Refining Risk Stratification of High-risk and Locoregional Prostate Cancer: A Pooled Analysis of Randomized Trials.

BACKGROUND AND OBJECTIVE: Radiotherapy (RT) and long-term androgen deprivation therapy (ltADT; 18-36 mo) is a standard of care in the treatment of high-risk localized/locoregional prostate cancer (HRLPC). We evaluated the outcomes in patients treated with RT + ltADT to identify which patients have poorer prognosis with standard therapy. METHODS: Individual patient data from patients with HRLPC (as defined by any of the following three risk factors [RFs] in the context of cN0 disease-Gleason score ≥8, cT3-4, and prostate-specific antigen [PSA] >20 ng/ml, or cN1 disease) treated with RT and ltADT in randomized controlled trials collated by the Intermediate Clinical Endpoints in Cancer of the Prostate group. The outcome measures of interest were metastasis-free survival (MFS), overall survival (OS), time to metastasis, and prostate cancer-specific mortality. Multivariable Cox and Fine-Gray regression estimated hazard ratios (HRs) for the three RFs and cN1 disease. KEY FINDINGS AND LIMITATIONS: A total of 3604 patients from ten trials were evaluated, with a median PSA value of 24 ng/ml. Gleason score ≥8 (MFS HR = 1.45; OS HR = 1.42), cN1 disease (MFS HR = 1.86; OS HR = 1.77), cT3-4 disease (MFS HR = 1.28; OS HR = 1.22), and PSA >20 ng/ml (MFS HR = 1.30; OS HR = 1.21) were associated with poorer outcomes. Adjusted 5-yr MFS rates were 83% and 78%, and 10-yr MFS rates were 63% and 53% for patients with one and two to three RFs, respectively; corresponding 10-yr adjusted OS rates were 67% and 60%, respectively. In cN1 patients, adjusted 5- and 10-yr MFS rates were 67% and 36%, respectively, and 10-yr OS was 47%. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRLPC patients with two to three RFs (and cN0) or cN1 disease had the poorest outcomes on RT and ltADT. This will help in counseling patients treated in routine practice and in guiding adjuvant trials in HRLPC. PATIENT SUMMARY: Radiotherapy and long-term hormone therapy are standard treatments for high-risk and locoregional prostate cancer. In this report, we defined prognostic groups within high-risk/locoregional prostate cancer and showed that outcomes to standard therapy are poorest in those with two or more "high-risk" factors or evidence of lymph node involvement. Such patients may therefore be the best candidates for intensification of treatment.

Assessing the Clinical Utility of Published Prostate Cancer Polygenic Risk Scores in a Large Biobank Data Set.

BACKGROUND AND OBJECTIVE: Polygenic risk scores (PRSs) have been developed to identify men with the highest risk of prostate cancer. Our aim was to compare the performance of 16 PRSs in identifying men at risk of developing prostate cancer and then to evaluate the performance of the top-performing PRSs in differentiating individuals at risk of aggressive prostate cancer. METHODS: For this case-control study we downloaded 16 published PRSs from the Polygenic Score Catalog on May 28, 2021 and applied them to Michigan Genomics Initiative (MGI) patients. Cases were matched to the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry to obtain granular clinical and pathological data. MGI prospectively enrolls patients undergoing surgery at the University of Michigan, and MUSIC is a multi-institutional registry that prospectively tracks demographic, treatment, and clinical variables. The predictive performance of each PRS was evaluated using the area under the covariate-adjusted receiver operating characteristic curve (aAUC), and the association between PRS and disease aggressiveness according to prostate biopsy data was measured using logistic regression. KEY FINDINGS AND LIMITATIONS: We included 18 050 patients in the analysis, of whom 15 310 were control subjects and 2740 were prostate cancer cases. The median age was 66.1 yr (interquartile range 59.9-71.6) for cases and 56.6 yr (interquartile range 42.6-66.7) for control subjects. The PRS performance in predicting the risk of developing prostate cancer according to aAUC ranged from 0.51 (95% confidence interval 0.51-0.53) to 0.67 (95% confidence interval 0.66-0.68). By contrast, there was no association between PRS and disease aggressiveness. CONCLUSIONS AND CLINICAL IMPLICATIONS: Prostate cancer PRSs have modest real-world performance in identifying patients at higher risk of developing prostate cancer; however, they are limited in distinguishing patients with indolent versus aggressive disease. PATIENT SUMMARY: Risk scores using data for multiple genes (called polygenic risk scores) can identify men at higher risk of developing prostate cancer. However, these scores need to be refined to be able to identify men with the highest risk for clinically significant prostate cancer.

