BACKGROUND:Management of retroperitoneal liposarcoma (RPLPS) is challenging and recurrence rates remain high despite aggressive surgical resections. Preoperative radiation alone lacks definitive benefit, thus we sought to evaluate combined chemoradiotherapy with the potential to enhance local efficacy of radiation as well as control micrometastatic disease. We assessed the safety and tolerability of preoperative eribulin, a cytotoxic microtubule inhibitor approved for the treatment of advanced liposarcoma, in combination with radiation in patients with RPLPS. METHODS:In this open-label dose-finding study, patients with primary or recurrent resectable RPLPS received preoperative intensity-modulated radiation therapy (IMRT) with escalating doses of eribulin. Eribulin was administered for three 21-day cycles at a starting dose of 1.1 mg/m2. Concurrent radiation to 50.4 Gy began during cycle 1. Surgical resection occurred 3-10 weeks after completion of chemoradiation. The primary endpoint was determination of the recommended phase 2 doses (RP2D) of concurrent eribulin and radiation. RESULTS:Between 2018-2023, fifteen patients were enrolled. Thirteen patients were evaluable for dose-determination. Four patients treated at starting dose level had no dose-limiting toxicities (DLTs). Two of nine patients treated with escalated eribulin dose had DLTs. The RP2D was established as eribulin 1.4 mg/m2 and IMRT 50.4 Gy. Eleven patients were evaluable for secondary efficacy endpoints. The median recurrence-free survival was 30.4 months (95% CI 12.0-NR) and the median overall survival was 54.1 months (95% CI 9.5-NR). Patient reported outcome data did not show any significant changes over the study period. CONCLUSION:A preoperative chemoradiation protocol of eribulin in combination with IMRT showed a manageable safety profile and warrants additional prospective evaluation for treatment of resectable RPLPS.

IntroductionCancer survivors and intimate care partners coping with cancer may each experience loneliness that impacts their health, but research within couples and potential benefit of interventions is scarce. METHODS: We added the Cancer Loneliness (CL) scale to measures of anxiety, depressive symptoms, pain and social and physical function mid-way through the Exercising Together trial (NCT03630354) in couples coping with breast (BC; n = 44) or prostate cancer (PC; n = 75). The prevalence of CL scores >1 indicated at least some loneliness and we ran correlations between CL and measures of social, physical and mental health. Within PC couples we explored the potential benefits of different types of dyadic exercise programs (supervised, group partnered exercise, supervised separate groups of survivors or partners, or unsupervised independent exercise) on CL over 6 months.Results96% of breast cancer survivors (BCS) and 77% of prostate cancer survivors (PCS) reported CL at baseline. CL was positively associated with anxiety (rho = 0.44, 0.77), depressive symptoms (rho = 0.60, 0.67) and pain (rho = 0.34, 0.23) and inversely associated with social functioning (rho = −0.54, −0.55) among BCS and PCS, respectively (all p < 0.01). CL was inversely associated with physical functioning in BCS (rho = −0.35), but not PCS. Among care partners, 74%–77% of care partners for each BCS and PCS reported CL related to their partner’s cancer at baseline. CL was positively associated with anxiety (rho = 0.43, 0.30) and depressive symptoms (rho = 0.62, 0.45) among BC and PC care partners, respectively (all p < 0.01). CL was inversely associated with social functioning in BC partners only (rho = −0.45, p < 0.01), but not with physical functioning in either group. Within PC couples, there was a significant (inverse) interaction between change in CL over six-months of exercise and baseline loneliness. Declines in CL for both PCS and care partners were steepest in the exercise program where they trained with other PCS or care partners.ConclusionRelationships may not offer enough social support to avoid feelings of loneliness associated with cancer that in turn affects the physical, emotional and social health of each partner. However, exercise may help rebuild connection within the couple and be an avenue for informal social support that together could reduce loneliness.Clinical Trial Registration[clinicaltrials.gov]: identifier, [NCT03630354].

