volume (NCPV). Other outcome measures included change in calcified plaque volume (CPV) and low-attenuation plaque volume (LAPV).ResultsOf 65 men enrolled, 62 (31 in each arm) completed all study procedures for analysis. Mean (SD) age was 68.5 (8.5) years, and 35 of 62 participants (56%) were taking statins. Compared with relugolix, leuprolide was associated with a significantly greater 12-month increase in TPV (estimated difference, +68.9 mm3; 95% CI, 23.2-114.5 mm3; P = .02) and NCPV (+64.5 mm3; 95% CI, 31.6-97.3 mm3; P = .004) after adjustment for baseline plaque volume, age, and statin use. There was no significant difference in 12-month change in CPV or LAPV between patients treated with leuprolide vs relugolix.Conclusions and RelevanceIn this randomized clinical trial in men with localized PCa treated with radiation plus ADT, the GnRH agonist leuprolide was associated with greater coronary plaque progression within 12 months compared with the GnRH antagonist relugolix. This change was driven by an increase in noncalcified plaque volume and may be mediating ADT-associated CV risk.Trial RegistrationClinicalTrials.gov Identifier: NCT05320406 This randomized clinical trial tests the hypothesis that androgen deprivation therapy is associated with accelerated coronary atherosclerosis and is more prominent with a gonadotropin-releasing hormone agonist vs an antagonist.

Objective.This study aims to develop a digital twin (DT) framework to achieve adaptive proton prostate stereotactic body radiation therapy (SBRT) with fast treatment plan selection and patient-specific clinical target volume (CTV) setup uncertainty. Prostate SBRT has emerged as a leading option for external beam radiotherapy due to its effectiveness and reduced treatment duration. However, interfractional anatomy variations can impact treatment outcomes. This study seeks to address these uncertainties using DT concept to improve treatment quality.Approach. A retrospective study on two-fraction prostate proton SBRT was conducted, involving a cohort of 10 randomly selected patient cases from an institutional database (n= 43). DT-based treatment plans were developed using patient-specific CTV setup uncertainty, determined through machine learning predictions. Plans were optimized using pre-treatment CT and corrected cone-beam CT (cCBCT). The cCBCT was corrected for CT numbers and artifacts, and plan evaluation was performed using cCBCT to account for actual patient anatomy. The ProKnow scoring system was adapted to determine the optimal treatment plans.Main Results.Average CTV D98 values for original clinical and DT-based plans across 10 patients were 99.0% and 98.8%, with hot spots measuring 106.0% and 105.1%. Regarding bladder, clinical plans yielded average bladder neck V100 values of 29.6% and bladder V20.8 Gy values of 12.0cc, whereas DT-based plans showed better sparing of bladder neck with values of 14.0% and 9.5cc. Clinical and DT-based plans resulted in comparable rectum dose statistics due to SpaceOAR. Compared to clinical plans, the proposed DT-based plans improved dosimetry quality, improving plan scores ranging from 2.0 to 15.5.Significance.Our study presented a pioneering approach that leverages DT technology to enhance adaptive proton SBRT, potentially revolutionizing prostate radiotherapy to offer personalized treatment solutions using fast adaptive treatment plan selections and patient-specific setup uncertainty. This research contributes to the ongoing efforts to achieve personalized prostate radiotherapy.

PURPOSE:To emulate the Selective Use of Postoperative Radiotherapy After Mastectomy (SUPREMO) phase III clinical trial using real-world data to assess the impact of postmastectomy radiation therapy (PMRT) on overall survival (OS) among patients with intermediate-risk breast cancer. PATIENTS AND METHODS:Using the National Cancer Database, women diagnosed between 2006 and 2013 with intermediate-risk breast cancer (defined as pT1-2N1; pT3N0; or pT2N0 and grade III or with lymphovascular invasion) and 0-3 positive axillary lymph nodes, who underwent total mastectomy, were identified as being in accordance with the SUPREMO trial protocol and included in this study. Multivariable logistic regression, Cox proportional hazards regression, and stabilized inverse probability of treatment weighting were used to explore the relationship between PMRT and OS. The effects of PMRT within subgroups were explored using multivariable interaction models. RESULTS:In total, 49335 patients were included in the study, with 6882 (13.9%) receiving PMRT. Patients with stage T3N0 cancer, 1-3 positive axillary lymph nodes, or positive surgical margins were more likely to receive PMRT. Overall, PMRT was associated with no significant improvement in OS (HR: 0.98, 95% CI, 0.92-1.04). However, improved survival was observed among women with stage T3N0 cancer who received PMRT (HR: 0.72, 95% CI, 0.58-0.89). CONCLUSION:Although PMRT may not be associated with improved OS among all intermediate-risk breast cancer patients with 0-3 positive axillary lymph nodes, the subgroup of patients with stage T3N0 cancer seemed to benefit from PMRT. The study's retrospective nature introduces some uncertainty, but preliminary findings of the SUPREMO trial support these results.

