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Active surveillance (AS) is recommended as a management option for men with favorable-risk (low risk and favorable intermediate risk) prostate cancer; however, national rates remain low. The Michigan Urological Surgery Improvement Collaborative (MUSIC) established a quality improvement (QI) initiative in June 2014 to increase AS utilization. In this report, we analyze the rates of AS utilization over time in the state of Michigan (MUSIC) for men with favorable-risk prostate cancer and compare these to rates for other men diagnosed with favorable-risk prostate cancer in the USA outside the state of Michigan. While the variables that influence AS utilization were the same in both cohorts, we found that the AS utilization rates and the rate of increase were significantly higher in MUSIC. We conclude that the QI initiative started in MUSIC should serve as a roadmap to increasing AS use nationwide. PATIENT SUMMARY: Active surveillance (AS), which involves close monitoring with blood tests and scans, is recommended for management of favorable-risk prostate cancer to avoid or delay unnecessary treatment. Our results show that a quality improvement program in Michigan increased AS use for prostate cancer patients in the state. This program should be used to increase AS uptake throughout the USA.

Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear.This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression.Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38).In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

PURPOSE We sought to investigate whether enzalutamide (ENZA), without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen (PSA) progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). PATIENTS AND METHODS Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double‐blind, phase II, placebo-controlled, multicenter study of SRT plus ENZA or placebo (ClinicalTrials.gov identifier: NCT02203695 ). Random assignment (1:1) was stratified by center, surgical margin status (R0 v R1), PSA before salvage treatment (PSA ≥ 0.5 v < 0.5 ng/mL), and pathologic Gleason sum (7 v 8‐10). Patients were assigned to receive either ENZA 160 mg once daily or matching placebo for 6 months. After 2 months of study drug therapy, external-beam radiation (66.6‐70.2 Gy) was administered to the prostate bed (no pelvic nodes). The primary end point was FFPP in the intention-to-treat population. Secondary end points were time to local recurrence within the radiation field, metastasis‐free survival, and safety as determined by frequency and severity of adverse events. RESULTS Eighty-six (86) patients were randomly assigned, with a median follow-up of 34 (range, 0-52) months. Trial arms were well balanced. The median pre-SRT PSA was 0.3 (range, 0.06-4.6) ng/mL, 56 of 86 patients (65%) had extraprostatic disease (pT3), 39 of 86 (45%) had a Gleason sum of 8-10, and 43 of 86 (50%) had positive surgical margins (R1). FFPP was significantly improved with ENZA versus placebo (hazard ratio [HR], 0.42; 95% CI, 0.19 to 0.92; P = .031), and 2-year FFPP was 84% versus 66%, respectively. Subgroup analyses demonstrated differential benefit of ENZA in men with pT3 (HR, 0.22; 95% CI, 0.07 to 0.69) versus pT2 disease (HR, 1.54; 95% CI, 0.43 to 5.47; Pinteraction = .019) and R1 (HR, 0.14; 95% CI, 0.03 to 0.64) versus R0 disease (HR, 1.00; 95% CI, 0.36 to 2.76; Pinteraction = .023). There were insufficient secondary end point events for analysis. The most common adverse events were grade 1-2 fatigue (65% ENZA v 53% placebo) and urinary frequency (40% ENZA v 49% placebo). CONCLUSION SRT plus ENZA monotherapy for 6 months in men with PSA-recurrent high-risk prostate cancer after RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time.

PURPOSE Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer. MATERIALS AND METHODS NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R2 between treatment hazard ratios for ICE and OS). RESULTS BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated ( R2 = 0.67), but this was not true for BF1 ( R2 = 0.09), BF2 ( R2 = 0.12), or DM ( R2 = 0.18) and OS. CONCLUSION MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

Context: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. Objective: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. Evidence acquisition: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. Evidence synthesis: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. Conclusions: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a “second wave” of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. Patient summary: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

The diagnosis of metastatic prostatic cancer (MPC) by fine needle aspiration (FNA) can usually be rendered by typical cytomorphologic and immunohistochemical (IHC) features. However, MPC diagnosis may be complicated by transformation to atypical phenotypes such as small cell carcinoma, typically under pressure from androgen deprivation therapy (ADT). Predictive and prognostic biomarkers can also be assessed by IHC. This study illustrates how careful assessment of cytologic and biomarker features may provide therapeutic and prognostic information in MPC.We reviewed our anatomic pathology archives for MPC diagnosed by FNA from January 2014 to June 2021. Clinical histories, cytology slides, and cell blocks were reviewed. Extensive IHC biomarker workup was performed, including markers of prostate lineage, cell-cycle dysfunction, Ki-67, neuroendocrine markers, PDL1, and androgen receptor splice variant 7. Cases were reclassified into three categories: conventional type, intermediary type, and high-grade neuroendocrine carcinoma (HGNC).Eighteen patients were identified. Twelve had conventional MPC, including six of six ADT-naive patients. Six of twelve (50%) with prior ADT were reclassified as intermediary or HGNC. Four intermediary cases included two with squamous differentiation and two with pro-proliferative features. Two HGNC cases had typical small cell carcinoma cytomorphology. Expression of PDL1 was identified in two cases and ARv7 in three cases. Five of five intermediary and HGNC patients died of disease versus six of eleven with with conventional type.Aggressive cytomorphologic variants were commonly identified in patients with prior ADT. Identification of nonconventional cytomorphology and increased proliferation can provide important prognostic information. Recognition of these changes is important for an accurate diagnosis, and the identification of high-grade variants can affect therapeutic decision-making. Clinically actionable biomarkers such as PDL1 and ARv7 can be assessed by IHC.

