Nonmetastatic Prostate Cancer Research Articles

Drug–drug interaction potential among patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with novel androgen receptor inhibitors

ABSTRACT Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) patients are often older and use concurrent medications that increase the potential for drug–drug interactions (pDDIs). This study assessed pDDI prevalence in real-world nmCRPC patients treated with apalutamide, darolutamide, or enzalutamide. Research design and methods Castrated prostate cancer patients without metastases prior to androgen receptor inhibitor initiation were identified retrospectively via Optum Clinformatics Data Mart claims data (8/2019–3/2021). The top 100 concomitant medications were assessed for pDDIs. Results Among 1,515 patients (mean age: 77 ± 8 years; mean Charlson Comorbidity Index: 3 ± 3), 340 initiated apalutamide, 112 darolutamide, and 1,063 enzalutamide. Common concomitant medication classes were cardiovascular (80%) and central nervous system (52%). Two-thirds of the patients received ≥5 concomitant medications; 30 (30/100 medications) pDDIs were identified for apalutamide and enzalutamide each and 2 (2/100 medications) for darolutamide. Most pDDIs had risk ratings of C or D, but four for apalutamide were rated X. Approximately 58% of the patients on apalutamide, 5% on darolutamide, and 54% on enzalutamide had ≥1 identified pDDI. Conclusions Results showed a higher frequency of pDDIs in patients receiving apalutamide and enzalutamide vs darolutamide. The impact of these could not be determined retrospectively. DDI risk should be carefully evaluated when discussing optimal therapy for patients with nmCRPC.

The clinical meaning of lymphovascular invasion: preoperative predictors and postoperative implications in prostate cancer - a retrospective study

IntroductionLymphovascular invasion (LVI) is a pivotal histopathological parameter in prostate cancer (PCa), holding significant prognostic implications. Our study pursued a dual objective: firstly, to identify preoperative factors associated with LVI, aiming to unveil markers facilitating the recognition of patients prone to LVI during postoperative examination; and secondly, to assess postoperative outcomes correlated with LVI.MethodsWe retrospectively analyzed 861 nonmetastatic PCa patients who underwent radical prostatectomy (RP), investigating preoperative factors and postoperative outcomes. Surgical specimens were processed following established guidelines. Statistical analyses utilized non-parametric tests to assess the association between LVI and both pre- and postoperative factors. Furthermore, logistic regression analyses were utilized to develop models aimed at identifying the most significant predictors of LVI and pN1 status, respectively.ResultsNumerous preoperative factors exhibited significant correlations with LVI, offering valuable clinical insights. Logistic regression identified magnetic resonance imaging (MRI)-based clinical tumor stage (cT) 3-4, biopsy Gleason Grading Group (GGG) 3-5, preoperative prostate specific antigen (PSA) ≥20 and percentage of positive biopsy cores (PPBC) ≥50% as the strongest preoperative predictors of LVI. Additionally, the study uncovered an association between LVI and postoperative outcomes, including postoperative PSA (p value <0.001), extracapsular extension (ECE) (<0.001), positive surgical margins (PSM) (<0.001), perineural invasion (PNI) (<0.001), pathological tumor stage (pT) (<0.001), pathological lymph node status (pN) (<0.001), postoperative GGG (<0.001), and operative time (0.023). Notably, the study revealed a novel and substantial association between LVI and an increased number of positive lymph nodes in pN+ patients in the univariate analysis (<0.001). Furthermore, we have found an association between LVI and pN1 status in the logistic regression analysis (odds ratio [OR] = 23.905; p <0.001).ConclusionOur findings underscore the pivotal role of LVI in influencing the prognosis of prostate cancer (PCa). The study acknowledges the challenges associated with preoperative LVI assessment and emphasizes the need for future research to unravel the factors associated with this histopathological finding. Significantly, our research stands out as the first, to the best of our knowledge, to reveal the association between LVI and the number of positive lymph nodes in pN+ patients.