Cardiovascular disease is a leading cause of death in men with localized prostate cancer, and treatment with androgen deprivation therapy (ADT) is known to exacerbate cardiovascular risk; however, the underlying mechanisms driving ADT-associated cardiotoxicity remain unclear. center dot In this case series, we observed significant alterations in circulating adipocytokine levels following 6 months of therapy with the gonadotropin-releasing hormone agonist, leuprolide, in 10 men with localized prostate cancer. center dot The significantly elevated adipocytokine levels following treatment with leuprolide highlight the potential role of ADT-induced systemic inflammation and metabolic dysregulation in the leptin (adipose)-osteopontin (bone) axis in men with localized prostate cancer treated with ADT.

Cardiovascular disease (CVD) remains the leading cause of death among patients with prostate cancer. While the American Heart Association’s PREVENT Score offers a comprehensive lab-based CVD risk prediction model, its integration into oncology workflows is hindered by logistical barriers. To address this gap, the GUHA-STABELLINI Score was developed as a simplified, lab-independent tool tailored for use in specialty care settings. To evaluate physician preferences, implementation feasibility, and contextual fit of the GUHA-STABELLINI versus PREVENT Score using the RE-AIM (i.e., Reach, Effectiveness, Adoption, Implementation, and Maintenance) model. A cross-sectional survey was administered to 45 oncology-specialized physicians across academic and community settings. The survey, structured around RE-AIM domains, assessed preferences, implementation perceptions, and perceived effectiveness of each tool. Quantitative responses were analyzed descriptively, and qualitative comments were thematically coded. A significant majority (93%) of respondents preferred the GUHA-STABELLINI Score over PREVENT, citing its ease of use and alignment with clinical workflows. Across RE-AIM domains, GUHA-STABELLINI scored highly in adaptability (71%), cost/resource feasibility (65%), perceived effectiveness (87%), and equity of reach and outcomes (75% and 73%, respectively). Respondents emphasized the tool’s real-time usability, low resource dependency, and ability to facilitate shared decision-making without laboratory input. Despite marginally lower predictive precision, the GUHA-STABELLINI Score demonstrates superior feasibility, reach, and clinical utility within oncology clinics. Findings highlight the importance of implementation-informed design in developing decision support tools. Future research should focus on validating clinical outcomes and expanding use across specialties. The GUHA-STABELLINI Score serves as a model for pragmatic, specialty-integrated preventive care solutions in resource-constrained environments. Among oncology-specialized physicians, does the simplified and laboratory-independent GUHA-STABELLINI cardiovascular risk score offer superior perceived implementability and clinical utility compared with the AHA PREVENT Score for prostate cancer patients on androgen deprivation therapy? In this cross-sectional survey of 45 physicians, 93% preferred the GUHA-STABELLINI Score over the AHA PREVENT Score. Respondents rated GUHA-STABELLINI as highly adaptable to workflow (71%), cost- and resource-feasible (65%), and likely to be effective (87%) and equitable in reach (75%), despite its slightly lower predictive precision. A context-aligned, low-burden cardiovascular risk tool such as GUHA-STABELLINI may achieve greater clinical uptake in oncology settings than more complex laboratory-dependent models, highlighting the central role of implementation-informed design in successful adoption.

Purpose We evaluated changes in radiation therapy target volume and acute toxicity using 68Ga-prostate specific membrane antigen (PSMA) versus 18F-fluciclovine positron emission tomography (PET)/computed tomography in postprostatectomy patients with biochemical recurrence. We hypothesized that both fluciclovine and PSMA-guided radiation therapy would (1) significantly change pre-PET radiation therapy volumes and (2) show similar toxicity. Methods and Materials We performed an institutional review board-approved, randomized trial comparing fluciclovine (Arm 1) and PSMA (Arm 2)-guided postprostatectomy radiation therapy in patients with detectable prostate-specific antigen after prostatectomy. Treatment volumes were rigidly defined based on PET, and simultaneous integrated boosts to PET uptake in the prostate bed (70.2-76.0 Gy) or pelvis (54.0-56.0 Gy) were allowed. Clinical target volumes (CTVs) included: prostate bed (CTVPB); pelvic lymph nodes (CTVPLV); and volumetric constraints for bladder(-CTV) and rectum. Acute genitourinary and gastrointestinal (GI) toxicity (per Common Terminology Criteria for Adverse Events v5.0) was assessed <90 days from treatment. Results In total, 140 patients were enrolled with 70 randomized to each arm; 11 Arm 1 and 10 Arm 2 patients did not receive radiation on study and were excluded. Fluciclovine and PSMA incorporation increased both CTVPB and CTVPLV (P < .01). More fluciclovine patients received prostate bed boosts (45 of 59 patients vs 26 of 60 patients; P < .01), but there was no difference in proportion receiving pelvic nodal boosts (10 of 15 patients vs 9of 16 patients, fluciclovine vs PSMA; P = .97). Dose constraints were met for most patients. Rates of grade 2 genitourinary (17.0% vs 6.7%, fluciclovine vs PSMA; P = .15) and GI (5.1% vs 1.7%, fluciclovine vs PSMA; P = .47) toxicity were low, with no grade 3+ events. Higher rectal and bladder dose metrics correlated with GI toxicity (P < .05), but use of simultaneous integrated boosts was not associated with acute toxicity. Conclusions Although both PSMA and fluciclovine use modestly increased target volumes, significantly more fluciclovine patients received prostate bed boosts. Planning directives were met for most patients, and acute toxicity was mild in both Arms. Analysis of biochemical control, late toxicity, and patient-reported outcomes are forthcoming.