Abstract Background Obese frailty is a growing national problem as trends towards aging and obesity converge. This problem is especially acute in men with prostate cancer treated with androgen deprivation therapy (ADT). ADT is the backbone of therapy for advanced prostate cancer, a disease which affects mostly older men. But, ADT accelerates muscle loss and gains in adiposity which threaten physical functioning and quality of life. Diet and resistance training may mitigate obese frailty but have rarely been combined in an accessible delivery format. Methods The Internet-Based Lifestyle Intervention to Eradicate Obese Frailty in Prostate Cancer Survivors (iLIVE) Randomized Controlled Trial (RCT) aims to mitigate obese frailty among men with prostate cancer treated with ADT. Participants (N=250) are being recruited across North America to participate in this RCT that is implemented entirely over the internet. Eligibility criteria include body mass index >25 kg/m2 and > 2 frailty symptoms [illness, fatigue, inactivity, weakness, slowness]). Consented participants undergo assessments that include: online surveys (medical status, falls, physical activity, quality-of-life, healthcare utilization); dietary recalls (kilocalories, diet quality); body weight (Aria® scales); physical activity (Fitbits®); 4) internet-based physical performance (chair stand, timed up-and-go, gait speed tests); and 5) muscle mass (D3 creatine dilution). Participants are then randomized to one of two 6-month interventions: 1) Enhanced Usual Care (EUC): Encouraged to continue Aria® scale and Fitbit® use with monthly emails of publicly available diet- and exercise-related information; or 2) iLIVE: Same as EUC, plus website access to weekly serialized sessions on weight loss and diet quality and thrice-weekly live remote supervised group resistance training sessions. Assessments are repeated at 6-months; at 12-months, questionnaires are repeated and data from digital devices are captured. Intent-to-treat analysis will compare EUC vs. iLIVE (baseline-to-6-months) using a composite measure of obese frailty as the primary outcome. Designed as a type I hybrid-effectiveness implementation trial, data on intervention feasibility (including safety), acceptability, adoption, appropriateness, fidelity, sustainability, and cost are assessed, tracked, and analyzed. Discussion The iLIVE RCT is implemented exclusively over the internet and provides a blueprint for other highly scalable lifestyle interventions with potential for rapid translation into nationwide practice. Trial registration ClinicalTrials.gov: NCT06011499 (5.31.2025: https://clinicaltrials.gov/study/NCT06011499 ).

Objectives:Approximately 15% of patients with localized prostate cancer are at high risk for disease recurrence. Many clinical trials have evaluated the impact of neoadjuvant therapy before radical prostatectomy with mixed results (NCT00321698).Methods:This phase I/II clinical trial evaluated the tolerability and preliminary efficacy of neoadjuvant radiation therapy and docetaxel before prostatectomy in 25 men with high-risk prostate cancer. The treatment regimen included 45 Gy radiotherapy in 25 fractions to the prostate and seminal vesicles over 5 weeks, along with weekly dose-escalated docetaxel up to 30 mg/m(2), followed by prostatectomy and bilateral lymph node dissection. The primary endpoint was the rate of pathologic complete response (pCR). Secondary endpoints included adverse events, symptom and quality of life measures, and prostate-specific antigen metrics.Results:All 25 patients completed the planned treatment. The primary endpoint of pCR was not achieved. Lymphopenia was the most common grade 3 or higher toxicity, with no grade 3 or higher genitourinary or gastrointestinal toxicities observed. With a median follow-up of 11.6 years, the 10-year biochemical recurrence-free survival was 60%, and distant metastasis-free survival was 80%. Prostate cancer-specific survival and overall survival at 10 years were 84% and 60%, respectively.Conclusions:Although pCR was not met, the treatment demonstrated a modest toxicity profile and reasonable long-term outcomes, suggesting feasibility and safety. Further studies are needed to optimize endpoints and assess the efficacy of neoadjuvant treatments compared with standard approaches in high-risk prostate cancer patients.

Prostate cancer can make men feel socially isolated, even from friends and family, leading to feelings of loneliness that negatively impact their health and quality of life. Group-based exercise shows promise in addressing the social, emotional, and physical needs of men with prostate cancer.