Deposition of collagen III and alterations in basement membrane integrity as candidate prognostic markers in prostate cancer

The extracellular matrix surrounding the tumor undergoes changes in its organization during the metastasis process. The present study aims to quantify total collagen, collagen I (Col I) and collagen III (Col III), analyze the alignment of collagen fibers and assess the basement membrane integrity in samples from patients with metastatic and non-metastatic prostate cancer. Tissue samples from 60 patients were classified into groups based on prognostic parameters: better prognosis (n=20), worse prognosis without metastasis (n=23) and metastatic (n=17). Picrosirius red with further analysis under polarizing microscope was used to quantify (with validation using immunohistochemistry) and analyze collagen alignment, and Periodic Acid Schiff staining was used to analyze the basement membrane integrity. The Col I/Col III ratio was found to be higher in the metastatic group than in the groups with better prognosis (p=0.012) and worse prognosis without metastasis (p=0.018). Basement membrane integrity constitution in malignant tumor tissue differed from that of adjacent non-tumor tissue (p<0.001). Moreover, the worsening in the tumor tissue integrity was positively correlated with worse prognostic parameters. All in all, absence of Col III and basement membrane integrity might be indicators of poor prognosis in prostate cancer.

A real world observational study characterizing patients with advanced prostate cancer treated with or without androgen receptor-pathway-inhibitor therapies in Alberta, Canada

BackgroundData are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. MethodsThis retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or non-metastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. ResultsThis study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI=32.84-NA). vs 34.19 (95% CI=33.33-38.83; p=0.03), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. ConclusionsOutcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Plant-Based Diets and Disease Progression in Men With Prostate Cancer.

Plant-based diets are associated with many health and environmental benefits, including primary prevention of fatal prostate cancer, but less is known about postdiagnostic plant-based diet patterns in individuals with prostate cancer. To examine whether postdiagnostic plant-based dietary patterns are associated with risk of prostate cancer progression and prostate cancer-specific mortality. This longitudinal observational cohort study included men with biopsy-proven nonmetastatic prostate cancer (stage ≤T3a) from the diet and lifestyle substudy within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) enrolled at 43 urology practices across the US from 1999 to 2018. Participants completed a comprehensive diet and lifestyle questionnaire (including a validated food frequency questionnaire [FFQ]) between 2004 and 2016. Data were analyzed from August 2022 to April 2023. Overall plant-based diet index (PDI) and healthful plant-based diet index (hPDI) scores were calculated from the FFQ. The primary outcome was prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer-specific mortality). The secondary outcome was prostate cancer-specific mortality. Among 2062 participants (median [IQR] age, 65.0 [59.0-70.0] years), 61 (3%) identified as African American, 3 (<1%) identified as American Indian or Alaska Native, 9 (<1%) identified as Asian or Pacific Islander, 15 (1%) identified as Latino, and 1959 (95%) identified as White. Median (IQR) time from prostate cancer diagnosis to FFQ was 31.3 (15.9-62.0) months after diagnosis. During a median (IQR) follow-up of 6.5 (1.3-12.8) years after the FFQ, 190 progression events and 61 prostate cancer-specific mortality events were observed. Men scoring in the highest vs lowest quintile of PDI had a 47% lower risk of progression (HR, 0.53; 95% CI, 0.37-0.74; P for trend = .003). The hPDI was not associated with risk of progression overall. However, among 680 individuals with Gleason grade 7 or higher at diagnosis, the highest hPDI quintile was associated with a 55% lower risk of progression compared with the lowest hPDI quintile (HR 0.45; 95% CI, 0.25-0.81; P for trend = .01); no association was observed in individuals with Gleason grade less than 7. In this cohort study of 2062 men with prostate cancer, higher intake of plant foods after prostate cancer diagnosis was associated with lower risk of cancer progression. These findings suggest nutritional assessment and counseling may be recommended to patients with prostate cancer to help establish healthy dietary practices and support well-being and overall health.

Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit

ObjectiveTo evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. MethodsAll Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20–50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry.Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). ResultsA total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80–0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85–1.07]). ConclusionsIn a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Relationship between circulating FSH levels and body composition and bone health in patients with prostate cancer who undergo androgen deprivation therapy: The BLADE study.

Among its extragonadal effects, follicle-stimulating hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM), and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD), and bone turnover markers at baseline conditions and after 12 months of ADT. Twenty-nine consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the luteinizing hormone-releasing hormone antagonist degarelix. FBM, LBM, and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase, and C-terminal telopeptide of type I collagen were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, t-test or sign test and Pearson or Spearman tests for continuous variables were used when indicated. At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms (r = 0.36) and legs (r = 0.33). Conversely, a stronger correlation was observed between FSH and total FBM (r = 0.52, p = 0.006), fat mass at arms (r = 0.54, p = 0.004), and fat mass at trunk (r = 0.45, p = 0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index/FBM ratio was observed (r = -0.64, p = 0.001). This is an ancillary study of a prospective trial and this is the main limitation. FSH serum levels after ADT could have an impact on body composition, in particular on FBM. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and to guide the clinicians in the tailored evaluation of body composition in PC patients undergoing ADT. This research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript. clinicalTrials.gov NCT03202381, EudraCT Number 2016-004210-10.