Risk Stratification of Patients with Recurrence After Primary Treatment for Prostate Cancer: A Systematic Review.

BACKGROUND AND OBJECTIVE: Biochemical recurrence (BCR) after primary definitive treatment for prostate cancer (PCa) is a heterogeneous disease state. While BCR is associated with worse oncologic outcomes, risk factors that impact outcomes can vary significantly, necessitating avenues for risk stratification. We sought to identify prognostic risk factors at the time of recurrence after primary radical prostatectomy or radiotherapy, and prior to salvage treatment(s), associated with adverse oncologic outcomes. METHODS: We performed a systematic review of prospective studies in EMBASE, MEDLINE, and ClinicalTrials.gov (from January 1, 2000 to October 16, 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (CRD42023466330). We reviewed the factors associated with oncologic outcomes among patients with BCR after primary definitive treatment. KEY FINDINGS AND LIMITATIONS: A total of 37 studies were included (total n = 10 632), 25 after prostatectomy (total n = 9010) and 12 after radiotherapy (total n = 1622). Following recurrence after prostatectomy, factors associated with adverse outcomes include higher pathologic T stage and grade group, negative surgical margins, shorter prostate-specific antigen doubling time (PSADT), higher prostate-specific antigen (PSA) prior to salvage treatment, shorter time to recurrence, the 22-gene tumor RNA signature, and recurrence location on molecular imaging. After recurrence following radiotherapy, factors associated with adverse outcomes include a shorter time to recurrence, and shorter PSADT or higher PSA velocity. Grade group, T stage, and prior short-term hormone therapy (4-6 mo) were not clearly associated with adverse outcomes, although sample size and follow-up were generally limited compared with postprostatectomy data. CONCLUSIONS AND CLINICAL IMPLICATIONS: This work highlights the recommendations and level of evidence for risk stratifying patients with PCa recurrence, and can be used as a benchmark for personalizing salvage treatment based on prognostics. PATIENT SUMMARY: We summarize the data from previously reported clinical trials on the topic of which factors predict worse cancer outcomes for patients who recur with prostate cancer after their initial treatment.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis.

BACKGROUND AND OBJECTIVE: The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC. METHODS: Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation. KEY FINDINGS AND LIMITATIONS: Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42). CONCLUSIONS AND CLINICAL IMPLICATIONS: There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.

A population-based study of COVID-19 mortality risk in US cancer patients.

BACKGROUND: In this study, we provide the largest analysis to date of a US-based cancer cohort to characterize death from COVID-19. METHODS: A total of 4,020,669 patients across 15 subtypes living with cancer in 2020 and included in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were abstracted. We investigated prognostic factors for death due to COVID-19 using a cox proportional hazards model and calculated hazard ratios (HRs). Standardized mortality ratios (SMRs) were calculated using observed mortality counts from SEER and expected mortality based on U.S. mortality rates. RESULTS: 291,323 patients died, with 14,821 (5.1%) deaths attributed to COVID-19 infection. The COVID-19 disease-specific mortality rate was 11.81/10,000-persons years, and SMR of COVID-19 was 2.30 (95% CI: 2.26-2.34, p < .0001). COVID-19 ranked as the second leading cause of death following ischemic heart disease (5.2%) among 26 non-cancer causes of death. Patients who are older (80+ vs < =49 years old: HR 21.47, 95% CI: 19.34-23.83), male (vs female: HR 1.46, 95% CI: 1.40-1.51), unmarried (vs married: HR 1.47, 95% CI: 1.42-1.53), and Hispanic or Non-Hispanic African American (vs Non-Hispanic White: HR 2.04, 95% CI: 1.94-2.14 and HR 2.03, 95% CI: 1.94-2.14, respectively) were at greatest risk of COVID-19 mortality. CONCLUSIONS AND RELEVANCE: We observed that people living with cancer are at two times greater risk of dying from COVID-19 compared to the general US population. This work may be used by physicians and public health officials in the creation of survivorship programs that mitigate the risk of COVID-19 mortality.

Major Complications and Adverse Events Related to Use of SpaceOAR Hydrogel for Prostate Cancer Radiotherapy.