Abstract Men with prostate cancer may experience cancer-related loneliness (CRL) that impacts their mental and physical health, yet research in this area remains sparse. We explored the relationship between cancer-related loneliness, anxiety, depressive symptoms, social and physical functioning and the potential benefits of group exercise in a subset of men with prostate cancer participating in a clinical exercise trial. We added the CRL questionnaire to measures of anxiety (PROMIS), depressive symptoms (CES-D) and social and physical function (QLQC30 subscales) mid-way through the GET FIT Prostate trial (NCT03741335). 145 men (mean age: 71.5 +/- 7.3 yrs) completed measures prior to participating in one of three online supervised group exercise programs for 6 months and another 68 also completed measures post-intervention. While exercise modalities differed among the three groups, all men participated in 15 minutes of semi-structured social time immediately prior to the start of their one-hour exercise class. 70% of men reported some level of CRL at baseline. CRL was significantly (p< 0.01) and positively associated with higher anxiety (r=0.61) and worse depressive symptoms (r=0.66) and inversely with social (r=-0.50) and physical (r=-0.23) functioning. After 6 months of group exercise, CRL decreased among men who reported experiencing CRL at least some of the time at baseline (p=0.017). Among the whole sample, higher baseline CRL was significantly associated with the greater declines in CRL over 6 months (adjusted-R2=0.16, p< 0.01). A majority of men with prostate cancer may experience cancer-related loneliness, but socially-enhanced group exercise could be an effective countermeasure to improve well-being.

OBJECTIVES:Approximately 15% of patients with localized prostate cancer are at high risk for disease recurrence. Many clinical trials have evaluated the impact of neoadjuvant therapy before radical prostatectomy with mixed results (NCT00321698). METHODS:This phase I/II clinical trial evaluated the tolerability and preliminary efficacy of neoadjuvant radiation therapy and docetaxel before prostatectomy in 25 men with high-risk prostate cancer. The treatment regimen included 45 Gy radiotherapy in 25 fractions to the prostate and seminal vesicles over 5 weeks, along with weekly dose-escalated docetaxel up to 30 mg/m², followed by prostatectomy and bilateral lymph node dissection. The primary endpoint was the rate of pathologic complete response (pCR). Secondary endpoints included adverse events, symptom and quality of life measures, and prostate-specific antigen metrics. RESULTS:All 25 patients completed the planned treatment. The primary endpoint of pCR was not achieved. Lymphopenia was the most common grade 3 or higher toxicity, with no grade 3 or higher genitourinary or gastrointestinal toxicities observed. With a median follow-up of 11.6 years, the 10-year biochemical recurrence-free survival was 60%, and distant metastasis-free survival was 80%. Prostate cancer-specific survival and overall survival at 10 years were 84% and 60%, respectively. CONCLUSIONS:Although pCR was not met, the treatment demonstrated a modest toxicity profile and reasonable long-term outcomes, suggesting feasibility and safety. Further studies are needed to optimize endpoints and assess the efficacy of neoadjuvant treatments compared with standard approaches in high-risk prostate cancer patients.

Radiotherapy is indicated for nearly all cancers and at all stages in one form or another. More than half of all cancer patients are treated with radiation at some point in their cancer treatment. Conventional X-ray (photon) based radiotherapy does have a number of physical limitations which were theorized to be overcome by instead employing proton based radiotherapy. The late 1990s and early 2000s saw a rapid adoption in proton therapy as many speculated a greatly improved therapeutic window compared with photon therapy. Only a few randomized clinical trials have been reported, but to-date proton therapy has not shown to improve cancer control metrics. There is improved treatment related toxicity which may be clinically meaningful in some scenarios, but further expansion and wide spread utilization of the technology may be drastically limited by the substantially higher start up and operational costs of a proton center. Nonetheless, proton therapy may be beneficial in select scenarios which warrant individualized consideration.

Commercial autosegmentation has entered clinical use, however real-world performance may suffer in certain cases. We aimed to assess the influence of anatomic variants on performance. We identified 112 prostate cancer patients with anatomic variations (edge cases). Pelvic anatomy was autosegmented using three commercial tools. To evaluate performance, Dice similarity coefficients, and mean surface and 95% Hausdorff distances were calculated versus clinician-delineated references. Deep learning autosegmentation outperformed atlas-based and model-based methods. However, edge case performance was lower versus the normal cohort (0.12 mean DSC reduction). Anatomic variation presents challenges to commercial autosegmentation.