A practical guide for the use of apalutamide for non-metastatic castration-resistant prostate cancer in Australia.

Studies of patients with castrate-resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non-metastatic castrate-resistant prostrate cancer have demonstrated increased metastasis-free survival and overall survival following treatment with the next-generation oral anti-androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone-releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be managed proactively to minimize their impact on patients. Monitoring of patients for apalutamide-specific toxicities, including skin rash, hypothyroidism, and QT prolongation should be carried out regularly, particularly in the first few months following initiation. Monitoring should continue alongside monitoring for toxicities of androgen deprivation, including cardiovascular risk, hot flashes, weight gain, bone health, muscle wasting, and diabetic risk. This review is a practical guide to the use of apalutamide describing the management of patients including dosing and administration, toxicities, potential drug interactions, and safety monitoring requirements.

In Curative Stereotactic Body Radiation Therapy for Prostate Cancer, There Is a High Possibility That 45 Gy in Five Fractions Will Not Be Tolerated without a Hydrogel Spacer.

The purpose of this study was to determine the maximum tolerated dose (MTD) for stereotactic body radiation therapy (SBRT) in the treatment of non-metastatic prostate cancer. This study was a phase 1 dose escalation trial conducted in Japan. Patients with histologically proven prostate cancer without lymph nodes or distant metastases were enrolled. The prescribed doses were 42.5, 45, or 47.5 Gy in five fractions. Dose-limiting toxicity (DLT) was defined as grade (G) 3+ gastrointestinal or genitourinary toxicity within 180 days after SBRT completion, and a 6 plus 6 design was used as the method of dose escalation. A total of 16 patients were enrolled, with 6 in the 42.5 Gy group and 10 in the 45 Gy group. No DLT was observed in the 42.5 Gy group. In the 45 Gy group, one patient experienced G3 rectal hemorrhage, and another had G4 rectal perforation, leading to the determination of 42.5 Gy as the MTD. None of the patients experienced biochemical recurrence or death during the follow-up period. We concluded that SBRT for non-metastatic prostate cancer at 42.5 Gy in five fractions could be safely performed, but a total dose of 45 Gy increased severe toxicity.

Role of enzalutamide in primary and recurrent non-metastatic hormone sensitive prostate cancer: a systematic review of prospective clinical trials.

Enzalutamide, a second-generation androgen receptor inhibitor, is indicated for the treatment of metastatic disease, as well as in the treatment of non-metastatic castration resistant prostate cancer (PCa). This systematic review aims to determine outcomes and toxicity in patients with non-metastatic castration sensitive prostate cancer (nmCSPC) treated with enzalutamide in the primary or salvage settings. We performed a systematic review focusing on the role of Enzalutamide in the treatment of nmCSPC, using the PubMed/Medline database. Articles focusing on androgen receptor inhibitors in nmCSPC were included, while articles discussing exclusively metastatic or castration-resistant PCa were excluded. The initial search retrieved 401 articles, of which 15 underwent a thorough assessment for relevance. Ultimately, 12 studies with pertinent outcomes were meticulously examined. Among these, seven studies were dedicated to the investigation of enzalutamide in the primary setting, while the remaining five publications specifically addressed its use in salvage settings. Regardless of the treatment setting, our data revealed two distinct therapeutic strategies. The first advocates for the substitution of enzalutamide for androgen deprivation therapy (ADT), based on the premise of achieving equivalent, if not superior, oncological outcomes while minimizing treatment-related toxicity. The second, adopting a more conventional approach, entails augmenting the effectiveness of ADT by incorporating enzalutamide. Enzalutamide has considerable potential as a therapeutic strategy for nmCSPC, either used alone or in combination with ADT in the primary or in the salvage settings. The use of enzalutamide instead of ADT is an appealing strategy. However, more trials will be required to further understand the efficacy and side-effect profile of enzalutamide monotherapy.