OBJECTIVE: To determine the prevalence and severity of SpaceOAR-related adverse events using the Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: We analyzed SpaceOAR-related adverse event reports in the Manufacturer and User Facility Device Experience (MAUDE) database from January 2015 to May 2023. For each report, the event type, associated device and patient problems, event description, event timing, and event severity stratified by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE) grading system were recorded. RESULTS: From 2015 to 2022, 206,619 SpaceOAR devices were sold. From January 2015 to May 2023, we identified 981 reports describing 990 SpaceOAR-related adverse events. Malfunctions were the most common event type (N = 626), followed by patient injuries (N = 350) with few reported deaths (N = 5). Device positioning problems were the most frequent device issue (N = 686). Pain was the most reported patient problem (N = 216). Abscesses and fistulas related to the device were each reported in 91 events. A noteworthy portion of relevant adverse events occurred before the initiation of radiation (N = 35, 22.4%), suggesting the device, rather than the radiation, was responsible. In total, 470 (50.2%) and 344 (36.7%) of the adverse events were CTCAE grade 1 and 2, respectively. There were 123 (13.1%) events that were CTCAE grade ≥3. CONCLUSION: We identified multiple reports of SpaceOAR-related adverse events, many of which are more serious than have been reported in clinical trials. While SpaceOAR use is common, suggesting these events are rare, these data highlight the need for continued postmarket surveillance.

Evaluating relugolix for the treatment of prostate cancer in real-world settings of care: the OPTYX study protocol.

OPTYX is a multi-center, prospective, observational study designed to further understand the actual experience of patients with advanced prostate cancer treated with relugolix (ORGOVYX®), an oral androgen deprivation therapy (ADT), by collecting clinical and patient-reported outcomes from routine care settings. The study aims to enroll 1000 consented patients with advanced prostate cancer from community, academic and government operated clinical practices across the USA. At planned timepoints, real-world data analysis on treatment patterns, adherence and safety as well as health outcomes and health-related quality-of-life (HRQOL) after treatment discontinuation will be published in scientific peer-reviewed journals and presented at relevant conferences. This study will provide real-world data for practitioners and researchers in their understanding of the safety and effectiveness of relugolix. Clinical Trial Registration: NCT05467176 (ClinicalTrials.gov).

What is this summary about? This is a protocol summary for a research study named OPTYX. Who can participate in this research? Men 18 or older with advanced prostate cancer initiating treatment with relugolix, an oral androgen deprivation therapy (ADT), at the time of enrollment or within the 1 month before enrollment (remaining on treatment at enrollment) and are willing and able to complete patient assessments during the study. What institutions are performing this research? Community practices, academic institutions and Veterans Health Administration facilities across the USA. What are the research assessments to obtain the results? Data will be collected from the routine medical visits twice yearly including patient demographics, medical history (co-morbidities and cardiac risk factors), prostate cancer history and treatments and test results (routine lab testosterone, PSA levels and imaging). Relugolix response and all serious adverse events (SAEs) and any nonserious adverse events (AE) leading to relugolix treatment discontinuation will be assessed. Patients will be asked to respond to evaluations about their health-related quality of life and adherence to relugolix treatment. How long would the study last? Up to 5 years from enrollment date and/or up to 2 years after relugolix discontinuation. Follow-up will end with consent withdrawal, loss to follow-up, death, or study termination, whichever comes first. What do the results of the study mean? Real-world understanding of the experience and clinical outcomes in patients with advanced prostate cancer in routine clinical care and their clinical trajectory following cessation of relugolix therapy.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer.

Importance: Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. Objective: To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. Design, Setting, and Participants: This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Interventions: Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Main Outcomes and Measures: Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Results: Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). Conclusions and Relevance: The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

External Validation of a Digital Pathology-based Multimodal Artificial Intelligence Architecture in the NRG/RTOG 9902 Phase 3 Trial.

BACKGROUND: Accurate risk stratification is critical to guide management decisions in localized prostate cancer (PCa). Previously, we had developed and validated a multimodal artificial intelligence (MMAI) model generated from digital histopathology and clinical features. Here, we externally validate this model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. OBJECTIVE: To externally validate the MMAI model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial. DESIGN, SETTING, AND PARTICIPANTS: Our validation cohort included 318 localized high-risk PCa patients from NRG/RTOG 9902 with available histopathology (337 [85%] of the 397 patients enrolled into the trial had available slides, of which 19 [5.6%] failed due to poor image quality). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two previously locked prognostic MMAI models were validated for their intended endpoint: distant metastasis (DM) and PCa-specific mortality (PCSM). Individual clinical factors and the number of National Comprehensive Cancer Network (NCCN) high-risk features served as comparators. Subdistribution hazard ratio (sHR) was reported per standard deviation increase of the score with corresponding 95% confidence interval (CI) using Fine-Gray or Cox proportional hazards models. RESULTS AND LIMITATIONS: The DM and PCSM MMAI algorithms were significantly and independently associated with the risk of DM (sHR [95% CI] = 2.33 [1.60-3.38], p < 0.001) and PCSM, respectively (sHR [95% CI] = 3.54 [2.38-5.28], p < 0.001) when compared against other prognostic clinical factors and NCCN high-risk features. The lower 75% of patients by DM MMAI had estimated 5- and 10-yr DM rates of 4% and 7%, and the highest quartile had average 5- and 10-yr DM rates of 19% and 32%, respectively (p < 0.001). Similar results were observed for the PCSM MMAI algorithm. CONCLUSIONS: We externally validated the prognostic ability of MMAI models previously developed among men with localized high-risk disease. MMAI prognostic models further risk stratify beyond the clinical and pathological variables for DM and PCSM in a population of men already at a high risk for disease progression. This study provides evidence for consistent validation of our deep learning MMAI models to improve prognostication and enable more informed decision-making for patient care. PATIENT SUMMARY: This paper presents a novel approach using images from pathology slides along with clinical variables to validate artificial intelligence (computer-generated) prognostic models. When implemented, clinicians can offer a more personalized and tailored prognostic discussion for men with localized prostate cancer.

