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Purpose: This study aimed to compare long-term patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) for localized prostate cancer. Methods and Materials: Patients with clinical T1–T2 prostate cancer receiving IMRT or IMPT at a tertiary cancer center from 2015–2018 were analyzed to determine the changes in the prospectively collected bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26. The mean changes in EPIC-26 scores were evaluated from pretreatment to 24 months post-radiotherapy for each modality. A score change >50% of the baseline standard deviation was considered a clinically meaningful change. Results: A total of 82 patients treated with IMRT (52.2%) and 56 patients treated with IMPT (53.3%) completed the questionnaire at baseline and 24 months post-RT. There were no baseline differences in domain scores between treatment modalities. At 24 months post-radiotherapy, there was a significant and clinically meaningful decline in the BF mean score in the IMRT cohort (−4.52 (range −50, 29.17), p = 0.003), whereas the decline in BF score did not reach clinical relevance or significance (−1.88 (range −37.5, 50), p = 0.046) when accounting for the Bonferroni adjustment in the IMPT cohort. A higher proportion of patients treated with IMRT had a clinically relevant reduction in BF when compared with IMPT (47.37% vs. 25.93%, p = 0.017). The mean changes in the UI and UO scores of the IMRT and IMPT cohorts were neither statically significant nor clinically relevant. Conclusions: IMPT leads to a smaller decrease in BF than IMRT at 24 months post-RT, while there was no differential effect on UO and UI.

129 Background: Few studies have explored the use of focal therapies to address select sites of resistant disease in men receiving 177-Lu-PSMA-617 for metastatic castrate resistant prostate cancer (mCRPC). Our institutional practice is to offer SBRT for patients with up to 5 sites of oligoprogression or non-responding lesions while undergoing 177Lu-PSMA-617 (every 6 weeks for 6 cycles total). This is determined by PSMA or choline PET imaging during the course of 177Lu-PSMA-617. Herein, we evaluated the safety of adding target SBRT during treatment with 177Lu-PSMA-617. Methods: This retrospective single institution analysis was conducted via systematic chart review to evaluate for adverse events during or after treatment. Grading of treatment-related adverse events was conducted using Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5). Results: Thirty-one patients receiving 177Lu-PSMA-617 with 51 sites of oligoprogressive or non-responding metastatic disease were treated with SBRT. The median number of sites treated was 1 (range 1-4). Most patients received SBRT immediately after cycle 6 (32%) or after cycle 3 or 4 (42%). Bone was the most commonly treated site of disease (90%) with the majority (54%) of bone sites being spine or sacrum, followed by lymph nodes (10%). Ultimately, 84% of patients completed all 6 cycles of 177Lu-PSMA-617 (range 4-6). The median follow-up time was 19.1 months (IQR 15.5-22.4) after 177Lu-PSMA-617 therapy start. A total of 2 patients experienced a pathologic fracture within the SBRT treatment field that could possibly be related to radiotherapy. One patient experienced a grade 2 neuropathy which may have been related to radiation therapy. Other potential adverse events are listed (Table). Conclusions: Our data demonstrates a low rate of significant toxicity with the use SBRT during treatment with 177Lu-PSMA-617. Further study is indicated to determine the oncologic efficacy and potential late side effects of this treatment strategy. Adverse events. Event All Grades Grade > 3 Any Adverse Event 104 2 Anemia 29 (94%) 0 Low Platelets 11 (35.5%) 1 (3.2%) Any Pathologic Fracture 7 (22.5%) 1 (3.2%) Possible SBRT-related Pathologic Fracture 2 (6.5%) 1 (3.2%) Bone Pain Flare 3 (9.6%) 0 Neuropathy 1 (3.2%) 0

424 Background: Advances in prostate cancer (PC) care have led to a 98% 10-year survival rate. Prostate Specific Antigen (PSA) is the primary method of follow-up after definitive radiotherapy (RT), with benign PSA ‘bounce’ occurring in up to 30% of patients, causing uncertainty and anxiety. Distinguishing between PSA bounce and biochemical recurrence (BCR) remains challenging. The Phoenix Criteria is the standard definition of BCR since 2006, defined as PSA nadir + 2 ng/dl, but does not consider patient specific information. Our study aims to explore factors associated with bounce and BCR and develop a predictive tool to differentiate between these two events. Methods: PC patients who received RT at our institution between 2006 and 2022 were identified, including only patients with a PSA increase during follow-up. Exclusion criteria included palliative RT, prostatectomy, or insufficient follow-up information. Patients’ clinical data was collected, and PSA increase was classified as bounce or BCR. Variables were compared using Kruskal Wallis or Chi-square. Multivariate logistic regression was performed in the subset of patients with absolute PSA value >2 (n= 581). Results: Of 1783 patients reviewed due to PSA rise after treatment, 694 met the inclusion criteria. There were 213 (30.7%) with PSA bounce and 481 (69.3%) with recurrence. Prior to meeting the Phoenix Criteria, 20 (4.2%) had biopsy-proven recurrence and 18 (3.7%) imaging-proven recurrence. The median delta PSA was 0.8 ng/mL for bounce vs 5 ng/mL for recurrence (p<0.001). The median time from treatment to event was 14.4 months for bounce vs 45.3 months for BCR (p<0.001). Recurrence was significantly associated (p<0.001) with older age at diagnosis, N1 stage, higher risk category, Gleason score, and higher baseline PSA. In the subgroup of patients without ADT, recurrence was associated with a lower median first PSA post-RT (1.9 vs. 2.4, p=0.046) and a lower median nadir before event (0.6 vs. 1.8, p<0.001). Multivariate logistic regression achieved an accuracy of 0.94, with a sensitivity of 0.83, specificity of 0.98, and an area under the curve (AUC) of 0.97. Conclusions: Our results highlight significant differences in clinical factors between bounce and recurrence in post-RT patients. The multivariate logistic regression differentiated the events with 94% accuracy for patients with a rising PSA value >2 subgroup. We highlight the possible improvement that could be accomplished by personalizing a PSA threshold for recurrence versus the Phoenix definition. This tool offers patients and providers a highly specific tool to differentiate between PSA recurrence and bounce, and may reduce stress and unnecessary testing, or help diagnosis recurrence faster. Next steps include prospective validation of the model to assess the impact on clinical practice costs, patient experience, and cancer outcomes.