Abstract 2256: Guideline-based physical activity and physical quality of life among individuals with nonmetastatic prostate cancer: A target trial emulation in the Health Professionals Follow-up Study

Abstract Introduction: Randomized trials have shown that physical activity can improve quality of life (QOL) among individuals with cancer. In the absence of a randomized trial of adequate size and follow-up to comprehensively evaluate this relationship for prostate cancer, we aim to emulate a target trial of guideline-based physical activity strategies and 6-year physical QOL. Methods: We will use observational data on individuals in the Health Professionals Follow-up Study diagnosed with nonmetastatic prostate cancer between 2010-2016 and free of conditions that could preclude following current physical activity recommendations at baseline (first post-diagnostic questionnaire). The physical activity strategies of interest are (1) engage in ≥150 minutes of moderate activity, or ≥75 minutes of vigorous activity per week, or an equivalent combination (i.e., ≥7.5 metabolic equivalent of task [MET]-hours/week of vigorous or moderate activity) and (2) no physical activity intervention. The outcomes of interest are 6-year mean physical QOL scores (based on EPIC-CP measures of bowel function, urinary incontinence, urinary irritation/obstruction, sexual function, and vitality/hormonal function). We will adjust for baseline and time-varying risk factors using the parametric g-formula. Conclusion: These findings may help to inform clinical recommendations to improve QOL among individuals with nonmetastatic prostate cancer. Further, the proposed approach will provide a framework for future studies designed to evaluate the effectiveness of any intervention strategies to improve patient-reported outcome measures in cancer survivorship research. Table 1. Specification and emulation of a target trial using observational data from HPFS Protocol component Target trial specification Target trial emulation Eligibility criteria (1) Individuals diagnosed with non-metastatic prostate cancer between 2010 and 2016; (2) No history of other cancers (Except nonmelanoma skin cancer); (3) No history of conditions that could preclude high levels of physical activity: myocardial infarction, stroke, congestive heart failure, amyotrophic lateral sclerosis, or functional impairment (defined as difficulty climbing a flight of stairs or walking eight blocks due to physical impairment) Same as for the target trial, except: We required complete data on physical activity, birth date, and other risk factors on the pre-diagnostic questionnaire and the first post-diagnostic (baseline) questionnaire. Physical activity strategies Each individual is assigned to one of the following strategies at baseline: (1) No intervention (usual physical activity) (2) Engage in ≥1.25 hours/week of vigorous activity or ≥2.5 hours/week of moderate activity or ≥7.5 MET-hours/week of vigorous or moderate activity (an equivalent combination). Strategies are initiated at baseline and continued over follow-up. Individuals are excused from following the physical activity intervention upon the development of myocardial infarction, stroke, congestive heart failure, amyotrophic lateral sclerosis, cancer metastasis, or functional impairment. Individuals must respond to surveys at every follow-up period to assess time-varying variables. Same as for the target trial, except: (1) Follow-up periods correspond to the questionnaire cycles in the cohort study. (2) We assumed that each 2-year physical activity questionnaire accurately reflects the individual's (1) average physical activity over the previous 2-year period and (2) intended physical activity that the individual would have reported at the start of the current period under no intervention. Strategy assignment Individuals are randomly assigned to a strategy at baseline and are aware of their assigned strategy. We assumed randomization conditional on the following baseline covariates: age; employment status; primary treatment; stage; Gleason score, and prostate-specifc antigen level at diagnosis; pre-baseline values of body-mass index and physical activity. Outcomes 6-year mean quality of life scores in the following physical domains: (1) Bowel function, (2) Urinary incontinence, (3) Urinary irritation/obstruction, (4) Sexual function, (5) Vitality/hormonal function. Individuals self-report their physical quality of life on EPIC (The Explanded Prostate Cancer Index Composite) questionnaires at every follow-up period. Same as for the target trial. Follow-up periods correspond to the questionnaire cycles in the cohort study. Follow-up For each eligible individual, follow-up starts at strategy assignment (baseline) and ends upon death, loss to follow-up, or the end of follow up in December 2018, whichever happens first. Same as for the target trial. Loss to follow-up was defined as questionnaire non-response. Causal contrasts Intention-to-treat and per-protocol effect. Observational analogue of per-protocol effect. Statistical analysis Intention-to-treat analysis. Per protocol analysis: Parametric g-formula to compare 6-year physical quality of life under each strategy via mean differences, with adjustment for pre- and post-baseline prognostic factors associated with adherence and loss to follow-up. Same as for the per-protocol analysis of the target trial. Citation Format: Naiyu Chen, Rachel C. Nethery, Lorelei A. Mucci, Barbra A. Dickerman. Guideline-based physical activity and physical quality of life among individuals with nonmetastatic prostate cancer: A target trial emulation in the Health Professionals Follow-up Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2256.