81 Background: Androgen deprivation therapy (ADT) for prostate cancer may result in accelerated aging that increases the risk for falls. Falls are higher in men with a history of ADT use, even if treatment is discontinued, compared to men never on ADT. Less is known, however, about the specific patient characteristics that might be associated with falls. Methods: We analyzed data from prostate cancer survivors with a history of ADT and who had enrolled in an ongoing NIH-funded fall prevention exercise trial (NCT03741335). To be eligible for the trial, men were 1) currently or previously treated with ADT and 2) reported a fall in the previous 6 months or had evidence of fall risk. Fall risk was assessed through slow times on a 5 time sit-to-stand test (5XSTS; sec) or timed up and go walk test (TUG; sec). For this analysis we compared men with a positive fall history to men with no recent falls but evidence of fall risk. We compared age, ADT history (past vs current), body mass index (BMI), self-report comorbidities from the Charlson Comorbidity Index, physical function and disability from the LLFDI, pain from the BPI, anxiety from PROMIS, depressive symptoms from the CES-D, fear of falling and activity restrictions from the SAFFE, and physical activity from CHAMPS, as well as objective measures of strength and mobility using 5XSTS and TUG. Results: A total of 171 cases (mean age 73.1 +/- 7.1 years of age) were available for analysis, with 58 men (34%) reporting a fall in the 6 months prior to enrollment. Of reported falls, 11% were injurious falls, with 4% requiring medical attention. Injuries included fractures (n = 4), head injury (n = 2), joint injury (n = 3), and bruises/scrapes (n = 8). Fallers reported significantly lower levels of physical functioning (p < 0.001), greater levels of disability (p < 0.01), greater fear of falling (p < 0.001), more activity restrictions due to falls worry (p < 0.02) and slower TUG times (p < 0.03), than men who had not recently fallen. There were no significant differences between men with established fall history and men with fall risk only on age, ADT history, comorbidities, BMI, pain, anxiety, depressive symptoms, physical activity, or 5XSTS (p for all > 0.05). Conclusions: Among our preliminary sample of men with a history of ADT use and enrolled in an ongoing fall prevention trial, men with an established fall history functioned less independently, were more worried about falls and apt to restrict their activities accordingly, and had poorer mobility than men who hadn’t recently fallen. From our cross-sectional design we cannot determine whether poorer functioning and mobility and greater fear of falling were antecedents or consequences of a recent fall. Regardless, interventions designed to prevent falls in men exposed to ADT are critical to prevent potential injurious falls and to keep men functioning independently.

Purpose: The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). Methods and Materials: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis. Results: The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multi-modality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%. Conclusions: The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis. (C) 2021 The Author(s). Published by Elsevier Inc.

Published systemic therapy options for metastatic extramammary Paget's disease have largely been anecdotal due to the rarity of this disease, which has precluded the ability to conduct clinical trials. We describe the favorable response of a 72-year-old man with extramammary Paget's disease, whose disease has been controlled with the CDK4/6 inhibitor, abemaciclib. The rationale behind the selection of this therapy is discussed.

Objectives: In the era of dose-escalated prostate radiation therapy (RT), the use of androgen deprivation therapy (ADT) is undefined for intermediate-risk (IR) prostate cancer. There is growing concern of the risk of ADT to be detrimental to quality of life. This single-institution retrospective analysis aimed to evaluate outcomes of IR patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with or without concurrent/adjuvant short-term ADT. Materials and Methods: Data was collected from 260 consecutive patients treated with dose-escalated IMRT with daily image-guided RT for newly diagnosed IR prostate cancer. Biochemical recurrence-free survival (BCRFS), distant metastasis-free survival, prostate cancer-specific survival, and overall survival (OS) were calculated using Kaplan-Meier methodology. Results: Median follow-up was 93 months. A total of 181 patients had unfavorable IR disease, and 36.2% (N=94) received ADT, with median ADT duration of 6 months. Seven-year BCRFS was 94.1% vs. 86.2% (P=0.067), for ADT and no ADT, respectively, and no difference in distant metastasis-free survival or prostate cancer-specific survival was observed. ADT was associated with significantly worse 7-year OS (80.0% vs. 91.3%, P=0.010). Analysis of the unfavorable IR cohort alone, showed similar results; 7-year BCRFS and 7-year OS in patients who received ADT versus no ADT were 93.7% vs. 85.9% (P=0.093), and 79.0% vs. 90.6% (P=0.019), respectively. Conclusions: In our 15-year experience treating IR prostate cancer with dose-escalated IMRT with daily image-guided RT, short-term concurrent ADT was associated with a statistically significant worse OS. Additional studies are needed to determine if ADT is beneficial or detrimental for patients with IR prostate cancer treated with dose-escalated radiation.