Pain is an important dimension of quality-of-life in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, it is unclear if dynamic change in pain over time can predict for overall survival (OS) or progression-free survival (PFS) in these patients.This is an exploratory analysis of LATITUDE, a phase III randomized study, in which men with de novo mCSPC were randomized to receive either ADT plus abiraterone versus ADT alone. Information was collected on patient-reported worst pain score (WPS) and pain-interference score (PIS) from the Brief Pain Inventory-Short Form. A Bayesian joint modelling approach was used determine the association of dynamic change in WPS and PIS with OS and PFS.Overall, 1125 patients with at least 3 measurements on pain scores were eligible. On Cox multivariable regression, increase in baseline WPS was associated with inferior OS (hazard ratio [HR] 1.049 [95% confidence intervals [CI] 1.015-1.085]; time dependent area under curve [tAUC] 0.64) and PFS (HR 1.045 [1.011-1.080]; tAUC: 0.64). Increase in baseline PIS was associated with inferior OS (HR 1.062 [1.020-1.105]; tAUC: 0.63) but not with PFS (HR 1.038 [0.996-1.08]). On independent joint models, an increase in the current value of WPS by 1-unit was associated with inferior OS (HR 1.316 [1.258-1.376]; tAUC 0.74) and PFS (HR 1.319 [1.260-1.382]; tAUC 0.70). Similar association was seen for increase in the current value of PIS with OS (HR 1.319 [1.261-1.381]; tAUC 0.73) and PFS (HR 1.282 [1.224-1.344]; tAUC 0.73).The above findings highlight the potential dynamic interplay between patient-reported pain with OS and PFS in mCSPC. Compared to baseline pain, such dynamic assessment of pain was found to have superior predictive ability and thus has the potential to tailor subsequent treatment based on response to initial therapy beyond its role as a very important dimension of quality-of-life.

Castration-sensitive metastatic prostate cancer is heterogeneous. Our objective is to identify metastatic prostate cancer phenotypes and their prognostic impact on survival.The National Cancer Database was queried. The Surveillance, Epidemiology, and End Results database was used for validation. Patterns were split into: nonregional lymph node, bone only, and visceral (any brain/liver/lung). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated for the univariate and multivariate Cox proportional hazards regression models, odds ratios were calculated, Kaplan-Meier curves were generated, and a nomogram of the multivariate regression model was created.The training set included 13,818 men; bone only was most common (n = 11,632, 84.2%), then nonregional lymph node (n = 1388, 10.0%), and any visceral (brain/liver/lung; n = 798, 5.8%). Risk of death was increased by metastases to a visceral organ versus nonregional lymph node (HR = 2.26; 95% CI [2.00, 2.56]), bone only metastases versus nonregional lymph node (HR = 1.57; 95% CI [1.43, 1.72]), T-stage 4 versus 1 (HR = 1.27; 95% CI [1.17, 1.36]), Grade Group 5 versus 1 (HR = 1.93; 95% CI [1.61, 2.31]), PSA20 ng/mL versus10 ng/mL (HR = 1.32; 95% CI [1.23, 1.42]), and age ≥ 80 versus50 (HR = 1.96; 95% CI [1.69, 2.29]). On internal validation, the model had C-indices 20.5%, 22.7%, and 14.6% higher than the current staging system for overall survival, 1-year, and 5-year survival, respectively.We developed and validated prognostic metastatic prostate cancer phenotypes that can assist risk stratification to potentially personalize therapy. Our nomogram (https://tinyurl.com/prostate-met) may be used to predict survival.

A number of genomic classifiers are available to aid in shared decision-making for men with localized prostate cancer; however, there is no high-level evidence assessing their clinical utility. The two randomized controlled trials in this report prospectively evaluate the use of gene expression classifier testing at the time of cancer diagnosis and after surgical treatment.