Abstract 2255: Social support with physical and psychosocial quality of life in individuals with prostate cancer in the Health Professionals Follow-up Study (HPFS)

Abstract Introduction: Social support is associated with improved cancer survivorship, but literature on its association with prostate cancer specific physical and psychosocial quality of life (QoL) is lacking. We investigated the associations of social support with physical and psychosocial QoL in individuals with prostate cancer in HPFS. Methods: We included 1,692 men (ages 61-95 years, mean: 71 years) diagnosed with non-metastatic prostate cancer between 2008 and 2016. Social support was measured by the Berkman-Syme Social Network Index (SNI) (a composite measure of marital status, sociability, membership in religious groups or other community organizations: socially isolated, moderately isolated, moderately integrated, socially integrated) and marital status (married, not married). Physical (measured by EPIC-CP: bowel function, urinary incontinence, urinary irritation/obstruction, sexual function, vitality/hormonal function) and psychosocial (memory function and wellbeing) QoL were measured through biennial questionnaires. We fit generalized linear and ordinal mixed effect models for the associations of SNI and marital status with physical and psychosocial QoL, adjusting for age, race, employment status, body mass index, comorbidities, smoking history, and clinical factors. We conducted stratified analyses by baseline age (&amp;lt;70, ≥70), baseline comorbidities (yes, no), primary treatment (active surveillance, radical prostatectomy, radiation), and D’Amico Risk Classification at diagnosis (low, intermediate, high risk). Results: Among those with baseline SNI (N=1,586), 740 were socially integrated, 309 were moderately integrated, 437 were moderately isolated, and 100 were isolated. Among those with baseline marital status (N=1,663), 89% were married. Physical QoL did not differ significantly by SNI. Married individuals (compared to not married) experienced less urinary incontinence (β -0.25, 95% confidence interval [CI]: -0.55, 0.05) and urinary irritation/obstruction (β -0.26, 95% CI: -0.52, 0.00). Those who were socially integrated (compared to isolated) reported better memory function (Odds ratio [OR] 1.47, 95% CI 1.06, 2.03) and wellbeing (OR 1.74, 95% CI 1.31, 2.31). The positive association between social support and QoL was stronger among those with baseline aged &amp;lt;70 years (for vitality/hormonal functioning and memory function), those without comorbidities at baseline (for memory function), those with radiation as primary treatment (for urinary incontinence, vitality/hormonal functioning, memory function, and wellbeing), and those with high risk (for memory function and wellbeing). Conclusion: Prostate cancer survivors with more social support experienced better quality of life, including less urinary incontinence and urinary irritation/obstruction, and better memory function and wellbeing. Citation Format: Naiyu Chen, Colleen B. McGrath, Barbra A. Dickerman, Rachel C. Nethery, Lorelei A. Mucci. Social support with physical and psychosocial quality of life in individuals with prostate cancer in the Health Professionals Follow-up Study (HPFS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2255.

Abstract 2220: Associations between post-diagnostic lifestyle and dietary patterns with prostate cancer survival in the Multiethnic Cohort