Effect of Concomitant Medications on Treatment Response and Survival in De Novo Metastatic Prostate Cancer: Secondary Analysis of the LATITUDE Study.

PURPOSE: It is unclear whether exposure to commonly prescribed medications influences survival and treatment response in patients with de novo high-risk metastatic prostate cancer (mPCa) treated with androgen receptor pathway inhibitors (ARPIs). METHODS: We performed a secondary analysis of the LATITUDE trial to determine whether receipt of concomitant medications influenced the effect of abiraterone acetate and prednisone, in addition to androgen deprivation therapy (ADT), on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with de novo mPCa. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors (PPIs), cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors). To account for multiple testing, a two-sided p < 0.0024 was set as the threshold for statistical significance. RESULTS: Overall, 1135 patients were eligible. There was some evidence of a differential treatment effect from abiraterone among patients who received concomitant NSAIDs (hazard ratio [HR] for OS: 0.54; 95% CI: 0.42-0.70) versus those who did not (HR: 0.74; 95% CI: 0.60-0.91), though this did not reach significance (interaction p = 0.05). A similar non-significant finding of heterogeneity of effect from abiraterone was noted among patients who received concomitant aspirin (HR for OS: 0.93 [0.63-1.36]) versus those who did not (HR: 0.61 [0.51-0.73]) (interaction p = 0.04). Receipt of NSAIDs was independently associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p < 0.001) and higher relative incidence of PCSM (sHR: 1.47 [1.21-1.78]; p < 0.001). CONCLUSIONS: This exploratory analysis did not find statistically significant evidence of differences in treatment effects from ADT plus abiraterone in de novo high-risk mPCa based on the receipt of concurrent medications. The receipt of NSAIDs was independently associated with increased PCSM and inferior OS.

Insurance Denial of Care for Randomized Controlled Trial-Eligible Patients: Incidence and Success Rate of Peer-To-Peer Authorization in Allowing Patients to Remain Trial-Eligible.

INTRODUCTION: Insurance denials for clinical trials serve as a pertinent barrier for patients to remain trial-eligible, thus hindering the development of therapies and the overall advancement of health care. We present results from an ongoing oncology randomized clinical trial regarding insurance denials and peer-to-peer authorization (P2PA) success rate in allowing patients to remain trial-eligible. METHODS: The ongoing Spine Patient Optimal Radiosurgery Treatment for Symptomatic Metastatic Neoplasms Phase II trial randomizes spine cancer patients to treatment with spine radiosurgery/stereotactic body radiation therapy (SBRT) versus conventional external beam radiation therapy (EBRT). Trial-eligible patients during the first 3 months of enrollment are examined to determine whether the option of SBRT was denied by their insurance. Advocacy for overcoming SBRT denial in P2PA centered on SBRT being recommended as a preferred treatment modality in the National Comprehensive Cancer Network guidelines, and the recent level I evidence demonstrating the advantages of SBRT over EBRT for symptomatic spine cancer. RESULTS: Of 15 trial-eligible patients, 3 (20%) experienced insurance denials for SBRT. P2PA resulted in the reversal of denials in all 3 patients, allowing each to remain trial-eligible for randomization between SBRT and cEBRT. CONCLUSIONS: Despite a clinical oncologic treatment modality for which recent Level 1 evidence is available, the insurance denial rate was 20%. A vigilant P2PA strategy focusing on highlighting National Comprehensive Cancer Network guidelines and the supporting Level 1 evidence resulted in a very high rate of reversing initial denial.

Artificial intelligence applications in prostate cancer.