Purpose/Objective(s)To assess the performance of commercially available autosegmentation solutions of pelvic anatomy in edge cases of anatomic variation among patients receiving definitive radiotherapy (RT) for prostate cancer.Materials/MethodsIn a single institution retrospective cohort of 830 patients with prostate cancer receiving definitive RT between 2011 and 2019, we identified 112 patients with anatomic variations seen on simulation CT imaging which may present challenging cases for precise delineation of anatomy, including reasons such as arthroplasty metal artifacts, extensive median lobe hypertrophy, “droopy” seminal vesicles, presence of urinary catheter, and history of transurethral resection of prostatic tissue. Three commercially available solutions for pelvic anatomy autosegmentation (AS) employing deep learning and model-based segmentation were applied to treatment planning CT scans to generate segmented volumes of the prostate, rectum, bladder and femoral heads in DICOM-RT format. To quantify the accuracy of software-generated contours, Dice similarity coefficients (DSC) and Hausdorff distances (HD) were calculated for each AS contour with a comparator manually segmented reference contour. Calculations were performed in R using the RadOnc package and manually segmented contours were approved by an expert radiation oncologist with 19 years of experience.ResultsA total of 112 patients were identified for inclusion after manual review of treatment planning CTs. Contours were generated using two atlas/model-based segmentation products and a deep learning segmentation method. The mean DSC for the prostate, bladder, rectum was calculated for each segmentation method (Table 1). Deep learning segmentation outperformed model-based methods for all structures with the highest mean DSC but still had significant disagreement with manually segmented structures. Hip arthroplasty in particular reduced overall performance more than other anatomical edge cases, followed by prostatic hypertrophy.ConclusionAnatomic edge cases present a challenging and relevant consideration in clinical implementation of autosegmentation software.

TPS193 Background: Many prostate cancer survivors are treated with androgen deprivation therapy (ADT), but these therapies may increase frailty, worsen physical functioning, and increase fall risk. While exercise may counter functional declines associated with ADT, no studies have tested whether and which type of exercise may reduce falls and frailty. The purpose of this trial is to compare the relative efficacy of strength training versus tai ji quan training against each other and to a stretching control group on falls, frailty and physical functioning in men expose to ADT for prostate cancer. Methods: Prostate cancer survivors treated with ADT (n = 360) will be recruited to participate in this single-blind, parallel group, randomized trial. To be eligible men must meet the following criteria: 1) histologically confirmed prostate cancer, 2) received at least 6 months of ADT within the past 10 years, 3) report >1 fall in the past year OR have a score on one of two physical performance tests that is associated with increased fall risk (i.e. ≥ 12.0 seconds to complete the 3 meter timed up and go (TUG), or ≥ 10.0 seconds to complete 5 chair stands), 4) completed any other treatment at least 6 weeks prior to enrollment and not be on any concurrent prostate cancer therapy besides ADT, 5) not currently participating in moderate-vigorous intensity lower-body strength training or tai ji quan training ≥ 2 times/week for ≥ 30 minutes per session, 6) no cognitive difficulties that limit ability to answer survey questions or participate in exercise classes and performance tests, 7) no medical condition, disorder, or take medication that contraindicates participation in moderate intensity exercise, and 8) are able to communicate in English. Participants will be randomized to one of three supervised, group training programs: i) strength training, ii) tai ji quan training, or iii) stretching (control), that train 3x/week for 6 months. Outcomes are assessed at baseline, 3 (mid-intervention), 6 (immediately post-intervention) and 12 (follow-up) months. The primary outcome is falls assessed by monthly self-report. Secondary outcomes include the following: Frailty (low lean body mass (by bioelectrical impedance analysis), exhaustion (by SF-36 vitality scale), low activity (by CHAMPS physical activity survey), slowness (by 4m usual walk speed), and weakness (by chair stand time)); Objective and subjective measures of physical function will also be collected. Negative binomial regression models will be used to assess differences in falls between groups, while mixed-effects modeling will be used to compare the relative efficacy of training group on secondary outcomes. Registered November 18, 2018. Clinical trial information: NCT03741335.