Background: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. Objective: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. Design, setting, and participants: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11 862 patients. Patients received one of the six permutations of low-dose RT (64 to

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Though most are indolent, clinical outcomes vary greatly based on histologic differentiation and grade. Peptide receptor radionuclide therapy has emerged as a promising treatment for patients with locally advanced and/or metastatic disease refractory to standard of care treatment. The phase III NETTER-1 trial found that [

BACKGROUND Salvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era. OBJECTIVE To characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Variables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation. RESULTS AND LIMITATIONS Factors associated with BF after SRT include PSA DT

Background Nodal staging systems vary substantially across solid tumors, implying heterogeneity in the behavior of nodal variables in various contexts. We hypothesized, in contradiction to this, that metastatic lymph node (LN) number is a universal and dominant predictor of outcome across solid tumors. Methods We performed a retrospective cohort analysis of 1 304 498 patients in the National Cancer Database undergoing surgery between 2004 and 2015 across 16 solid cancer sites. Multivariable Cox regression analyses were constructed using restricted cubic splines to model the association between nodal number and mortality. Recursive partitioning analysis (RPA) was used to derive nodal classification systems for each solid cancer based on metastatic LN count. The reproducibility of these findings was assessed in 1 969 727 patients from the Surveillance, Epidemiology, and End Results registry. Two-sided tests were used for all statistical analyses. Results Consistently across disease sites, mortality risk increased continuously with increasing number of metastatic LNs (P Conclusions Quantitative metastatic LN burden is a fundamental driver of mortality across solid cancers and should serve as a foundation for pathologic nodal staging across solid tumors.

Introduction: Little data have been reported about the patient experience during curative radiotherapy for lung cancer in routine clinical practice, or how this relates to treatment toxicity reported by clinicians. The purpose of this study was to compare clinician-reported adverse events (AEs) with patient-reported outcomes (PROs) including both specific symptoms/side effects as well as overall quality of life (QOL) during and after definitive radiotherapy (RT) for locally advanced lung cancer (LALC) in a large statewide cohort. Methods and Materials: Patient-reported outcomes (PROs) were prospectively collected from patients treated with definitive radiotherapy for LALC at 24 institutions within the XXXX Radiation Oncology Quality Consortium between 2012-2018 using the Functional Assessment of Cancer Therapy Trial Outcome Index (FACT-TOI). Physicians prospectively recorded adverse events (AEs) using CTCAE version 4.0. Patient-reported quality of life (QOL) changes from baseline were assessed during and after radiotherapy using the FACT-TOI. Spearman correlation coefficients were calculated for AEs and similar PROs, and multivariable analysis was used to assess associations with QOL. Results: 1361 patients were included and 53% of respondents reported clinically meaningful declines in QOL at the end of RT. Correlation between clinician-reported esophagitis and patient-reported trouble swallowing was moderate (R=0.67) while correlations between clinician-reported pneumonitis and patient-reported shortness of breath (R=0.13) and cough (R=0.09) were weak. Clinician-reported AEs were significantly associated with clinically meaningful declines inpatient-reported QOL, with R=-0.46 for a summary AE-score. QOL was more strongly associated with fatigue (R=-0.41) than lung-specific AEs. Conclusions: AEs are associated with clinically meaningful declines in QOL during and after RT for LALC, but associations between AEs and QOL are only modest. This highlights the importance of PRO data, and future research should assess whether earlier detection of PRO changes could allow for interventions that reduce the frequency of treatment-related clinically meaningful declines in QOL.

Background Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life and there remain no validated predictive models to guide its use. Methods Digital pathology image and clinical data from pre-treatment prostate tissue from 5,727 patients enrolled on five phase III randomized trials treated with radiotherapy +/- ADT were used to develop and validate an artificial intelligence (AI)-derived predictive model to assess ADT benefit with the primary endpoint of distant metastasis. After the model was locked, validation was performed on NRG/RTOG 9408 (n = 1,594) that randomized men to radiotherapy +/- 4 months of ADT. Fine-Gray regression and restricted mean survival times were used to assess the interaction between treatment and predictive model and within predictive model positive and negative subgroup treatment effects. Results In the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis (subdistribution hazard ratio [sHR] = 0.64, 95%CI [0.45–0.90], p = 0.01). The predictive model-treatment interaction was significant (p-interaction = 0.01). In predictive model positive patients (n = 543, 34%), ADT significantly reduced the risk of distant metastasis compared to radiotherapy alone (sHR = 0.34, 95%CI [0.19–0.63], p

Supplementary Figure S1 - PDF file 1194K, Gamma-H2AX foci and Comet assay normalized of LNCaP plus or minus androgen normalized to time 0

Supplementary Table S2 - PDF file 250K, Defining AR-regulated DNA repair genes in LNCaP

Supplementary Figure S1: Additional expression data and comparisons of AR expression by subtype, age, sex, and common molecular alterations. Supplementary Figure S2. Tumor growth plots and mice weights for in vivo studies. Supplementary Figure S3: Heat map of down-regulated genes from the GBM 26 RNA-seq experiment. Supplementary Figure S4: Effects of seviteronel on dsDNA break repair in AR-positive and negative models post-radiation. Supplementary Figure S5: Effects of enzalutamide on dsDNA break repair in AR-positive and negative models post-radiation. Supplementary Figure S6. Effects of enzalutamide and seviteronel on alkaline tail moment in AR-positive models post-radiation. Method: alkaline comet assay.

Supplemental Tables 1-7

Supplementary Table S5 from BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Purpose:Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response.Experimental Design:Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.Results:We found that all epithelial tumors demonstrated similar gene expression–based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity in vitro to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel.Conclusions:This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.

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