Background: Rural areas have higher cardiovascular disease (CVD) incidence and age-adjusted mortality rates in the general population. However, the impact of rurality on CVD development and outcomes in patients with prostate cancer (PC) remains unclear. Patients and Methods: This retrospective cohort study used the SEER-Medicare database to analyze males aged ≥65 years diagnosed with PC between 2009 and 2017. The primary exposures were patient rurality status (metropolitan, urban, or rural) and patient–provider rurality, which combined the provider’s status (metropolitan vs nonmetropolitan) with the patient’s rurality. The primary outcomes included post-PC CVD (comprising heart failure, atrial fibrillation, acute myocardial infarction, peripheral artery disease, and ischemic stroke), cardiovascular mortality (CVDm), prostate cancer–specific mortality (PCSm), and all-cause mortality. Multivariable Fine-Gray and extended Cox models were used to assess the impact of rurality impact on these outcomes. Results: A total of 103,327 older men were included in the study, of whom 3,631 were from rural areas and 1,857 were rural patients with nonmetropolitan providers. Compared with metropolitan patients, those from rural areas had a 28% higher risk of PCSm (subdistribution hazard ratio [SHR], 1.28; 95% CI, 1.14–1.44) and a 15% higher risk of all-cause mortality (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.07–1.23). Compared with urban patients, rural patients had a 7% higher risk of CVD (SHR, 1.07; 95% CI, 1.01–1.13). No significant differences were observed in CVDm. Among patients receiving androgen deprivation therapy (n=16,811), rurality was associated with a 27% higher risk of PCSm (SHR, 1.27; 95% CI, 1.07–1.51) and a 29% higher risk of all-cause mortality (aHR, 1.29; 95% CI, 1.12–1.49). Rural patients who received care from nonmetropolitan providers had higher risks of PCSm and all-cause mortality compared with those treated by metropolitan providers. Conclusions: Rurality is associated with higher risks of CVD, PCSm, and all-cause mortality compared with metropolitan and urban patients. Provider rurality further increases these risks, underscoring the critical role of health care access and quality in rural health disparities.

Radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have emerged as a sensitive tool for PET imaging of prostate cancer (PCa) recurrence. Yet urinary bladder activity may obscure the visualization of prostate bed recurrence. Among the Food and Drug Administration-approved PSMA radiopharmaceuticals, 18F-flotufola- stat (rhPSMA-7.3) has the lowest urinary excreted activity. We investigated the impact of diuresis with intravenous furosemide and oral hydration on bladder activity and PCa recurrence detection in patients with PCa after prostatectomy with biochemical recurrence. Methods: This phase II study (NCT05779943) prospectively recruited men with PCa after prostatectomy with a rising prostate-specific antigen (PSA) level of at least 0.1 ng/mL. All patients had 2 18F-flotufolastat PET/CT scans, one with 20 mg of furosemide administered intravenously with the radiotracer and the other without. SUVmean, SUVmax, and bladder volume were compared between the with- and without-furosemide PET/CT studies. PCa lesion detection was compared between the 2 sets of scans. Results: Twenty men with a median PSA of 0.61 ng/mL (interquartile range, 0.18-1.15) completed both sets of scans. Bladder activity was significantly lower for the with- than the without-furosemide studies, at a median SUVmax of 4.20 (range, 1.70-19.80) versus 13.35 (range, 3.90-165.4), respectively (P = 0.014), and a median SUVmean of 2.95 (range, 0.80-17.60) versus 10.00 (range, 1.90-140.00), respectively (P = 0.017). Multivariable analysis demonstrated that both furosemide administration and bladder distention were independent covariates for reduced bladder activity. At the prostate bed region level, the recurrence detection rates were 17 of 20 (85%) and 12 of 20 (60%) for the with- and without-furosemide studies, respectively (P = 0.025). No difference in detection rates was present at the per-patient, pelvic, or extrapelvic regions between the 2 sets of studies. Three of 20 without-furosemide studies had a mild noninterfering peribladder halo artifact, but none had an artifact with furosemide. Conclusion: In men with biochemical recurrence and a PSA level of at least 0.1 ng/mL after prostatectomy for PCa, a strategy with 18F-flotufolastat PET/CT and concordant low-dose furosemide further reduces urinary bladder intensity and increases local recurrence detection. Even without the use of a diuretic, relative bladder distension alone also reduces bladder activity, though not to the same degree as with a diuretic.