BackgroundPatients with high‐risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost.MethodsThe authors compared quality‐adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external‐beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low‐dose‐rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479).ResultsTreatment strategies were compared using the incremental cost‐effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost‐effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost‐effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost.ConclusionsEBRT with LDR brachytherapy boost may be a cost‐effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high‐value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost‐effective care, despite no change in overall survival.

AbstractBackgroundThe objective of this study was to report acute changes in patient‐reported quality of life (PRQOL) using the 26‐item Expanded Prostate Index Composite (EPIC‐26) questionnaire in a prospective study using hypofractionated intensity‐modulated proton beam therapy (H‐IMPT) targeting the prostate and the pelvic lymph nodes for high‐risk or unfavorable intermediate‐risk prostate cancer.MethodsFifty‐five patients were enrolled. H‐IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC‐26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation.ResultsThe mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (−13.5 and −2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (−13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful.ConclusionsUO, UI, and BF scores of PRQOL declined at the end of H‐IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.

Abstract Background Radium (Ra)‐223 is an established treatment option for patients with metastatic castrate‐resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP‐ribose polymerase inhibitors and platinum‐based therapies. This study aims to evaluate mCRPC response to Ra‐223 stratified by tumor genomics. Methods This is a retrospective study of mCRPC patients who received Ra‐223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate‐specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression‐free survival (PFS) and overall survival (OS) from time of first radium treatment. Results One hundred and twenty‐seven mCRPC patients treated with Ra‐223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra‐223 treatment was 61.0 and 68.6 years, respectively. Seventy‐nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2‐ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2‐ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0−NR) versus 26.8 months (95% CI 20.9−35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28−NR) versus 9.0 months (95% CI 7.3−11.1) and a lower OS 13.9 months (95% CI 5.2−NR) versus 26.5 months (95% CI 19.8−33.8). Conclusions Among mCRPC patients treated with Ra‐223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2‐ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra‐223.

248 Background: Hypofractionated prostate cancer radiation has showed similar results in several prior phase III studies (PCG GU 003, PACE-B, and Hypo PC RT). However, prospective phase II-III clinical trial data testing 5 tx after prostatectomy is scarce. Methods: Between 2018 and 2019, 41 patients were treated after postprostatectomy for high risk features. 5 patients were treated adjuvantly, 36 for salvage including 8 with oligometastatic disease. Indications for adjuvant RT included a PSA < 0.2 and +margins, SVI, or EPE. Salvage RT was offered for PSA ≥0.2. Oligometastatic RT for patients with ≤5 RT targets. Staging included C11 PET for all cases. Total dose to the prostate bed was 30-32 Gy in 5tx QOD with IMRT, conebeam IGRT, and MRI registration. All salvage patients received ADT for 6 months and oligometastatic patients for 18 months. Dose to the metastatic sites was 30 in 5tx QOD. Of the 41 patients 8 also received SBRT to the sites of oligometastatic disease. We looked at clinical outcomes defining biochemical failure as a PSA > 0.2 after treatment, baseline adjusted CTC AE V5.0, baseline adjusted patient reported toxicities (PRO CTC AE), QOL (EPIC, PROMIS), and AUA was used for all cases. Results: Median follow up was 23 months (range 10-37). Pre-RT T stage was T2-T3b, with 47% being T3a-b; Pre RT Median PSA of 0.4 (range < 0.1-1.9); Median GS 8 (6-9); and (+) margins in 48.8%. Sites of oligometastatic disease radiated included the LN and bone. Treatment related AE were grade 0-1 in all cases, except for one patient with G2 GU incontinence. Overall QOL remained high during follow including Promis 10 overall, mental, and physical scores; urinary bother, irritative/obstructive, and AUA scores; bowel overall, bowel bother, and bowel function scores; and overall sexual, sexual function, and sexual bother scores remained at baseline levels during follow up. Only hormonal overall, hormonal function, and hormonal bother had lower scores at 3 months that recovered by 12 months in patients treated with ADT for 6 months and by 24 months in patients treated with ADT for 18 months. A total of 3 clinical failure have been seen; 2 patients with regional failures alone; and one with axial skeleton bony failures for 93% clinical control at median follow up of 23 months. All 3 patients with clinical failure were salvaged successfully with SBRT and all patients remain disease free at last follow up. A total 5 patients with raising PSAs alone have been seen. All patients have been re-staged with C11 PET. No failures in the prostate bed or previously radiated sites have been seen. Conclusions: Toxicity for RT over 5tx is lower than expected with only one case of grade 2 urinary incontinence. QOL scores remained high during follow up, minor changes in hormonal scores were seen during ADT, but recovered after. 30-32 Gy over 5 tx provided 100% control in radiated targets and metastatic sites. Clinical trial information: NCT03570827.

Abstract Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.