Artificial intelligence (AI) applications have enabled remarkable advancements in healthcare delivery. These AI tools are often aimed to improve accuracy and efficiency of histopathology assessment and diagnostic imaging interpretation, risk stratification (i.e., prognostication), and prediction of therapeutic benefit for personalized treatment recommendations. To date, multiple AI algorithms have been explored for prostate cancer to address automation of clinical workflow, integration of data from multiple domains in the decision-making process, and the generation of diagnostic, prognostic, and predictive biomarkers. While many studies remain within the pre-clinical space or lack validation, the last few years have witnessed the emergence of robust AI-based biomarkers validated on thousands of patients, and the prospective deployment of clinically-integrated workflows for automated radiation therapy design. To advance the field forward, multi-institutional and multi-disciplinary collaborations are needed in order to prospectively implement interoperable and accountable AI technology routinely in clinic.

Effect of Pelvic External Beam Radiation Therapy on Bone Mineral Density: A Secondary Analysis of a Phase 3 Randomized Controlled Trial.

PURPOSE: Pelvic radiation therapy may lead to decreased bone mineral density (BMD) and increased risk of fracture that could be of particular concern in patients with prostate cancer who also receive androgen deprivation therapy (ADT). We performed an exploratory analysis of a randomized, double-masked, placebo-controlled trial to determine whether exposure to prior pelvic external beam radiation therapy (XRT) affects BMD and risk of fracture in patients with prostate cancer treated with ADT. METHODS AND MATERIALS: Patients with nonmetastatic prostate cancer aged ≥70 years or <70 years with low BMD (T-score < -1) or osteoporotic fracture who had been receiving ADT for ≥12 months were randomly assigned to receive densoumab or placebo every 6 months for 3 years. BMD was measured at baseline and at months 1, 3, 6, 12, 24, and 36. We applied multivariable linear mixed-effects models with an interaction term between the treatment arm and exposure to prior pelvic XRT to evaluate differential XRT effect on percent BMD change between the 2 treatment arms. RESULTS: Among 1407 eligible patients, 31% (n = 447) received prior pelvic XRT. There was no significant difference in any clinical fractures among patients with (5.8%, 26 of 447) or without (5.2%, 50 of 960) prior pelvic XRT (P = .42). Prior pelvic XRT was associated with a significant (0.54%) improvement in BMD (95% CI, 0.05-1.02) in the placebo group and a nonsignificant (0.04%) decline in BMD (95% CI, -0.47 to -0.35) in the denosumab group (interaction P = .007). There was no significant difference in pelvic XRT effect on percent BMD change in the lumbar spine (P = .65) or total hip (P = .39) between the 2 treatment groups. CONCLUSIONS: We did not find sufficient evidence to suggest any detrimental effect of pelvic XRT on the treatment effect from denosumab on percent BMD change, with only an approximately 5% incidence of clinical fractures.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials.

PURPOSE: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Impact of sequencing of androgen receptor-signaling inhibition and radiotherapy in prostate cancer: importance of homologous recombination disruption.

PURPOSE: The synergy of combining androgen receptor-signaling inhibition (ARSI) to radiotherapy (RT) in prostate cancer has been largely attributed to non-homologous end joining (NHEJ) inhibition. However, this mechanism is unlikely to explain recently observed trial results that demonstrated the sequencing of ARSI and RT significantly impacts clinical outcomes, with adjuvant ARSI following RT yielding superior outcomes to neoadjuvant/concurrent therapy. We hypothesized this is driven by differential effects on AR-signaling and alternative DNA repair pathway engagement based on ARSI/RT sequencing. METHODS: We explored the effects of ARSI sequencing with RT (neoadjuvant vs concurrent vs adjuvant) in multiple prostate cancer cell lines using androgen-deprived media and validation with the anti-androgen enzalutamide. The effects of ARSI sequencing were measured with clonogenic assays, AR-target gene transcription and translation quantification, cell cycle analysis, DNA damage and repair assays, and xenograft animal validation studies. RESULTS: Adjuvant ARSI after RT was significantly more effective at killing colony forming cells and decreasing the transcription and translation of downstream AR-target genes across all prostate cancer models evaluated. These results were reproduced in xenograft studies. The differential effects of ARSI sequencing were not fully explained by NHEJ inhibition alone, but by the additional disruption of homologous recombination specifically with adjuvant sequencing of ARSI. CONCLUSION: We demonstrate that altered sequencing of ARSI and RT mediates differential anti-AR-signaling and anti-cancer effects, with the greatest benefit from adjuvant ARSI following RT. These results, combined with our prior clinical findings, support the superiority of an adjuvant-based sequencing approach when using ARSI with RT.