195 Background: This study evaluated the ability of the combined clinical cell-cycle risk score (CCR) to prognosticate the risk of prostate cancer metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). Methods: The CCR score is a validated model that combines the cell cycle progression score (CCP) with the UCSF Cancer of the Prostate Risk Assessment score (CAPRA). The CCR score and a CCR-based multimodality threshold score (2.112) were evaluated in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Center (NCCN) intermediate- or high-risk localized disease (N = 741) who received single (RT) or multimodality therapy (ADT with RT). Effects of prognostic variables were analyzed using Kaplan-Meier and Cox regression methods. Results: Median follow-up was 5.9 years. CCR predicted metastasis [hazard ratio (HR) 2.21, 95% Confidence Interval (CI) 1.70-2.87, p < 0.001]. The CCR score was a better prognosticator of metastasis (C-index 0.78) than either NCCN-risk group (C-index 0.70), CAPRA score (C-index 0.71), or CCP score (C-index 0.69) alone. In bivariate analyses, the CCR score remained highly prognostic for metastasis when comparing any ADT vs none (HR 2.19, 95% CI 1.62 to 2.97, p < 0.001), ADT duration as a continuous variable (HR 2.05, 95% CI 1.54-2.72, p < 0.001), or ADT use given as less than or at the recommended duration for each NCCN risk group (HR 2.22, 95% CI 1.71-2.88, p < 0.001). Men with CCR scores either below or above the threshold (2.112) had a 10-year risk of metastasis of 4.2% and 25.3%, respectively. For men below the threshold receiving RT alone versus RT+ADT, the 10-year risk of metastasis was 4.2% and 3.9%, respectively. Conclusions: CCR is a highly precise and accurate predictor of metastasis in men undergoing dose-escalated RT, with or without ADT. CCR adds clinically actionable information relative to guideline recommended therapies that are based on NCCN risk groups or CAPRA alone. Men with scores below the multimodality threshold may not significantly reduce their 10-year risk of metastasis with the addition of ADT.

Abstract Introduction Prostate cancer can negatively impact the health of patients and their spouse, particularly early on in the cancer trajectory. Purpose To determine the feasibility and acceptability of dyadic exercises during radiation therapy and preliminary efficacy on physical, mental, and relational outcomes for men and their spouses. Exercising Together©, originally designed as a 6-month dyadic resistance training program for couples post-treatment, was adapted for the radiation setting. Methods We conducted a single-group pilot feasibility study of Exercising Together© in men scheduled for radiation therapy for prostate cancer and their spouse. Couples attended supervised exercise sessions thrice weekly throughout radiation treatment and were followed up 8 weeks later. Primary outcomes were feasibility and acceptability with secondary outcomes of changes in physical (physical functioning (short physical performance battery (sPPB)), gait speed (m/s), functional capacity (400-m walk (min), physical activity (min/week)), mental (depressive symptoms (CES-D), and anxiety (SCL-90 ANX)), and relationship (Dyadic Coping, Role Overload, and Physical Intimacy Behavior Scales) health outcomes for each partner. Participants completed an evaluation post-intervention. Results Ten couples enrolled and 8 completed the intervention, attending 83% of scheduled sessions. Couple satisfaction with the intervention was high (patients: mean difference (MD) = 9.4 ± 1.9 and spouses: MD = 10.0 ± 0.0, on a 1–10 scale). At post-intervention, gait speed (MD = 0.1; 95%CI: 0.1, 0.2; p = 0.003; d = 0.94) and functional capacity (MD = −0.6; 95%CI: −0.9, 0.3; p = 0.002; d = −0.42) improved in patients and sPPB in spouses (MD = 1.3; 95%CI: 0.3, 2.2; p = 0.02; d = 0.71). Total physical activity increased non-significantly for patients and significantly for spouses at post-intervention and decreased at follow-up (MD = 179.6; 95%CI: 55.4, 303.7; p = 0.01; d = 1.35 and MD = −139.9; 95%CI: −266.5, 13.3; p = 0.03; d=1.06). Among patients, anxiety and active engagement significantly improved post-intervention (MD = −2.3; 95%CI: −3.8, 0.7; p = 0.01; d = −0.43 and MD = 2.5; 95%CI: 0.7, 4.3; p = 0.01; d = 0.98, respectively). There were modest effects on other physical, mental, and relationship health domains in patients and spouses. Conclusion A modified version of Exercising Together© is a feasible and acceptable program during radiation therapy for prostate cancer and shows preliminary evidence for improvements on physical, mental, and relational health in both patient and spouse. A larger, fully powered randomized controlled trial is warranted and could help shift the landscape toward dyadically targeted interventions. Trial registration This study was registered on ClinicalTrials.gov on February 18th, 2018 ( NCT03418025 ).