Abstract Background: Prostate cancer (PCa) remains a leading cause of cancer-related death among men despite high 5-year survival rates for localized and regional diseases. This study evaluated healthy lifestyle and dietary patterns in relation to PCa survival in a multiethnic population. Methods: We prospectively followed 2,603 men with non-metastatic PCa in the Multiethnic Cohort (MEC) for a median duration of 10.9 years (497 African American, 754 Japanese American, 577 Latino, 129 Native Hawaiian, and 646 White men) starting in 1993. We documented 1,321 deaths, including 196 from PCa. Lifestyle pattern was assessed after diagnosis by a previously reported PCa Behavior Score, which includes BMI, physical activity, and smoking, and a modified version including diet (based on the sum of saturated fat, whole milk, alcohol, and processed meat intake). We also evaluated six indices of inflammatory and insulinemic potential of diet and lifestyle patterns (E-DII, EDIP, EDIH, ELIH, EDIR, and ELIR); and three indices of plant-based diets: an overall plant-based diet index (PDI), a healthful PDI (hPDI), and an unhealthful PDI (uPDI). We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between each index with PCa-specific and all-cause mortality. We adjusted for education, race/ethnicity, smoking, BMI, physical activity (if not part of the score), family history of PCa, and first course of treatment. Results: Across the five racial/ethnic groups, Japanese American men exhibited healthier lifestyle and dietary patterns post-diagnosis, while African American and Native Hawaiian men tended to have less healthy behaviors. The PCa Behavior Score was statistically significantly associated with a reduced risk of all-cause mortality (HR per point=0.71, 95% CI 0.63-0.80), and a similar trend persisted when incorporating diet into the score. The PDI was statistically significantly inversely associated with all-cause mortality (HR per SD=0.90, 95% CI 0.83-0.97), while the uPDI showed a positive association (HR=1.10, 95% CI 1.12-1.18). None of the lifestyle or dietary patterns were associated with PCa mortality (p-values&amp;gt;0.05). No clear trends were observed for inflammatory and insulinemic dietary patterns after PCa diagnosis with all-cause or PCa-specific mortality. Conclusion: Adopting a healthy lifestyle and diet was associated with longer overall survival among men with PCa. We did not find these practices to be associated with a lower risk of PCa-specific mortality among men diagnosed with non-metastatic disease. However, 85% of the observed deaths during follow-up were due to other causes; this underscores the importance of counseling all men, including those with non-metastatic prostate cancer on health behaviors to manage comorbidities. Citation Format: Anqi Wang, Erin L. Van Blarigan, Iona Cheng, June M. Chan, Peggy Wan, Song-Yi Park, Fei Chen, Loic Le Marchand, Lynne Wilkens, Stacey A. Kenfield, Christopher A. Haiman. Associations between post-diagnostic lifestyle and dietary patterns with prostate cancer survival in the Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2220.

Abstract 4570: Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer

Abstract Introduction: Prostate cancer is the most prevalent cancer among men in the United States and is their second leading cause of cancer death. During initial screen, about 17-31% of patients are diagnosed with non-metastatic high-risk localized prostate cancer. These patients have an increased risk of treatment failure and oncological progression. The contemporary treatment paradigm of high risk localized prostate cancer is moving toward a multidisciplinary integrated approach of systemic and local therapy. In addition, incorporation of molecular biomarkers can also improve the risk stratification and treatment of prostate cancer. Among the biomarkers for prostate cancer, prostate specific membrane antigen (PSMA) has been proven to be an excellent target for diagnosis and treatment of prostate cancer. We have generated a PSMA-targeted photodynamic therapy (PDT) agent, PSMA-1-Pc413, and a PSMA-targeted chemotherapeutic agent, PSMA-1-MMAE. The objective of this study is to generate a new molecule that combines PDT and chemotherapy to achieve improved antitumor activity. Methods: Using a bifunctional PSMA ligand, a novel theranostic PSMA-targeting conjugate was synthesized, which integrated both the photosensitizer Pc413 and the microtubular inhibitor monomethyl auristatin E (MMAE) in one simple molecule, PSMA-1-MMAE-Pc413. This molecule was first tested for in vitro uptake and cytotoxicity studies using PSMA-positive PC3pip and PSMA-negative PC3flu cells. The conjugate was then tested for in vivo fluorescence imaging using mice bearing both PC3pip and PC3flu tumors. Finally, the antitumor activity of PSMA-1-MMAE-Pc413 was tested in mice with PC3pip tumors with and without light irradiation. Results: In in vitro uptake studies, the uptake of PSMA-1-MMAE-Pc413 in PC3pip tumor was about 3-fold higher than that in PC3flu cells. In in vitro cytotoxicity studies, when exposed to 5 J/cm2 of 672nm light, PSMA-1-MMAE-Pc413 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells (IC50=2.77nM) when compared to PSMA-1-Pc413 with light irradiation (IC50=372nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50=12.6nM). In in vivo imaging studies, PSMA-1-MMAE-Pc413 demonstrated selective uptake in PC3pip tumors. Further, antitumor activity studies showed that PSMA-1-MMAE-Pc413 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving equimolar amounts of PSMA-1-Pc413 with light irradiation or PSMA-1-MMAE-Pc413 without light irradiation. Conclusion: We have synthesized a new theranostic agent PSMA-1-MMAE-Pc413 that combines imaging, chemotherapy and PDT. The new molecule dramatically improves the treatment effect as compared to each single treatment alone. (The work is supported by NIH 1RO1CA255925-01A.) Citation Format: Xinning Wang, Aditi Shirke, Sriprada Chavali, Lifang Zhang, Ethan Walker, Gopolakrishnan Ramamurthy, James Basilion. Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4570.

Abstract 2745: Sequential tracking of PD-L1 expression on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer

Abstract Background: Radiotherapy (RT) is an essential component of multimodality therapy in the primary or postoperative treatment of prostate cancer with curative intent by preventing local recurrence and distant metastases, indicating its impact on residual occult tumor, such as circulating tumor cells. Immunogenic changes in cancer cells induced by RT can lead to adaptive up-regulation of PD-L1 expression. As immune checkpoint inhibition plays an increasingly important role in prostate cancer, radiogenic PD-L1 upregulation may be of therapeutic importance. The aim of this study was to determine PD-L1 status on CETCs before and during RT. Methods: Peripheral blood samples were collected from 52 primary non-metastatic prostate cancer patients. CETCs were enumerated and analyzed for PDL-L1 expression prior to (baseline), 3 and 6 weeks after the start of RT using fluorescence scanning microscopy. Results: PD-L1 expression was detectable in CETCs and localized in the membrane and/or cytoplasm. We found a correlation between PD-L1 status in CETCs and aggressiveness of cancer disease prior to RT. The frequency of PD-L1 positive CETCs depended on the grading and Gleason score of the primary tumor. Patients with a high Gleason score and G3 tumors had significantly more PD-L1 positive CETCs compared to patients with a low Gleason Score and G1 tumors. Moreover, patients in stage I/II had significantly less PD-L1 positive CETCs compared to patients in stage III/IV (mean 54.25 vs. mean 69.65; p&amp;lt;0.05). A higher number of PD-L1 positive CETCs were detected in patients who had radical prostatectomy before start of RT than in those who had no surgical intervention (mean 66.24 vs. mean 47.46; p&amp;lt;0.01). Interestingly, the fraction of PD-L1 positive CETCs decreased significantly during RT only in patients with G3 tumors and a high Gleason Score. Conclusion: Our results indicated that PD-L1 in CETCs is closely related to the aggressiveness of the primary tumor and may be a co-factor associated with the progression of prostate cancer. PD-1/PD-L1 blockade combined with RT represents a novel and promising treatment strategy that could contribute to improve the treatment efficacy of prostate cancer. Citation Format: Dorothea Schott, Monika Pizon, Ulrich Pachmann, Katharina Pachmann, Matthias Mäurer. Sequential tracking of PD-L1 expression on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2745.

Time trends in the use of curative treatment in men 70 years and older with nonmetastatic prostate cancer.

Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously. Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics. During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above. Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

Online decision aid for patients with prostate cancer evaluated by 11 290 patients and 91 urologists in Germany.

To evaluate the nationwide online decision aid 'Entscheidungshilfe Prostatakrebs' (established in 2016, >11.000 users and 60 new users/week) for patients with non-metastatic prostate cancer (PCa), from the perspective of patients and urologists. To provide personalised information, the tool collects most of the International Consortium for Health Outcomes Measurement standard set, personal preferences, psychological features, and a validated rating of the tool. To evaluate urologists' opinions, we developed a structured two-page questionnaire. All data were collected anonymously. From June 2016 to December 2020, 11 290 patients used the PCa decision aid. Their median (interquartile range [IQR]) age was 67 (61-72) years. The median (IQR) time from initial diagnosis to using the tool was 4 (3-7) weeks. In all, 87.7% of users reported high satisfaction. In a multivariable model, predictors for considering observation were higher knowledge, using the decision aid alone, lower oncological risk, normal erectile function, and respective personal preferences. Of 194 urologists, 91 (47%) had implemented the decision aid in their clinical practice. The urologists' mean (SD) satisfaction score (1 'very good'; 6 'unsatisfactory') with it was 1.45 (0.55), and 92% recommended it. Half of the urologists reported time savings. Patients and urologists report a very high level of acceptance and satisfaction with this online tool. It offers advantages in shared decision-making and time efficiency. The usage of the decision aid might improve the adoption of active surveillance and watchful waiting when indicated.

Multivitamin use after diagnosis and prostate cancer survival among men with nonmetastatic prostate cancer.

Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm. We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI], 0.98 [0.74-1.30]) or all-cause mortality (1.00 [0.88-1.12]), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 [0.72-1.28]) and all-cause mortality (0.99 [0.88-1.12]). We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.

Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).